期刊
NATURE NEUROSCIENCE
卷 16, 期 11, 页码 1652-1661出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3540
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资金
- National Institute on Drug Abuse (NIDA), National Institutes of Health, Department of Health and Human Services, NIDA Residential Research Support Services [N01 DA59909]
- Italian Ministry of University and Scientific Research [DA023142, DA035974]
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine
- Regione Autonoma della Sardegna
- European Social Fund [LR7 2007]
In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (alpha 7nAChRs) modulate effects of Delta(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of alpha 7nAChRs. 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 alpha 7nAChRs. 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.
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