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

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 kynur...

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Autores principales: Justinova, Zuzana, Mascia, Paola, Wu, Hui-Qiu, Secci, Maria E., Redhi, Godfrey H., Panlilio, Leigh V., Scherma, Maria, Barnes, Chanel, Parashos, Alexandra, Zara, Tamara, Fratta, Walter, Solinas, Marcello, Pistis, Marco, Bergman, Jack, Kangas, Brian D., Ferré, Sergi, Tanda, Gianluigi, Schwarcz, Robert, Goldberg, Steven R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835353/
https://www.ncbi.nlm.nih.gov/pubmed/24121737
http://dx.doi.org/10.1038/nn.3540
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author Justinova, Zuzana
Mascia, Paola
Wu, Hui-Qiu
Secci, Maria E.
Redhi, Godfrey H.
Panlilio, Leigh V.
Scherma, Maria
Barnes, Chanel
Parashos, Alexandra
Zara, Tamara
Fratta, Walter
Solinas, Marcello
Pistis, Marco
Bergman, Jack
Kangas, Brian D.
Ferré, Sergi
Tanda, Gianluigi
Schwarcz, Robert
Goldberg, Steven R.
author_facet Justinova, Zuzana
Mascia, Paola
Wu, Hui-Qiu
Secci, Maria E.
Redhi, Godfrey H.
Panlilio, Leigh V.
Scherma, Maria
Barnes, Chanel
Parashos, Alexandra
Zara, Tamara
Fratta, Walter
Solinas, Marcello
Pistis, Marco
Bergman, Jack
Kangas, Brian D.
Ferré, Sergi
Tanda, Gianluigi
Schwarcz, Robert
Goldberg, Steven R.
author_sort Justinova, Zuzana
collection PubMed
description 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.
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spelling pubmed-38353532014-05-01 Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid Justinova, Zuzana Mascia, Paola Wu, Hui-Qiu Secci, Maria E. Redhi, Godfrey H. Panlilio, Leigh V. Scherma, Maria Barnes, Chanel Parashos, Alexandra Zara, Tamara Fratta, Walter Solinas, Marcello Pistis, Marco Bergman, Jack Kangas, Brian D. Ferré, Sergi Tanda, Gianluigi Schwarcz, Robert Goldberg, Steven R. Nat Neurosci Article 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. 2013-10-13 2013-11 /pmc/articles/PMC3835353/ /pubmed/24121737 http://dx.doi.org/10.1038/nn.3540 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Justinova, Zuzana
Mascia, Paola
Wu, Hui-Qiu
Secci, Maria E.
Redhi, Godfrey H.
Panlilio, Leigh V.
Scherma, Maria
Barnes, Chanel
Parashos, Alexandra
Zara, Tamara
Fratta, Walter
Solinas, Marcello
Pistis, Marco
Bergman, Jack
Kangas, Brian D.
Ferré, Sergi
Tanda, Gianluigi
Schwarcz, Robert
Goldberg, Steven R.
Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
title Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
title_full Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
title_fullStr Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
title_full_unstemmed Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
title_short Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
title_sort reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835353/
https://www.ncbi.nlm.nih.gov/pubmed/24121737
http://dx.doi.org/10.1038/nn.3540
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