Central amygdala extracellular signal-regulated kinase signaling pathway is critical to incubation of opiate craving

J Neurosci. 2008 Dec 3;28(49):13248-57. doi: 10.1523/JNEUROSCI.3027-08.2008.

Abstract

Cue-induced drug-seeking in rodents progressively increases after withdrawal from operant self-administration of cocaine, heroin, methamphetamine, and alcohol, a phenomenon termed "incubation of drug craving." Here, we used the opiate drug morphine and explored whether incubation of drug craving also occurs in a pavlovian conditioned place preference (CPP) procedure in which rats learn to associate drug effects with a distinct environmental context. We also explored the role of amygdala extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in this incubation. We found that the expression of morphine CPP progressively increases over the first 14 d after the last drug exposure in rats receiving four pairings of low-dose (1 or 3 mg/kg) but not high-dose (10 mg/kg) morphine with a distinct environment. The progressive increase in low-dose (3 mg/kg) morphine CPP was associated with increased ERK phosphorylation (a measure of ERK activity) and CREB (a downstream target of ERK) phosphorylation in central but not basolateral amygdala. Furthermore, inhibition of central but not basolateral amygdala ERK and CREB phosphorylation by U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene] decreased the enhanced (incubated) drug CPP after 14 d of withdrawal from morphine. Finally, stimulation of central amygdala ERK and CREB phosphorylation by NMDA enhanced drug CPP after 1 d of withdrawal from morphine, an effect reversed by U0126. These findings indicate that the rat's response to environmental cues previously paired with morphine progressively increases or incubates over the first 14 d of withdrawal from low but not high morphine doses. Additionally, this "incubation of morphine craving" is mediated by acute activation of central amygdala ERK pathway.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects
  • Amygdala / enzymology*
  • Amygdala / physiopathology
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Butadienes / pharmacology
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Cues
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dose-Response Relationship, Drug
  • Environment
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Male
  • Morphine / pharmacology
  • Nitriles / pharmacology
  • Opioid-Related Disorders / enzymology*
  • Opioid-Related Disorders / physiopathology
  • Phosphorylation / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Recurrence
  • Time Factors

Substances

  • Analgesics, Opioid
  • Butadienes
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Nitriles
  • U 0126
  • Morphine
  • Extracellular Signal-Regulated MAP Kinases