Abstract
In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / administration & dosage
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Animals
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Benzoxazines / administration & dosage
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Brain / metabolism*
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Cannabinoid Receptor Agonists / pharmacology
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Conditioning, Operant / drug effects
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Cues
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Discrimination, Psychological / drug effects
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Dronabinol / pharmacology
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Drug-Seeking Behavior / drug effects
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Kynurenic Acid / metabolism*
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Male
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Memory, Short-Term / drug effects
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Morpholines / administration & dosage
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Naphthalenes / administration & dosage
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Rats
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Rats, Long-Evans
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Rats, Sprague-Dawley
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Reinforcement, Psychology
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Saimiri
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Secondary Prevention
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Self Administration
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Substance-Related Disorders* / drug therapy
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Substance-Related Disorders* / metabolism
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Substance-Related Disorders* / pathology
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Sulfonamides / pharmacology
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Thiazoles / pharmacology
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Time Factors
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Wakefulness
Substances
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Analgesics
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Benzoxazines
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Cannabinoid Receptor Agonists
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Morpholines
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Naphthalenes
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Ro 61-8048
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Sulfonamides
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Thiazoles
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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Dronabinol
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Kynurenic Acid