Wikipedia:Featured article candidates/Amphetamine/archive5: Difference between revisions

Addiction and dependence glossary^[8]^[20]^[21]
Addiction and dependence glossary
	addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences; addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems; dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake); drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose; drug withdrawal – symptoms that occur upon cessation of repeated drug use; physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens); psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome); reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them; rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach; sensitization – an amplified response to a stimulus resulting from repeated exposure to it; substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress; tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose;
	v; t; e;

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Amphetamine

Nominator(s): Seppi333 (Insert 2¢ | Maintained) & Boghog (talk) 00:25, 6 December 2014 (UTC)[reply]

I'd be surprised if anyone doesn't know what this article is about, based from the name alone, so I'll forego a description. Seppi333 (Insert 2¢ | Maintained) 00:25, 6 December 2014 (UTC)[reply]

Comments from AmericanLemming

@AmericanLemming: I'm renominating this now, though I assume you'll be busy until later in the month, so no worries. I've made this section for you in advance. Seppi333 (Insert 2¢ | Maintained) 00:25, 6 December 2014 (UTC)[reply]

I quickly went through the Interactions subsection to give you some new comments to work with, but I need a few days to reread the first half of the article, both to refamiliarize myself with the material and tweak the prose further if need be. I also need to look at the "Overdose" section again and take a look at the changes you've made in response to my comments. Reviewing this is priority number one for my Christmas break, so I should be able to finish it before classes start up again. AmericanLemming (talk) 08:11, 15 December 2014 (UTC)[reply]

American Lemming's comments from peer review/4th FAC

Lead Just finished reading through this part. It looks well-written, well-organized, and well-sourced. The first paragraph is a bit on the long side, as is the lead as a whole, but I'm not really sure you can cut anything out without losing something important. My four comments/questions are as follows:

“At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.” This wording implies to me that there aren’t any side effects at therapeutic doses, which probably isn’t the case.

After rereading it, I think I agree about the sentence on physical effects. The statement on psychological effects seems more or less neutral, since increased arousal can lead to insomnia or increased wakefulness. Similarly, changes in libido can be desirable or undesirable depending on the individual. I'll tweak the the physical effects clause over the next day or so to address this. Seppi333 (Insert 2¢ | Maintained)

Now that I look at it again, just leave the sentence alone. Sometimes less is more, and I think making it any wordier would decrease the intelligibility to the general reader. Besides, it is correct as it stands.

Good point; I'm okay with that. Seppi333 (Insert 2¢ | Maintained) 08:59, 10 August 2014 (UTC)[reply]

“Very high doses can result in a psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use.” First, “a psychosis” sounds awkward to me. If it’s consistent with medical terminology, then by all means keep it, but otherwise I would drop the “a”. Second, so it’s pretty difficult to die of an overdose of amphetamine? That’s the impression I’m getting here.

There's different types of psychoses, though I agree it sounds weird so I'd be ok with removing it. As for overdoses, it's pretty rare to die from an overdose when medical treatment is sought. The doses that recreational users take are roughly 10-100 times higher than the maximum dose when its used medically. Seppi333 (Insert 2¢ | Maintained)

I've gone and removed the "a".

“Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked.” So if you can inhale amphetamine (see infobox), why can’t you smoke it? Or am I confusing smoking cigarettes and smoking other drugs?

The salts can't be smoked, but they can be snorted (insufflated) as a powder. That's really only a recreational route though. The medical route involves inhaling small amounts of the freebase via an inhaler (e.g., File:Benzedrine_inhaler_for_wiki_article.jpg). Unlike the salts, the freebase is a liquid at room temperature and CAN be smoked. Illicit amphetamine is almost never trafficked/sold as the freebase, which I'm assuming is due to its volatility. Seppi333 (Insert 2¢ | Maintained)

“Amphetamine is also chemically related to the naturally occurring trace amine neurotransmitters, specifically phenethylamine and N-methylphenethylamine” Two questions here: 1. Does phenethylamine = trace amine neurotransmitters? 2. Is it that amphetamine is chemically related to trace amine neurotransmitters but is most closely related to phenethylamine and N-methylphenethylamine? That’s what it sounds like to me. AmericanLemming (talk) 06:26, 4 August 2014 (UTC)[reply]

Both phenethylamine and N-methylphenethylamine are trace amines; N-methylphenethylamine is the most closely chemically-related trace amine to amphetamine since it's an amphetamine isomer. If you can think of a better way to word it, feel free to change it! Seppi333 (Insert 2¢ | Maintained) 19:06, 5 August 2014 (UTC)[reply]

I've taken a shot at that; please do double-check to make sure it's accurate.

Looks good. Seppi333 (Insert 2¢ | Maintained) 08:59, 10 August 2014 (UTC)[reply]

I've made two edits to the lead, and I think that will do. The lead is meant to be the most accessible part of the article, and it really isn't the place to be explaining nuances and technicalities.

Medical

Question about this section in general: when we’re talking about medical uses of amphetamine, we’re almost always talking about Adderall, right?

Adderall (no generic name - i.e., a USAN/INN - even though it's almost always sold as a generic), dextroamphetamine (tons of brand names/generic forms), and lisdexamfetamine (brand:Vyvanse, still patented) are the currently available amphetamine-based pharmaceuticals; it covers this group of drugs. Seppi333 (Insert 2¢ | Maintained)

“Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function of the right caudate nucleus.” So it decreases abnormalities in brain structure and function in general and improves function of the right caudate nucleus in particular? If that’s so, I would suggest changing the second half to “ADHD; in particular, it improves the function of the right caudate nucleus.”

The caudate nucleus was one example that was highlighted in one of the reviews; there's improvement in function in more than one brain structure along the dopamine pathways that it acts upon. Seppi333 (Insert 2¢ | Maintained)

“but high doses of dextroamphetamine in such people should be avoided.” Because of the side effects? Long-term damage to some part of the body?

It exacerbates motor tics in people with Tourette's, which is a harmless but undesirable/annoying side-effect. Seppi333 (Insert 2¢ | Maintained)

“task saliency” this may warrant a quick note to define saliency; the Wikipedia article on the subject isn’t terribly helpful.

Good point; I'll go through later today and add this based upon the definition used in the textbook that cited that passage. Seppi333 (Insert 2¢ | Maintained)

Added - Diff Seppi333 (Insert 2¢ | Maintained)

“but this is prohibited at events regulated by the World Anti-Doping Agency.” From what I can gather, the World Anti-Doping Agency regulates just about every international and professional sporting event. I think this warrants another note/quick explanation in text, perhaps.

~~That's fine with me if you'd like to add this.~~ Found a suitable ref, how's this look? Diff Seppi333 (Insert 2¢ | Maintained)

Better and worse. On one hand, I think adding the "regulated by collegiate, national, and international anti-doping agencies" does a much better job of explaining that amphetamine is widely prohibited in sporting events; on the other hand, expanding the tidbit about the World Anti-Doping Agency (WADA) turned the sentence into a run-on. I've trimmed the part on WADA to fix the sentence, and I think you could cut it out entirely if you wanted to. Your fix (adding "regulated by collegiate, national, and international anti-doping agencies") was a lot better than the one I suggested, and we don't need both. AmericanLemming (talk) 06:30, 11 August 2014 (UTC)[reply]

Removed the WADA mention - Shudde insisted I add it during the FAC review that he didn't finish. I didn't really want it to include it anyway - seemed like trivia. Seppi333 (Insert 2¢ | Maintained) 16:00, 11 August 2014 (UTC)[reply]

“In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, etc.” It may be worthwhile mentioning that there are some minor side-effects, even in healthy people at oral therapeutic doses. Otherwise, why aren’t we all on amphetamine? :)

There's actually a lot of discussion among the academic community about the use of performance enhancing agents in the general population (e.g., this paper elicited quite a lot of responses). It was only recently determined that low doses of ADHD psychostimulants improve cognitive control in everyone via their effect on dopamine D1 receptors in the prefrontal cortex.

Back to the issue: I tried to keep this section disjoint from the side effects section to avoid redundancy and maintain neutrality when covering it. I think it'd be alright to mention that there are additional physical side effects in that paragraph; however, I'm not sure it's a good idea to re-list the physical side effects alongside these, since it's both redundant with the side effects section and isn't relevant to the performance enhancing effect. This list of physical enhancement effects isn't included in the side effects section for the same reason. That said, I'll go ahead and add a clause mentioning the presence of additional side effects if that's what you had in mind. Seppi333 (Insert 2¢ | Maintained)

I would suggest adding something along the lines of "At these doses, the side effects are minimal." That's enough to help the reader keep the existence of side effects in mind without the unnecessary repetition of listing them all in two places. AmericanLemming (talk) 06:47, 11 August 2014 (UTC)[reply]

Added - Seppi333 (Insert 2¢ | Maintained)

Also, with that same sentence, it does seem that this is one place where WP:OVERKILL might apply. I understand that the article’s on a fairly technical subject, but do you really need four inline citations of the exact same two sources for four words in a row? I suggest you put all three sources at the end of the sentence, like you do elsewhere. AmericanLemming (talk) 09:03, 6 August 2014 (UTC)[reply]

I'd be okay with grouping them at the end of the sentence, though the main reason I did this is because the performance enhancing use of these drugs has generated much controversy, and until recently there hasn't been much high quality research/review supporting these effects in humans. I imagine that some people reading this article might come into it with a bias, which is why I cited them by effect. I'll go ahead and group the citations if you think it improves readability - let me know. Seppi333 (Insert 2¢ | Maintained)

I recommend doing that. Besides, you quote directly from the source in the inline citation, so if someone doubts whether the sentence is true they can just mouse over the citation and read it for themselves. And as it currently stands it's just hard to read. AmericanLemming (talk) 06:53, 11 August 2014 (UTC)[reply]

Erledigt - Seppi333 (Insert 2¢ | Maintained)

Sorry for the late follow-up; I've been pretty busy this past week. ~~I'll address these points momentarily!~~ Regards, Seppi333 (Insert 2¢ | Maintained) 16:16, 9 August 2014 (UTC)[reply]

Contraindications

I don’t think there’s anything in the manual of style against a one-paragraph section, but it does look somewhat odd. What do you think about combining the “Contraindications” section with the “Interactions” section? The “Interactions” section does a nice job of explaining why people with certain conditions or on certain drugs (MAOIs, for instance) shouldn’t take amphetamine.

I actually agree that it would make sense to combine these, since serious drug interactions give rise to contraindications; however, the current layout of level-2 headers is indicated in MOS:MED, so I can't really deviate from the present state. Barring unusual or unique circumstances, there isn't much wiggle room in the section ordering. Seppi333 (Insert 2¢ | Maintained) 14:19, 11 August 2014 (UTC)[reply]

After further thought, I think it may be better to keep these sections separate; most of the drug databases we link to in the drugbox don't provide this information together. The FDA uses distinct sections for the information as well. Seppi333 (Insert 2¢ | Maintained) 18:17, 12 August 2014 (UTC)[reply]

I agree with you; you really can't go against the MOS, especially when you want to get the article to FA status. As the next best alternative, I've added explanatory hatnotes to each section that tell the reader what the section is about and that direct them to the other section if that's not what they were looking for. AmericanLemming (talk) 06:39, 13 August 2014 (UTC)[reply]

I think it might be best to use {{see also}} templates here, since some of the contraindications aren't substance-related. It seemed a bit difficult for me to summarize the relationship in a hatnote without it being really long. The first sentence of each section (I think) more or less implies how they're related though. Seppi333 (Insert 2¢ | Maintained) 09:31, 13 August 2014 (UTC)[reply]

“Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.” This contradicts the statement in the first paragraph of the “Medical uses” section that “humans experience normal development and nerve growth”. Do humans experience normal development when using amphetamine or not? AmericanLemming (talk) 07:20, 11 August 2014 (UTC)[reply]

It's technically a transient effect due to a rebound growth spurt associated with a temporary cessation of treatment. IIRC, all dopaminergic stimulants suppress growth hormone release in adolescents (see page 4, paragraph 2 in this ref), so it's not unique to amphetamine. See section 5.3 of this ref for more detail. Seppi333 (Insert 2¢ | Maintained) 14:19, 11 August 2014 (UTC)[reply]

Follow-up: After rereading the sentence I wrote in medical uses, I noticed there isn't actually a contradiction here. The full statement in medical uses is:

Long-term amphetamine exposure in some species is known to produce abnormal dopamine system development or nerve damage,[35][36] but humans experience normal development and nerve growth.

The "normal development" is in reference to the development of neural systems (not just dopaminergic systems) and the brain, as opposed to the body and physical development. All the citations included in that sentence are confined to this context as well.
I've clarified the point in the contraindications section. diff These are the references cited: see P125-127, see page 2-4, see P546. Seppi333 (Insert 2¢ | Maintained) 18:17, 12 August 2014 (UTC)[reply]

I've changed "normal development" to "normal brain development" and similarly tweaked the note added in the "Contraindications" section. AmericanLemming (talk) 06:54, 13 August 2014 (UTC)[reply]

Side effects

“Amphetamine may reduce gastrointestinal motility (i.e., intestinal peristalsis) if intestinal activity is high, or increase motility if the smooth muscle of the tract is relaxed.” I have no idea what this sentence means. You do a really nice job explaining what “contraction of the urinary bladder sphincter” means in plain English earlier in this paragraph; I would use that as a model here. AmericanLemming (talk) 07:20, 11 August 2014 (UTC)[reply]

Added clarification earlier - I forgot to reply here after I did this. Please let me know if the current section is understandable! The current version:

If intestinal activity is high, amphetamine may reduce gastrointestinal motility, i.e., the rate at which content moves through the digestive system; however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.

Seppi333 (Insert 2¢ | Maintained) 18:19, 12 August 2014 (UTC)[reply]

Much better. I've put the definition in parentheses. Personally, I'm curious to know what causes the smooth muscle of the gastrointestinal tract to relax, but I'm not sure if the average reader shares my interest. :) AmericanLemming (talk) 07:02, 13 August 2014 (UTC)[reply]

I'm not entirely sure to be honest. The enteric nervous system isn't well understood at the moment. Seppi333 (Insert 2¢ | Maintained) 20:47, 15 August 2014 (UTC)[reply]

Overdose Update: I've finished going through the prose of the Overdose section, though I do plan to go through it again, as it's hard to catch everything the first time around. One general note: I have some issues with the organization of the section, particularly with the beginning and ending and with the subheadings. See the suggestions below. I would like to log in every day and keep an eye on developments here, but in reality we're probably looking at middle to end of next week or possible next weekend; I'm kind of busy through Wednesday. AmericanLemming (talk) 09:09, 14 September 2014 (UTC)[reply]

1. This section is technical enough that I think a introduction paragraph is warranted. Give the general reader the bottom line about the most effective treatments, give a simplified description of the bimolecular mechanism of addiction, ditto with psychosis, toxicity, and withdrawal. Don't make them go digging for what they're looking for, especially when some of the content is highly technical.

2. Also, I don't think the "Psychosis" and "Toxicity" sections are long enough to warrant their own level 3 headings when "Dependence and addiction" is a level 3 heading with five paragraphs and those two are half-paragraphs. I suggest either significant expansion, consolidation of the two into one level 3 heading subsection, or addition to the top of the section with the rest of the overdose symptoms.

3. Put the Overdose symptoms into a chart as we talked about above and then move the giant annotated image further down so we're not sandwiching text between images.

4. I have some more ideas for rearranging and adding/moving subsection headers, but I'll wait on those until we've decided what to do with the above three proposals. AmericanLemming (talk) 09:09, 14 September 2014 (UTC)[reply]

Most of that section is arranged according to MOS:MED#Drugs, medications and devices and a current proposal on MOS:MED's talkpage. Addiction is in that section because the phenomenon only develops with chronic high-dose use; it literally requires a pathological overactivation of the mesolimbic DA pathway (either directly through DA receptors or indirectly through a possibly complex mechanism, e.g., alcohol). Toxicity is an indicated subsection of overdose, so it kind of needs to be there. I could merge toxicity and psychosis into one section if you'd prefer. Seppi333 (Insert 2¢ | Maintained) 03:37, 11 October 2014 (UTC)[reply]

And now for the prose comments for the rest of the section:

“Cognitive behavioral therapy” Could we give a brief definition in-text?

I'm not sure this would be easy for me to define succinctly... e.g., see Cognitive behavioral therapy#Description. I could probably define it in a note, I'd be more or less be restating parts of that section. Seppi333 (Insert 2¢ | Maintained)

“Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction” So even though it’s the most effective clinical treatment, isn’t that based on extremely limited evidence? Or does the Cochrane Collaboration review from the “Pharmacological treatments” subsection only refer to drugs?

Cochrane's review was just pharmacological therapy.Seppi333 (Insert 2¢ | Maintained)

The last sentence in the “Behavioral treatments” paragraph is pretty much unintelligible to the general reader. While I think the whole sentence is in need of some improvement, the very last part is the worst offender: I’ll start from the beginning of the sentence and take it by parts:
1. “aerobic exercise decreases psychostimulant self-administration” I added a definition of self-administration in the above paragraph, so this is good.

2. “attenuates sensitization to the rewarding effects of psychostimulants” So basically you don’t feel as good when you take the drug?

I'm just deleting that clause because its explanation is a lot longer than the clause itself. I'm not sure it affects reward perception necessarily; psychostimulant sensitization involves an increased of dopamine response in the nucleus accumbens from psychostimulant use, which increases the likelihood of developing an addiction.

3. “reduces the reinstatement of drug-seeking behavior” So you’re less likely to relapse?

Yep, I've noted this. Seppi333 (Insert 2¢ | Maintained)

4. induces opposite effects on striatal dopamine receptor D2 signaling to those induced by pathological stimulant use.” What are the “opposite effects” on striatal dopamine receptor D2 signaling caused be aerobic exercise, and what are the effects caused by pathological stimulant use?

I think I've addressed this. Let me know. Seppi333 (Insert 2¢ | Maintained)

“Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain.” Based on what I read later, I take it that “certain parts of the brain” really means the nucleus accumbens. How about “in certain parts of the brain, especially the nucleus accumbens”?

Erledigt Seppi333 (Insert 2¢ | Maintained)

“The most important transcription factors” I would suggest adding a note explaining the role of transcription factors in gene expression.

In progress I need to find a MEDRS-quality source first, but I intend to do this. Seppi333 (Insert 2¢ | Maintained)

Erledigt Added this as a note next to the first use of the "transcription factor" phrase. Seppi333 (Insert 2¢ | Maintained)

“since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction” I assume you’re referencing necessary and sufficient cause here, but the fact that you neither mention the word “cause” nor link to Necessary and sufficient causes is cause for confusion. Also, why is ΔFosB considered a “necessary and sufficient cause” of these neural changes? And what are these neural adaptations, anyway? If the neural adaptations are talked about in the caption to the giant annotated image, you should add “(see caption below image to the right)” so people can read up on that if they want to.

I meant to link to necessary and sufficient; I did it in other articles, but oddly enough, I missed it here. Essentially it means that the plasticity of addiction and ΔFosB overexpression always occur together, never alone. It's necessary and sufficient because it's been observed to produce this plasticity with viral overexpression (using viral vector gene transfer) and their occurrence doesn't occur with a viral block of ΔFosB expression (i.e., viral overexpression of ΔJunD opposes ΔFosB and hence this plasticity with concurrent drug use). This is rather technical - the reference that quotes that sentence explains it more. As for the plasticity, some of it is indicated in the psychostimulant column of the table below, which I've transcluded to several articles from FOSB. Seppi333 (Insert 2¢ | Maintained)

An Error has occurred retrieving Wikidata item for infobox Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.^[1]^[2]^[3]

The FOS gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.^[1] FosB and its truncated splice variants, ΔFosB and further truncated Δ2ΔFosB, are all involved in osteosclerosis, although Δ2ΔFosB lacks a known transactivation domain, in turn preventing it from affecting transcription through the AP-1 complex.^[4]

The ΔFosB splice variant has been identified as playing a central, crucial^[5]^[6] role in the development and maintenance of addiction.^[5]^[7]^[8] ΔFosB overexpression (i.e., an abnormally and excessively high level of ΔFosB expression which produces a pronounced gene-related phenotype) triggers the development of addiction-related neuroplasticity throughout the reward system and produces a behavioral phenotype that is characteristic of an addiction.^[5]^[8]^[9] ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs.^[10]

DeltaFosB

DeltaFosB – more commonly written as ΔFosB – is a truncated splice variant of the FOSB gene.^[11] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.^[6]^[7]^[12] In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.^[13]^[14]^[15] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.^[16]

In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.^[5]^[17]^[18] In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately produce an addictive state (i.e., compulsive reward-seeking involving a particular stimulus); this state is sustained for months after cessation of drug use due to the abnormal and exceptionally long half-life of ΔFosB isoforms.^[5]^[17]^[18] ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.^[5]^[8] Based upon the accumulated evidence, a medical review from late 2014 argued that accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.^[5]

Chronic administration of anandamide, or N-arachidonylethanolamide (AEA), an endogenous cannabinoid, and additives such as sucralose, a noncaloric sweetener used in many food products of daily intake, are found to induce an overexpression of ΔFosB in the infralimbic cortex (Cx), nucleus accumbens (NAc) core, shell, and central nucleus of amygdala (Amy), that induce long-term changes in the reward system.^[19]

Role in addiction

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

The signaling cascade involved in psychostimulant addiction

Note: colored text contains article links.

G_s

cAMP

ΔFosB

JunD

c-Fos

SIRT1

HDAC1

^{[Color legend 1]}

This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,^[22]^[23] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.^[22]^[24]^[25] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;^[22]^[17]^[26] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.^[27] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.^[17]^[26] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.^[17]^[26]

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.^[6]^[28]^[29] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB).^[6] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.^[5]^[6]^[8] ΔFosB overexpression has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.^[5]^[6]^[28]^[30]^[31] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.^[6]^[8]^[32] Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).^[9]^[6] Repression of c-Fos by ΔFosB, which consequently further induces expression of ΔFosB, forms a positive feedback loop that serves to indefinitely perpetuate the addictive state.

ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.^[6]^[12] Natural rewards, similar to drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.^[6]^[7]^[12] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;^[6]^[7]^[12] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.^[12] Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional reward cross-sensitization effects^{[note 1]} that are mediated through ΔFosB.^[7]^[33] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.^[7]

ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.^[34] Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors^{[note 2]} – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use.^[9]^[32]^[35]^[36] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals^{[note 3]} that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;^[32]^[36]^[37]^[38] however, as of August 2015^[update], few clinical trials involving humans with addiction and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.^{[note 4]}

Plasticity in cocaine addiction

ΔFosB accumulation from excessive drug use

Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.^[18]^[26]

ΔFosB levels have been found to increase upon the use of cocaine.^[40] Each subsequent dose of cocaine continues to increase ΔFosB levels with no apparent ceiling of tolerance.^{[citation needed]} Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug.

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine.^[41] They self-administer cocaine at lower doses than control,^[42] but have a greater likelihood of relapse when the drug is withheld.^[18]^[42] ΔFosB increases the expression of AMPA receptor subunit GluR2^[41] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.^[18]

Neural and behavioral effects of validated ΔFosB transcriptional targets^[5]^[13]
Target gene	Target expression	Neural effects	Behavioral effects
c-Fos	↓	Molecular switch enabling the chronic induction of ΔFosB^{[note 5]}	-
dynorphin	↓ ^{[note 6]}	• Downregulation of κ-opioid feedback loop	• Diminished self-extinguishing response to drug
NF-κB	↑	• Expansion of Nacc dendritic processes • NF-κB inflammatory response in the NAcc • NF-κB inflammatory response in the CPTooltip caudate putamen	• Increased drug reward • Locomotor sensitization
GluR2	↑	• Decreased sensitivity to glutamate	• Increased drug reward
Cdk5	↑	• GluR1 synaptic protein phosphorylation • Expansion of NAcc dendritic processes	• Decreased drug reward (net effect)

Summary of addiction-related plasticity


Form of neuroplasticity or behavioral plasticity	Type of reinforcer						Sources
Form of neuroplasticity or behavioral plasticity	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment	Sources
ΔFosB expression in nucleus accumbens D1-type MSNsTooltip medium spiny neurons	↑	↑	↑	↑	↑	↑	^[7]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				^[7]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	^[7]
Psychostimulant self-administration	↑	↑	↓		↓	↓	^[7]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	^[7]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	^[7]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	^[7]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			^[7]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	^[7]
Altered striatal opioid signaling	No change or ↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change	^[7]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	^[7]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			^[7]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			^[7]

Other functions in the brain

Viral overexpression of ΔFosB in the output neurons of the nigrostriatal dopamine pathway (i.e., the medium spiny neurons in the dorsal striatum) induces levodopa-induced dyskinesias in animal models of Parkinson's disease.^[43]^[44] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;^[44] postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.^[44] Levetiracetam, an antiepileptic drug, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa;^[44] the signal transduction involved in this effect is unknown.^[44]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.^[45]^[46]^[47]

Antipsychotic drugs have been shown to increase ΔFosB as well, more specifically in the prefrontal cortex. This increase has been found to be part of pathways for the negative side effects that such drugs produce.^[48]

Notes

^ In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward sensitization, this effect occurs with the other as well.
^ Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;^[35]^[36] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.
^ Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.^[32]^[36]^[37]
^ Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.^[39]
^ In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly because it is selectively induced in this state.^[8]
^ ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;^[5]^[13] this table entry reflects only a decrease.

Image legend

^
  Ion channel
  G proteins & linked receptors
  (Text color) Transcription factors

References

^ ^a ^b "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B".
^ Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (Oct 1990). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA and Cell Biology. 9 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID 1702972.
^ Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI (Apr 1992). "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nature Genetics. 1 (1): 34–9. doi:10.1038/ng0492-34. PMID 1301997. S2CID 1986255.
^ Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R (May 2008). "Doubly truncated FosB isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in osteoblasts independent of intrinsic AP-1 activity". Journal of Bone and Mineral Research. 23 (5): 584–95. doi:10.1359/jbmr.080110. PMC 2674536. PMID 18433296.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Ruffle JK (Nov 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711.
ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Robison AJ, Nestler EJ (Nov 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews. Neuroscience. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s Olsen CM (Dec 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008).
Table 1
^ ^a ^b ^c ^d ^e ^f ^g Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹ ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
^ ^a ^b ^c Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Annals of Agricultural and Environmental Medicine. 19 (3): 491–6. PMID 23020045. For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
^ Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ (Jan 2015). "Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse". Neuroscience. 284: 165–70. doi:10.1016/j.neuroscience.2014.10.002. PMC 4268105. PMID 25313003.
^ Nakabeppu Y, Nathans D (Feb 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell. 64 (4): 751–9. doi:10.1016/0092-8674(91)90504-R. PMID 1900040. S2CID 23904956.
^ ^a ^b ^c ^d ^e Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964.
^ ^a ^b ^c Nestler EJ (Oct 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3
^ Renthal W, Nestler EJ (Aug 2008). "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine. 14 (8): 341–50. doi:10.1016/j.molmed.2008.06.004. PMC 2753378. PMID 18635399.
^ Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (May 2009). "Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins". Neuron. 62 (3): 335–48. doi:10.1016/j.neuron.2009.03.026. PMC 2779727. PMID 19447090.
^ Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (Sep 2000). "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis". Nature Medicine. 6 (9): 985–90. doi:10.1038/79683. PMID 10973317. S2CID 20302360.
^ ^a ^b ^c ^d ^e Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression
^ ^a ^b ^c ^d ^e Nestler EJ, Barrot M, Self DW (Sep 2001). "DeltaFosB: a sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11042–6. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966.
^ Salaya-Velazquez NF, López-Muciño LA, Mejía-Chávez S, Sánchez-Aparicio P, Domínguez-Guadarrama AA, Venebra-Muñoz A (February 2020). "Anandamide and sucralose change ΔFosB expression in the reward system". NeuroReport. 31 (3): 240–244. doi:10.1097/WNR.0000000000001400. PMID 31923023. S2CID 210149592.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 978-0-07-148127-4.
^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
^ ^a ^b ^c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events
^ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
^ ^a ^b ^c ^d Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
^ Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
^ ^a ^b Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annual Review of Neuroscience. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.
^ Steiner H, Van Waes V (Jan 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Progress in Neurobiology. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425.
^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (Feb 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2915–20. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072.
^ ^a ^b ^c ^d Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.
^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (Feb 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–385. ISBN 9780071481274.
^ ^a ^b McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC 4955852. PMID 27453897. Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD.
^ ^a ^b ^c ^d Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure
^ ^a ^b Primary references involving sodium butyrate:

• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113. While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine^1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity^3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug^1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression³ or decreased acquisition of behavioral adaptations to drug^5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.

• Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–689. doi:10.1111/adb.12161. PMID 25041570. S2CID 28667144. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE. 10 (4): e0124796. Bibcode:2015PLoSO..1024796C. doi:10.1371/journal.pone.0124796. PMC 4399837. PMID 25880762. treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.
^ Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–9. doi:10.1016/j.neulet.2015.01.051. PMC 4506731. PMID 25623036. Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above [25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention.
^ Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research. 5: 149. doi:10.4103/2277-9175.187404. PMC 5025910. PMID 27656618.
^ Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Annals of the New York Academy of Sciences. 844 (1): 1–6. Bibcode:1998NYASA.844....1H. doi:10.1111/j.1749-6632.1998.tb08216.x. PMID 9668659. S2CID 11683570.
^ ^a ^b Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (Sep 1999). "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. Bibcode:1999Natur.401..272K. doi:10.1038/45790. PMID 10499584. S2CID 4390717.
^ ^a ^b Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (Mar 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". The Journal of Neuroscience. 23 (6): 2488–93. doi:10.1523/JNEUROSCI.23-06-02488.2003. PMC 6742034. PMID 12657709.
^ Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM (May 2010). "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.
^ ^a ^b ^c ^d ^e Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878. PMC 4322303. PMID 25692070. Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ± 1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with L-DOPA [26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic effects of levetiracetam remains uncertain.
^ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Archived from the original on 28 June 2017. Retrieved 6 September 2014.
^ Furuyashiki T, Deguchi Y (Aug 2012). "[Roles of altered striatal function in major depression]". Brain and Nerve = Shinkei Kenkyū No Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883.
^ Nestler EJ (Apr 2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses". European Journal of Pharmacology. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034. PMC 4380559. PMID 25446562. In more recent years, prolonged induction of ∆FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.
^ Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ (February 2014). "ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes". Neuropsychopharmacology. 39 (3): 538–44. doi:10.1038/npp.2013.255. PMC 3895248. PMID 24067299.

External links

ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS Archived 28 June 2017 at the Wayback Machine
KEGG Pathway – human alcohol addiction
KEGG Pathway – human amphetamine addiction
KEGG Pathway – human cocaine addiction
FOSB+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

“Since natural rewards induce ΔFosB just like drugs of abuse do” What does it mean that they “induce” ΔFosB? They cause the body to make more of it?

It means it increases gene expression of ΔFosB. I've clarified this and linked to inducible gene with a pipe as "Since natural rewards induce expression of ΔFosB..." Seppi333 (Insert 2¢ | Maintained)

“and amphetamine-induced sex addictions.” Do these amphetamine-induced sex addictions occur frequently at therapeutic and/or recreational doses? How does amphetamine cause sex addictions? Does an amphetamine-induced sex addiction mean that you’re addicted to both amphetamine and sex? I’m not harping on this just because it mentions sex; I feel that the sentence as is introduces a condition/disease without really explaining it.

I clarified the text a little and added the appropriate quote to the reference ("In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex"). It's simply compulsive sexual behavior as a result of amphetamine use. There is a notable interaction between reward perception with sexual behavior and amphetamine use, and an overactivation of DA networks involved in reward perception and reinforcement mediate that phenomenon. I actually rewrote sex addiction recently to try to explain that concept better (and because I got into an edit war with another editor...). Let me know if you think it needs more work in the article. Seppi333 (Insert 2¢ | Maintained)

“Psychosis” subsection: I feel that the current length of this section doesn’t do the topic justice. We don’t need four full paragraphs about it, but how about 8-10 sentences instead of the current four?

I'll look through the Cochrane review soon and see if I can add more material. Most of the content in the amphetamine psychosis section either isn't particularly relevant (e.g., first paragraph) or isn't cited by a MEDRS-quality source. Seppi333 (Insert 2¢ | Maintained) 03:47, 11 October 2014 (UTC)[reply]

“Toxicity” subsection: Same concern as with the Psychosis subsection. Again, I’d feel much more comfortable with the article’s comprehensiveness with 8-10 sentences here instead of three.

There really isn't much to say about amphetamine toxicity in humans. Direct toxicity simply does not occur. I could probably write a whole paper on direct DA toxicity in rats, but including that in the article would be sort of POV because it's misleading. The mechanics of indirect toxicity are mediated entirely through oxidative events related to excessive dopamine release. I could probably add a sentence or two on its mechanics, but these are necessarily going to be fairly technical descriptions compared to the text currently in that section. Seppi333 (Insert 2¢ | Maintained) 03:47, 11 October 2014 (UTC)[reply]

Actually, as I come to think about it, how about we expand the above two subsections slightly, delete the subsection headings, and then move them to the topic of the section where the other overdose side-effects are found?

Due to the the MOS indications that I mentioned in a #previous bullet, and the points I raised in the above two bullets, it may be best to simply combine the two sections if you'd prefer to have fewer subsections under the Overdose heading. Seppi333 (Insert 2¢ | Maintained)

“Manufacturer prescribing information does not indicate the presence” Which manufacturer? Or are we talking about US FDA prescribing regulations? I’m confused. AmericanLemming (talk) 09:09, 14 September 2014 (UTC)[reply]

This actually refers to the prescribing information from all manufacturers of amphetamine pharmaceuticals. The prescribing information is under copyright, and they vary in format, but they're pretty much standardized in the information in they provide (I can link you to a few examples for amphetamine pharmaceuticals on pubchem if you'd like to see what I mean), even though it is copyrighted. Seppi333 (Insert 2¢ | Maintained)

@AmericanLemming: I've pasted this from the review so that I can address/reply the points by issue here. I've added the table for the symptoms - let me know what you think. There was a small addition of content in the behavioral treatments section since you last checked it as well. Seppi333 (Insert 2¢ | Maintained) 01:25, 11 October 2014 (UTC)[reply]

Interactions

“Inhibitors of the enzymes that metabolize amphetamine…will prolong its elimination half-life” What the clinical significance of having amphetamine in your system longer? Does that make it easier to overdose on it?
“increase plasma catecholamines” I know we’re mentioned it in the lead, but adding “(i.e. norepinephrine and dopamine” after catecholamines may be helpful for the general reader. AmericanLemming (talk) 08:11, 15 December 2014 (UTC)[reply]

Comments from Jfdwolff

This is a very good article. Balanced in an area where there's information from numerous domains to compare and weigh. Using every way possible to clarify difficult concepts using notes and tooltips etc.

While almost all sections are supported heavily by secondary sources, I still find a number of primary sources in some sections. I found one of these to be over 20 years old (e.g. Imperato et al 1993). They may not have been reproduced or included in the current paradigm.
A number of references currently contains a message that the "chapter" parameter is being ignored. Can this be fixed?

I will see if any other concerns arise from reviews by others (as I cannot claim much expertise in the subject matter) but I have a low threshold for support provided the primary sources concern is addressed. JFW | T@lk 22:18, 6 December 2014 (UTC)[reply]

Don't bother with doing so - I replaced it with a new review. I don't mind cutting primary sources because any that are included are unnecessary for WP:V, so if any others are a concern, let me know. The few primary sources covering medical content in humans are all coupled to WP:MEDRS-quality reviews, as far as I'm aware. I'm quite pedantic about citing anything medical regarding humans with medical reviews or high-quality pharmacology references. In any case, I replaced it with a new medical review covering preclinical evidence (I assume this means "lab animals", so I kept that phrase). That sentence was just meant to provide context to indicate that dopamine and acetylcholine interactions from amphetamine are not unique to humans.

In the few other cases that I included the primary sources with reviews, I did so because: (1) I found it hard to find the information in the review when re-checking (the review on flavin-containing monooxygenase, where it's in a table instead of the article) or (2) I thought the material was important, but not widely covered in reviews in a relevent context or relevant databases (e.g., the dopamine beta-hydroxylase references). Seppi333 (Insert 2¢ | Maintained) 23:53, 6 December 2014 (UTC)[reply]

Edit: Forgot to note, I'm discussing the citation error issue on the CS1 module talkpage. Will probably have them fixed by tomorrow. Seppi333 (Insert 2¢ | Maintained) 00:35, 7 December 2014 (UTC)[reply]

@Jfdwolff: Everything should be fixed now; let me know if anything is still amiss. Citation errors were really just an error in the module script. Seppi333 (Insert 2¢ | Maintained) 03:51, 8 December 2014 (UTC)[reply]

Comments from Axl

This is a point that I made at previous FACs: From "Uses", subsection "Medical", paragraph 4: "A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine in such people should be avoided." Should high doses be avoided in children with tic disorders more so than in children without tic disorders? Axl ¤ [Talk] 10:51, 8 December 2014 (UTC)[reply]

Sorry, I hadn't realized my previous comment didn't address your concern - I reworded the sentence to how I interpreted what Cochrane was essentially saying: "A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in such individuals."
If you'd prefer different wording, feel free to edit that line to your liking. I very seldom revert a reviewers changes to an article in the event you're concerned about it. Seppi333 (Insert 2¢ | Maintained)

No, not in "such individuals", in "some" individuals. Stimulants do not exacerbate tics. *SOME* people may have issues, though. Here are the words from the Cochrane review:

To evaluate evidence for this reported phenomenon we searched for clinical trials of medications for ADHD used specifically in children with tic disorders. The trials indicate that a number of stimulant and non-stimulant medications are safe and effective treatments for ADHD symptoms and do not worsen tics. High dose stimulants may transiently worsen tics in some children, and worsening tics may limit dose increases of stimulants in some children, but in the majority of children both tics and ADHD symptoms improve with use of stimulant medications.

And, surprise, that is correct :) "Some" is the correct word. SandyGeorgien (Talk) 22:09, 10 December 2014 (UTC)[reply]

I don't mind how the statement is worded, though I think this is worth noting: Cochrane's samples were entirely upon individuals with ADHD and some form of tic disorder, so they technically can't generalize the population outside that group without it producing biased statistical inference (i.e., the samples are nonrespresentative of individuals with ADHD in general with or without tic disorders). That's why I assumed their analysis was always in context of the sample and consequently worded that sentence with "such"; in any event, I actually agree completely that dopaminergic-related movement side effects are not specific to individuals with tic disorders. Anyone can develop abnormal involuntary movements and hypersensitive locomotor responses using dopaminergic stimulants because, as in the nucleus accumbens, dopamine (and hence DA stims like amphetamine) induces nigrostriatal ΔFosB in response to chronic sufficiently high dosing.([1] - epigenetics/pharmacogenomics of involuntary motor activity from chronic high-dose L-dopa therapy) Nigrostriatal ΔFosB overexpression, coupled with high-dose amphetamine/methamphetamine, would necessarily produce abnormal motor function and dysregulated motor responses (e.g., substituted amphetamine induced stereotypies). This may or may not contribute to tics though, depending upon which neural pathways give rise to tic disorders. Seppi333 (Insert 2¢ | Maintained) 01:11, 11 December 2014 (UTC)[reply]

Thank you. The current text is fine. Axl ¤ [Talk] 09:48, 12 December 2014 (UTC)[reply]

From "Contraindications": "It is also contraindicated in people currently experiencing... severe hypertension." The FDA reference states "Moderate to severe hypertension". The Inchem reference just states "hypertension". Axl ¤ [Talk] 11:07, 8 December 2014 (UTC)[reply]

That was probably pruned during previous copyediting - I've cut the word "severe" and left it at hypertension. Seppi333 (Insert 2¢ | Maintained) 13:46, 8 December 2014 (UTC)[reply]

I am wary of adding "elevated blood pressure" in parentheses after "hypertension". Hypertension is more than simply elevated blood pressure. Also, elevated blood pressure is subsequently noted as a cautionary feature that should be monitored. (This statement is in line with the references.)

I am inclined to delete the "clarification" of the meaning of hypertension from the text. (I note that the subsequent cautionary features such as bipolar disorder, psychosis and Raynaud's phenomenon do not have associated short definitions.) If you insist that a short definition should be included for hypertension, perhaps change it to "persistent blood pressure"? Axl ¤ [Talk] 09:56, 12 December 2014 (UTC)[reply]

Deleted it; I don't care for the parenthetical clarification - I only added them in cases where they were requested. In this case, it was redundant anyway. Seppi333 (Insert 2¢ | Maintained) 09:12, 14 December 2014 (UTC)[reply]

The clarification seems to have been changed to "high blood pressure". Axl ¤ [Talk] 21:40, 16 December 2014 (UTC)[reply]

From "Side effects", subsection "Physical", paragraph 1: "Cardiovascular side effects can include irregular heartbeat (usually an increased heart rate)." Not all arrhythmias are irregular. Indeed atrial fibrillation is the only common arrhythmia that is irregular. I am aware that the linked article, "Cardiac dysrhythmia", states that "irregular heartbeat" is a synonym. The statement is inaccurate. The reference seems to be inaccessible at the moment. Axl ¤ [Talk] 10:15, 12 December 2014 (UTC)[reply]

I tweaked this as such. Let me know if that works. Wasn't sure how you wanted it. Seppi333 (Insert 2¢ | Maintained) 09:12, 14 December 2014 (UTC)[reply]

No! I recommend "cardiac dysrhythmia (abnormal heart rhythm)." Axl ¤ [Talk] 21:45, 16 December 2014 (UTC)[reply]

Comments from Abductive

I feel that the lead is a bit overlong.
The lead certainly is too technical, and jumps around between the historical, medical, chemical, abuse, and legal aspects of the topic. I'll break this down by coding each sentence or part of sentence: 1st paragraph; m,hc,c,c,m,ma,la. Second paragraph; h,hm,m,m,m. 3rd; a,am,am,a. 4th; c,ca,m,c. Abductive (reasoning) 04:36, 18 December 2014 (UTC)[reply]

[34] In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward sensitization, this effect occurs with the other as well.

[39] Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;^[35]^[36] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.

[41] Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.^[32]^[36]^[37]

[44] Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.^[39]

[48] In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly because it is selectively induced in this state.^[8]

[49] ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;^[5]^[13] this table entry reflects only a decrease.

[22] 
Ion channel
G proteins & linked receptors
(Text color) Transcription factors

[entrez-1] "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B".

[pmid1702972-2] Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (Oct 1990). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA and Cell Biology. 9 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID 1702972.

[pmid1301997-3] Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI (Apr 1992). "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nature Genetics. 1 (1): 34–9. doi:10.1038/ng0492-34. PMID 1301997. S2CID 1986255.

[Δ2ΔFosB_transactivation_osteoclast-4] Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R (May 2008). "Doubly truncated FosB isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in osteoblasts independent of intrinsic AP-1 activity". Journal of Bone and Mineral Research. 23 (5): 584–95. doi:10.1359/jbmr.080110. PMC 2674536. PMID 18433296.

[What_the_ΔFosB?-5] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Ruffle JK (Nov 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711.
ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.

[Nestler-6] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Robison AJ, Nestler EJ (Nov 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews. Neuroscience. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

[Natural_and_drug_addictions-7] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s Olsen CM (Dec 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008).
Table 1

[Cellular_basis-8] ^ ^a ^b ^c ^d ^e ^f ^g Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹ ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.

[G9a_reverses_ΔFosB_plasticity-9] Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Annals of Agricultural and Environmental Medicine. 19 (3): 491–6. PMID 23020045. For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription

[FosB_ΔFosB_Δ2ΔFosB_drugs-10] Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ (Jan 2015). "Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse". Neuroscience. 284: 165–70. doi:10.1016/j.neuroscience.2014.10.002. PMC 4268105. PMID 25313003.

[pmid1900040-11] Nakabeppu Y, Nathans D (Feb 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell. 64 (4): 751–9. doi:10.1016/0092-8674(91)90504-R. PMID 1900040. S2CID 23904956.

[ΔFosB_reward-12] Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964.

[pmid18640924-13] Nestler EJ (Oct 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3

[pmid18635399-14] Renthal W, Nestler EJ (Aug 2008). "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine. 14 (8): 341–50. doi:10.1016/j.molmed.2008.06.004. PMC 2753378. PMID 18635399.

[pmid19447090-15] Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (May 2009). "Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins". Neuron. 62 (3): 335–48. doi:10.1016/j.neuron.2009.03.026. PMC 2779727. PMID 19447090.

[pmid10973317-16] Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (Sep 2000). "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis". Nature Medicine. 6 (9): 985–90. doi:10.1038/79683. PMID 10973317. S2CID 20302360.

[Nestler1-17] Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression

[pmid11572966-18] Nestler EJ, Barrot M, Self DW (Sep 2001). "DeltaFosB: a sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11042–6. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966.

[19] Salaya-Velazquez NF, López-Muciño LA, Mejía-Chávez S, Sánchez-Aparicio P, Domínguez-Guadarrama AA, Venebra-Muñoz A (February 2020). "Anandamide and sucralose change ΔFosB expression in the reward system". NeuroReport. 31 (3): 240–244. doi:10.1097/WNR.0000000000001400. PMID 31923023. S2CID 210149592.

[Addiction_glossary-20] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 978-0-07-148127-4.

[Brain_disease-21] Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.

[Nestler-Renthal_Figure_2-23] Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events

[Glutamate-dopamine_cotransmission_review-24] Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.

[Amphetamine_KEGG_ΔFosB-25] Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.

[Meth_cAMP/calcium-dependent_cascade-26] Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.

[Nestler2-27] Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase

[c-Fos_repression-28] Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure

[Nestler,_Hyman,_and_Malenka_2-29] Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annual Review of Neuroscience. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.

[Addiction_genetics-30] Steiner H, Van Waes V (Jan 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Progress in Neurobiology. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425.

[Alcoholism_ΔFosB-31] Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.

[MPH_ΔFosB-32] Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (Feb 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2915–20. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072.

[Nestler_2014_epigenetics-33] Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.

[Amph_and_sex_addiction-35] Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (Feb 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671.

[Malenka_2009_04-36] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–385. ISBN 9780071481274.

[Amphetamine_epigenetics-37] McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC 4955852. PMID 27453897. Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD.

[Chromatin_states-38] Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure

[HDACi_primaries-40] Primary references involving sodium butyrate:

• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113. While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine^1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity^3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug^1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression³ or decreased acquisition of behavioral adaptations to drug^5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.

• Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–689. doi:10.1111/adb.12161. PMID 25041570. S2CID 28667144. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE. 10 (4): e0124796. Bibcode:2015PLoSO..1024796C. doi:10.1371/journal.pone.0124796. PMC 4399837. PMID 25880762. treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.

[HDAC_alcoholism_review-42] Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–9. doi:10.1016/j.neulet.2015.01.051. PMC 4506731. PMID 25623036. Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above [25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention.

[Valproate_for_methamphetamine_addiction_primary_source-43] Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research. 5: 149. doi:10.4103/2277-9175.187404. PMC 5025910. PMID 27656618.

[pmid9668659-45] Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Annals of the New York Academy of Sciences. 844 (1): 1–6. Bibcode:1998NYASA.844....1H. doi:10.1111/j.1749-6632.1998.tb08216.x. PMID 9668659. S2CID 11683570.

[pmid10499584-46] Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (Sep 1999). "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. Bibcode:1999Natur.401..272K. doi:10.1038/45790. PMID 10499584. S2CID 4390717.

[pmid12657709-47] Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (Mar 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". The Journal of Neuroscience. 23 (6): 2488–93. doi:10.1523/JNEUROSCI.23-06-02488.2003. PMC 6742034. PMID 12657709.

[pmid20505100-50] Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM (May 2010). "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.

[Levetiracetam-51] Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878. PMC 4322303. PMID 25692070. Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ± 1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with L-DOPA [26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic effects of levetiracetam remains uncertain.

[Nestler's_lab-52] "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Archived from the original on 28 June 2017. Retrieved 6 September 2014.

[Stress_and_NAcc_shell-53] Furuyashiki T, Deguchi Y (Aug 2012). "[Roles of altered striatal function in major depression]". Brain and Nerve = Shinkei Kenkyū No Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883.

[NAcc_∆FosB_depression-54] Nestler EJ (Apr 2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses". European Journal of Pharmacology. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034. PMC 4380559. PMID 25446562. In more recent years, prolonged induction of ∆FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.

[pmid24067299-55] Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ (February 2014). "ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes". Neuropsychopharmacology. 39 (3): 538–44. doi:10.1038/npp.2013.255. PMC 3895248. PMID 24067299.

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 :I quickly went through the ''Interactions'' subsection to give you some new comments to work with, but I need a few days to reread the first half of the article, both to refamiliarize myself with the material and tweak the prose further if need be. I also need to look at the "Overdose" section again and take a look at the changes you've made in response to my comments. Reviewing this is priority number one for my Christmas break, so I should be able to finish it before classes start up again. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 08:11, 15 December 2014 (UTC)
+{{collapse top|1=American Lemming's comments from peer review/4th FAC}}
+'''Lead'''
+Just finished reading through this part. It looks well-written, well-organized, and well-sourced. The first paragraph is a bit on the long side, as is the lead as a whole, but I'm not really sure you can cut anything out without losing something important. My four comments/questions are as follows:
+* “At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.” This wording implies to me that there aren’t any side effects at therapeutic doses, which probably isn’t the case.
+:* After rereading it, I think I agree about the sentence on physical effects.  The statement on psychological effects seems more or less neutral, since increased arousal can lead to insomnia or increased wakefulness. Similarly, changes in libido can be desirable or undesirable depending on the individual.  I'll tweak the the physical effects clause over the next day or so to address this. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+::*Now that I look at it again, just leave the sentence alone. Sometimes less is more, and I think making it any wordier would decrease the intelligibility to the general reader. Besides, it is correct as it stands.
+::::Good point; I'm okay with that. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 08:59, 10 August 2014 (UTC)
+* “Very high doses can result in a psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use.” First, “a psychosis” sounds awkward to me. If it’s consistent with medical terminology, then by all means keep it, but otherwise I would drop the “a”. Second, so it’s pretty difficult to die of an overdose of amphetamine? That’s the impression I’m getting here.
+:* There's different types of psychoses, though I agree it sounds weird so I'd be ok with removing it.  As for overdoses, it's pretty rare to die from an overdose when medical treatment is sought.  The doses that recreational users take are roughly 10-100 times higher than the maximum dose when its used medically. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+::*I've gone and removed the "a".
+* “Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked.” So if you can inhale amphetamine (see infobox), why can’t you smoke it? Or am I confusing smoking cigarettes and smoking other drugs?
+:*The salts can't be smoked, but they can be snorted (insufflated) as a powder.  That's really only a recreational route though.  The medical route involves inhaling small amounts of the freebase via an inhaler (e.g., [[:File:Benzedrine_inhaler_for_wiki_article.jpg]]).  Unlike the salts, the freebase is a liquid at room temperature and CAN be smoked. Illicit amphetamine is almost never trafficked/sold as the freebase, which I'm assuming is due to its volatility. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+* “Amphetamine is also chemically related to the naturally occurring trace amine neurotransmitters, specifically phenethylamine and N-methylphenethylamine” Two questions here: 1. Does phenethylamine = trace amine neurotransmitters? 2. Is it that amphetamine is chemically related to trace amine neurotransmitters but is most closely related to phenethylamine and N-methylphenethylamine? That’s what it sounds like to me. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 06:26, 4 August 2014 (UTC)
+:*Both phenethylamine and N-methylphenethylamine are trace amines; N-methylphenethylamine is the most closely chemically-related trace amine to amphetamine since it's an amphetamine isomer.  If you can think of a better way to word it, feel free to change it! [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 19:06, 5 August 2014 (UTC)
+::*I've taken a shot at that; please do double-check to make sure it's accurate.
+::::Looks good. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 08:59, 10 August 2014 (UTC)
+I've made two edits to the lead, and I think that will do. The lead is meant to be the most accessible part of the article, and it really isn't the place to be explaining nuances and technicalities.
+'''Medical'''
+* Question about this section in general: when we’re talking about medical uses of amphetamine, we’re almost always talking about Adderall, right?
+:* Adderall (no generic name - i.e., a [[United States Adopted Name|USAN]]/[[International Nonproprietary Name|INN]] - even though it's almost always sold as a generic), dextroamphetamine (tons of brand names/generic forms), and lisdexamfetamine (brand:Vyvanse, still patented) are the currently available amphetamine-based pharmaceuticals; it covers this group of drugs. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*  “Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function of the right caudate nucleus.” So it decreases abnormalities in brain structure and function in general and improves function of the right caudate nucleus in particular? If that’s so, I would suggest changing the second half to “ADHD; in particular, it improves the function of the right caudate nucleus.”
+:* The caudate nucleus was one example that was highlighted in one of the reviews; there's improvement in function in more than one brain structure along the dopamine pathways that it acts upon. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+* “but high doses of dextroamphetamine in such people should be avoided.” Because of the side effects? Long-term damage to some part of the body?
+:* It exacerbates motor tics in people with Tourette's, which is a harmless but undesirable/annoying side-effect. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+* “task saliency” this may warrant a quick note to define saliency; the Wikipedia article on the subject isn’t terribly helpful.
+:* Good point; I'll go through later today and add this based upon the definition used in the textbook that cited that passage. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+::{{added}} - [https://en.wikipedia.org/w/index.php?title=Amphetamine&diff=620611114&oldid=620324694 Diff] [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+* “but this is prohibited at events regulated by the World Anti-Doping Agency.” From what I can gather, the World Anti-Doping Agency regulates just about every international and professional sporting event. I think this warrants another note/quick explanation in text, perhaps.
+:* <s>That's fine with me if you'd like to add this.</s>  Found a suitable ref, how's this look? [https://en.wikipedia.org/w/index.php?title=Amphetamine&diff=620712448&oldid=620660052 Diff] {{P|1}} [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+::* Better and worse. On one hand, I think adding the "regulated by collegiate, national, and international anti-doping agencies" does a much better job of explaining that amphetamine is widely prohibited in sporting events; on the other hand, expanding the tidbit about the World Anti-Doping Agency (WADA) turned the sentence into a run-on. I've trimmed the part on WADA to fix the sentence, and I think you could cut it out entirely if you wanted to. Your fix (adding "regulated by collegiate, national, and international anti-doping agencies") was a lot better than the one I suggested, and we don't need both. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 06:30, 11 August 2014 (UTC)
+::::{{Removed}} the WADA mention - {{noping|Shudde}} insisted I add it during the FAC review that he didn't finish. I didn't really want it to include it anyway - seemed like trivia. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 16:00, 11 August 2014 (UTC)
+* “In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, etc.” It may be worthwhile mentioning that there are some minor side-effects, even in healthy people at oral therapeutic doses. Otherwise, why aren’t we all on amphetamine? :)
+:* There's actually a lot of discussion among the academic community about the use of performance enhancing agents in the general population (e.g., [http://www.ncbi.nlm.nih.gov/pubmed/23767434 this paper elicited quite a lot of responses]).  It was only recently determined that low doses of ADHD psychostimulants improve cognitive control in everyone via their effect on [[dopamine D1 receptor]]s in the [[prefrontal cortex]].
+:: Back to the issue: I tried to keep this section disjoint from the side effects section to avoid redundancy and maintain neutrality when covering it.  I think it'd be alright to mention that there are additional physical side effects in that paragraph; however, I'm not sure it's a good idea to re-list the physical side effects alongside these, since it's both redundant with the side effects section and isn't relevant to the performance enhancing effect. This list of physical enhancement effects isn't included in the side effects section for the same reason. That said, I'll go ahead and add a clause mentioning the presence of additional side effects if that's what you had in mind. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+::: I would suggest adding something along the lines of "At these doses, the side effects are minimal." That's enough to help the reader keep the existence of side effects in mind without the unnecessary repetition of listing them all in two places. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 06:47, 11 August 2014 (UTC)
+::::{{added}} – [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+* Also, with that same sentence, it does seem that this is one place where [[WP:OVERKILL]] might apply. I understand that the article’s on a fairly technical subject, but do you really need four inline citations of the exact same two sources for four words in a row? I suggest you put all three sources at the end of the sentence, like you do elsewhere. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 09:03, 6 August 2014 (UTC)
+:* I'd be okay with grouping them at the end of the sentence, though the main reason I did this is because the performance enhancing use of these drugs has generated much controversy, and until recently there hasn't been much high quality research/review supporting these effects in humans.  I imagine that some people reading this article might come into it with a bias, which is why I cited them by effect.  I'll go ahead and group the citations if you think it improves readability - let me know. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+::* I recommend doing that. Besides, you quote directly from the source in the inline citation, so if someone doubts whether the sentence is true they can just mouse over the citation and read it for themselves. And as it currently stands it's just hard to read. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 06:53, 11 August 2014 (UTC)
+::::{{done}} – [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+Sorry for the late follow-up; I've been pretty busy this past week.  <s>I'll address these points momentarily!</s> Regards, [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 16:16, 9 August 2014 (UTC)
+'''Contraindications'''
+* I don’t think there’s anything in the manual of style against a one-paragraph section, but it does look somewhat odd. What do you think about combining the “Contraindications” section with the “Interactions” section? The “Interactions” section does a nice job of explaining why people with certain conditions or on certain drugs (MAOIs, for instance) shouldn’t take amphetamine.
+:: I actually agree that it would make sense to combine these, since serious drug interactions give rise to contraindications; however, the current layout of level-2 headers is indicated in [[MOS:MED]], so I can't really deviate from the present state.  Barring unusual or unique circumstances, there isn't much wiggle room in the section ordering. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 14:19, 11 August 2014 (UTC)
+:: After further thought, I think it may be better to keep these sections separate; most of the drug databases we link to in the drugbox don't provide this information together.  The FDA uses distinct sections for the information as well. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 18:17, 12 August 2014 (UTC)
+::: I agree with you; you really can't go against the MOS, especially when you want to get the article to FA status. As the next best alternative, I've added explanatory hatnotes to each section that tell the reader what the section is about and that direct them to the other section if that's not what they were looking for. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 06:39, 13 August 2014 (UTC)
+::::I think it might be best to use {{tl|see also}} templates here, since some of the contraindications aren't substance-related. It seemed a bit difficult for me to summarize the relationship in a hatnote without it being really long.  The first sentence of each section (I think) more or less implies how they're related though. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 09:31, 13 August 2014 (UTC)
+* “Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.” This contradicts the statement in the first paragraph of the “Medical uses” section that “humans experience normal development and nerve growth”. Do humans experience normal development when using amphetamine or not? [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 07:20, 11 August 2014 (UTC)
+:: It's technically a transient effect due to a rebound growth spurt associated with a temporary cessation of treatment.  IIRC, all dopaminergic stimulants suppress growth hormone release in adolescents (see [https://docs.google.com/viewer?a=v&pid=sites&srcid=ZGVmYXVsdGRvbWFpbnxzZXBwaWx1cnZlc3BhbmNha2VzfGd4OjcwNTJhNGQ5N2FkYTJiNQ page 4, paragraph 2 in this ref]), so it's not unique to amphetamine.  See section 5.3 of [http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf this ref] for more detail. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 14:19, 11 August 2014 (UTC)
+:::Follow-up: After rereading the sentence I wrote in medical uses, I noticed there isn't actually a contradiction here.  The full statement in medical uses is:<blockquote>Long-term amphetamine exposure in some species is known to produce <u>abnormal dopamine system development</u> or nerve damage,[35][36] but humans experience <u>normal development</u> and nerve growth.</blockquote> The "normal development" is in reference to the development of neural systems (not just dopaminergic systems) and the brain, as opposed to the body and physical development.  All the citations included in that sentence are confined to this context as well. <br />I've clarified the point in the contraindications section. [https://en.wikipedia.org/w/index.php?title=Amphetamine&diff=620947321&oldid=620789989 diff]  These are the references cited: [https://docs.google.com/viewer?a=v&pid=sites&srcid=ZGVmYXVsdGRvbWFpbnxzZXBwaWx1cnZlc3BhbmNha2VzfGd4OjU0ZGJjN2RhYTkwNTlhNmI see P125-127], [https://docs.google.com/viewer?a=v&pid=sites&srcid=ZGVmYXVsdGRvbWFpbnxzZXBwaWx1cnZlc3BhbmNha2VzfGd4OjcwNTJhNGQ5N2FkYTJiNQ see page 2-4], [https://docs.google.com/viewer?a=v&pid=sites&srcid=ZGVmYXVsdGRvbWFpbnxzZXBwaWx1cnZlc3BhbmNha2VzfGd4OjNhMzBjOGJiN2E4YjQ2OTg see P546]. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 18:17, 12 August 2014 (UTC)
+:::I've changed "normal development" to "normal brain development" and similarly tweaked the note added in the "Contraindications" section. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 06:54, 13 August 2014 (UTC)
+'''Side effects'''
+* “Amphetamine may reduce gastrointestinal motility (i.e., intestinal peristalsis) if intestinal activity is high, or increase motility if the smooth muscle of the tract is relaxed.” I have no idea what this sentence means. You do a really nice job explaining what “contraction of the urinary bladder sphincter” means in plain English earlier in this paragraph; I would use that as a model here. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 07:20, 11 August 2014 (UTC)
+::{{added}} clarification earlier - I forgot to reply here after I did this.  Please let me know if the current section is understandable! The current version:<blockquote>If intestinal activity is high, amphetamine may reduce [[gastrointestinal motility]], i.e., the rate at which content moves through the digestive system; however, amphetamine may increase motility when the [[smooth muscle tissue|smooth muscle]] of the tract is relaxed.</blockquote>[[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 18:19, 12 August 2014 (UTC)
+:::Much better. I've put the definition in parentheses. Personally, I'm curious to know ''what'' causes the smooth muscle of the gastrointestinal tract to relax, but I'm not sure if the average reader shares my interest. :) [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 07:02, 13 August 2014 (UTC)
+::::I'm not entirely sure to be honest.  The [[enteric nervous system]] isn't well understood at the moment. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 20:47, 15 August 2014 (UTC)
+'''Overdose'''
+'''Update''': I've finished going through the prose of the Overdose section, though I do plan to go through it again, as it's hard to catch everything the first time around. One general note: I have some issues with the organization of the section, particularly with the beginning and ending and with the subheadings. See the suggestions below. I would like to log in every day and keep an eye on developments here, but in reality we're probably looking at middle to end of next week or possible next weekend; I'm kind of busy through Wednesday. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 09:09, 14 September 2014 (UTC)
+:1. This section is technical enough that I think a introduction paragraph is warranted. Give the general reader the bottom line about the most effective treatments, give a simplified description of the bimolecular mechanism of addiction, ditto with psychosis, toxicity, and withdrawal. Don't make them go digging for what they're looking for, especially when some of the content is highly technical.
+:2. Also, I don't think the "Psychosis" and "Toxicity" sections are long enough to warrant their own level 3 headings when "Dependence and addiction" is a level 3 heading with five paragraphs and those two are half-paragraphs. I suggest either significant expansion, consolidation of the two into one level 3 heading subsection, or addition to the top of the section with the rest of the overdose symptoms.
+:3. Put the Overdose symptoms into a chart as we talked about above and then move the giant annotated image further down so we're not sandwiching text between images.
+:4. I have some more ideas for rearranging and adding/moving subsection headers, but I'll wait on those until we've decided what to do with the above three proposals. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 09:09, 14 September 2014 (UTC)
+{{anchor|previous}}
+::Most of that section is arranged according to [[MOS:MED#Drugs, medications and devices]] and a current proposal on MOS:MED's talkpage.  Addiction is in that section because the phenomenon only develops with chronic high-dose use; it literally requires a pathological overactivation of the mesolimbic DA pathway (either directly through DA receptors or indirectly through a possibly [http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 complex mechanism, e.g., alcohol]).  Toxicity is an indicated subsection of overdose, so it kind of needs to be there.  I could merge toxicity and psychosis into one section if you'd prefer. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 03:37, 11 October 2014 (UTC)
+And now for the prose comments for the rest of the section:
+*“Cognitive behavioral therapy” Could we give a brief definition in-text?
+::I'm not sure this would be easy for me to define succinctly... e.g., see [[Cognitive behavioral therapy#Description]].  I could probably define it in a note, I'd be more or less be restating parts of that section. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*“Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction” So even though it’s the most effective clinical treatment, isn’t that based on extremely limited evidence? Or does the Cochrane Collaboration review from the “Pharmacological treatments” subsection only refer to drugs?
+::Cochrane's review was just pharmacological therapy.[[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*The last sentence in the “Behavioral treatments” paragraph is pretty much unintelligible to the general reader. While I think the whole sentence is in need of some improvement, the very last part is the worst offender: I’ll start from the beginning of the sentence and take it by parts:
+*:1. “aerobic exercise decreases psychostimulant self-administration” I added a definition of self-administration in the above paragraph, so this is good.
+*:2. “attenuates sensitization to the rewarding effects of psychostimulants” So basically you don’t feel as good when you take the drug?
+:::I'm just deleting that clause because its explanation is a lot longer than the clause itself.  I'm not sure it affects reward perception necessarily; psychostimulant sensitization involves an increased of dopamine response in the nucleus accumbens from psychostimulant use, which increases the likelihood of developing an addiction.
+*:3. “reduces the reinstatement of drug-seeking behavior” So you’re less likely to relapse?
+:::Yep, I've noted this. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*:4. induces opposite effects on striatal dopamine receptor D2 signaling to those induced by pathological stimulant use.” What are the “opposite effects” on striatal dopamine receptor D2 signaling caused be aerobic exercise, and what are the effects caused by pathological stimulant use?
+::: I think I've addressed this. Let me know. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*“Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain.” Based on what I read later, I take it that “certain parts of the brain” really means the nucleus accumbens. How about “in certain parts of the brain, especially the nucleus accumbens”?
+:::{{Done}} [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*“The most important transcription factors” I would suggest adding a note explaining the role of transcription factors in gene expression.
+::{{in progress}} I need to find a MEDRS-quality source first, but I intend to do this. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+:::{{done}} Added this as a note next to the first use of the "transcription factor" phrase. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*“since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction” I assume you’re referencing necessary and sufficient cause here, but the fact that you neither mention the word “cause” nor link to [[Causality#Logic|Necessary and sufficient causes]] is cause for confusion. Also, why is ΔFosB considered a “necessary and sufficient cause” of these neural changes? And what are these neural adaptations, anyway? If the neural adaptations are talked about in the caption to the giant annotated image, you should add “(see caption below image to the right)” so people can read up on that if they want to.
+:::I meant to link to [[necessary and sufficient]]; I did it in other articles, but oddly enough, I missed it here.  Essentially it means that the plasticity of addiction and ΔFosB overexpression always occur together, never alone.  It's necessary and sufficient because it's been observed to produce this plasticity with viral overexpression (using [[viral vector]] gene transfer) and their occurrence doesn't occur with a viral block of ΔFosB expression (i.e., viral overexpression of ΔJunD opposes ΔFosB and hence this plasticity with concurrent drug use). This is rather technical - the reference that quotes that sentence explains it more. As for the plasticity, some of it is indicated in the psychostimulant column of the table below, which I've transcluded to several articles from [[FOSB]]. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+{{:FOSB|Table title=Summary of addiction-related plasticity|class=wikitable mw-collapsible mw-collapsed}}
+*“Since natural rewards induce ΔFosB just like drugs of abuse do” What does it mean that they “induce” ΔFosB? They cause the body to make more of it?
+:::It means it increases [[gene expression]] of ΔFosB. I've clarified this and linked to [[inducible gene]] with a pipe as "Since natural rewards [[inducible gene|induce expression]] of ΔFosB..." [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*“and amphetamine-induced sex addictions.” Do these amphetamine-induced sex addictions occur frequently at therapeutic and/or recreational doses? How does amphetamine cause sex addictions? Does an amphetamine-induced sex addiction mean that you’re addicted to both amphetamine and sex? I’m not harping on this just because it mentions sex; I feel that the sentence as is introduces a condition/disease without really explaining it.
+:::I clarified the text a little and added the appropriate quote to the reference ("In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex").  It's simply compulsive sexual behavior as a result of amphetamine use.  There is a notable interaction between reward perception with sexual behavior and amphetamine use, and an overactivation of DA networks involved in reward perception and reinforcement mediate that phenomenon.  I actually rewrote [[sex addiction]] recently to try to explain that concept better (and because I got into an edit war with another editor...). Let me know if you think it needs more work in the article. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*“Psychosis” subsection: I feel that the current length of this section doesn’t do the topic justice. We don’t need four full paragraphs about it, but how about 8-10 sentences instead of the current four?
+::I'll look through the Cochrane review soon and see if I can add more material.  Most of the content in the [[amphetamine psychosis]] section either isn't particularly relevant (e.g., first paragraph) or isn't cited by a MEDRS-quality source. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 03:47, 11 October 2014 (UTC)
+*“Toxicity” subsection: Same concern as with the Psychosis subsection. Again, I’d feel much more comfortable with the article’s comprehensiveness with 8-10 sentences here instead of three.
+::There really isn't much to say about amphetamine toxicity in humans.  Direct toxicity simply does not occur.  I could probably write a whole paper on direct DA toxicity in rats, but including that in the article would be sort of POV because it's misleading.  The mechanics of indirect toxicity are mediated entirely through oxidative events related to excessive dopamine release. I could probably add a sentence or two on its mechanics, but these are necessarily going to be fairly technical descriptions compared to the text currently in that section.  [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 03:47, 11 October 2014 (UTC)
+*Actually, as I come to think about it, how about we expand the above two subsections slightly, delete the subsection headings, and then move them to the topic of the section where the other overdose side-effects are found?
+::Due to the the MOS indications that I mentioned in a [[#previous]] bullet, and the points I raised in the above two bullets, it may be best to simply combine the two sections if you'd prefer to have fewer subsections under the Overdose heading. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+*“Manufacturer prescribing information does not indicate the presence” Which manufacturer? Or are we talking about US FDA prescribing regulations? I’m confused. [[User:AmericanLemming|AmericanLemming]] ([[User talk:AmericanLemming|talk]]) 09:09, 14 September 2014 (UTC)
+:::This actually refers to the prescribing information from all manufacturers of amphetamine pharmaceuticals.  The prescribing information is under copyright, and they vary in format, but they're pretty much standardized in the information in they provide (I can link you to a few examples for amphetamine pharmaceuticals on pubchem if you'd like to see what I mean), even though it is copyrighted. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']])
+::::{{ping|AmericanLemming}} I've pasted this from the review so that I can address/reply the points by issue here. I've added the table for the symptoms - let me know what you think. There was a small addition of content in the behavioral treatments section since you last checked it as well. [[User:Seppi333|'''<font color="#32CD32">Seppi</font>''<font color="Black">333</font>''''']]&nbsp;([[User Talk:Seppi333|Insert&nbsp;'''2¢''']]&nbsp;&#124;&nbsp;[[Special:WhatLinksHere/User:Seppi333/Maintenance|''Maintained'']]) 01:25, 11 October 2014 (UTC)
+{{collapsebottom}}
 '''Interactions'''