Justinova, ZuzanaMascia, PaolaWu, Hui-QiuSecci, Maria E.Redhi, Godfrey H.Panlilio, Leigh V.Scherma, MariaBarnes, ChanelParashos, AlexandraZara, TamaraFratta, WalterSolinas, MarcelloPistis, MarcoBergman, JackKangas, BrianFerré, SergiTanda, GianluigiSchwarcz, RobertGoldberg, Steven R.2014-07-072013Justinova, Z., P. Mascia, H. Wu, M. E. Secci, G. H. Redhi, L. V. Panlilio, M. Scherma, et al. 2013. “Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.” Nature neuroscience 16 (11): 10.1038/nn.3540. doi:10.1038/nn.3540. http://dx.doi.org/10.1038/nn.3540.1097-6256http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406984In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-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 re-exposure 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 currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse.en-USJournal Article2014-07-0710.1038/nn.3540