Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
| Autor: | Robert Schwarcz, Walter Fratta, Gianluigi Tanda, Jack Bergman, Chanel Barnes, Paola Mascia, Tamara Zara, Zuzana Justinova, Sergi Ferré, Godfrey H. Redhi, Brian D. Kangas, Maria Scherma, Hui-Qiu Wu, Leigh V. Panlilio, Marcello Solinas, Marco Pistis, Alexandra Parashos, Maria E Secci, Steven R. Goldberg |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Drug Time Factors Substance-Related Disorders Morpholines medicine.medical_treatment media_common.quotation_subject Drug-Seeking Behavior Self Administration Endogeny Naphthalenes Pharmacology Kynurenic Acid Article Rats Sprague-Dawley chemistry.chemical_compound Discrimination Psychological Kynurenic acid mental disorders Secondary Prevention medicine Animals Rats Long-Evans Dronabinol Wakefulness Saimiri Acetylcholine receptor media_common Cannabinoid Receptor Agonists Analgesics Sulfonamides Dose-Response Relationship Drug organic chemicals General Neuroscience Addiction Brain Endogenous modulator Benzoxazines Rats Disease Models Animal Thiazoles Memory Short-Term chemistry Conditioning Operant Cannabinoid Cues Psychology Reinforcement Psychology Neuroscience |
| Zdroj: | Nature neuroscience |
| ISSN: | 1546-1726 1097-6256 |
| Popis: | In 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. |
| Databáze: | OpenAIRE |
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