title: Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.
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.
authors.affiliation: 1] Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA. [2] Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA. [3].
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.forename: Paola
authors.initials: P
authors.lastname: Mascia
authors.forename: Hui-Qiu
authors.initials: HQ
authors.lastname: Wu
authors.forename: Maria E
authors.initials: ME
authors.lastname: Secci
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.forename: Leigh V
authors.initials: LV
authors.lastname: Panlilio
authors.forename: Maria
authors.initials: M
authors.lastname: Scherma
authors.forename: Chanel
authors.initials: C
authors.lastname: Barnes
authors.forename: Alexandra
authors.initials: A
authors.lastname: Parashos
authors.forename: Tamara
authors.initials: T
authors.lastname: Zara
authors.forename: Walter
authors.initials: W
authors.lastname: Fratta
authors.forename: Marcello
authors.initials: M
authors.lastname: Solinas
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
authors.forename: Jack
authors.initials: J
authors.lastname: Bergman
authors.forename: Brian D
authors.initials: BD
authors.lastname: Kangas
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000700:Analgesics / Q000008:administration & dosage; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage; D001921:Brain / Q000378:metabolism*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004192:Discrimination, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D058999:Drug-Seeking Behavior / Q000187:drug effects; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009025:Morpholines / Q000008:administration & dosage; D009281:Naphthalenes / Q000008:administration & dosage; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012453:Saimiri; D055502:Secondary Prevention; D012646:Self Administration; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014851:Wakefulness
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D007736:Kynurenic Acid