Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

Justinova Z;Mascia P;Wu HQ;Secci ME;Redhi GH;Panlilio LV;SCHERMA, MARIA;Barnes C;Parashos A;Zara T;FRATTA, WALTER;Solinas M;PISTIS, MARCO;Bergman J;Kangas BD;Ferré S;Tanda G;Schwarcz R;Goldberg S.R.

2013-01-01

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Abstract

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ9-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.