Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.
Zuzana Justinova, Paola Mascia, Hui-Qiu Wu, Maria E Secci, Godfrey H Redhi, Leigh V Panlilio, Maria Scherma, Chanel Barnes, Alexandra Parashos, Tamara Zara, Walter Fratta, Marcello Solinas, Marco Pistis, Jack Bergman, Brian D Kangas, Sergi Ferré, Gianluigi Tanda, Robert Schwarcz, Steven R Goldberg
Nature Neuroscience November 2013 DOI: 10.1038/nn.3540 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Squirrel monkeys and rats |
| Interventions | Ro 61-8048 THC WIN 55 212-2 |
| Key points | The KMO inhibitor Ro 61-8048 increased brain KYNA levels, attenuated cannabinoid-induced dopamine increases in reward-related areas, reduced self-administration of THC and WIN 55,212-2, and prevented relapse to drug-seeking induced by cannabinoids or associated cues; these effects were blocked by α7nAChR positive allosteric modulators. The authors propose that modulating KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse. |
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.
Citations in the library
Cited by 5
- Effects of nicotinic receptor antagonism on nicotine and THC self-administration in a model of polysubstance use The International Journal of Neuropsychopharmacology April 1, 2026
- Chronic Δ9-tetrahydrocannabinol exposure in adolescent nonhuman primates: persistent abnormalities in economic demand and brain functional connectivity. Neuropsychopharmacology February 1, 2025
- Risks and Benefits of Cannabis and Cannabinoids in Psychiatry. American Journal of Psychiatry February 2022
- Astrocytic Mechanisms Involving Kynurenic Acid Control Δ9-Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas. Molecular Neurobiology May 2019
- Effects of Adolescent Cannabinoid Self-Administration in Rats on Addiction-Related Behaviors and Working Memory. Neuropsychopharmacology April 2017
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