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The Journal of Neuroscience, May 23, 2007, 27(21):5615-5620; doi:10.1523/JNEUROSCI.0027-07.2007

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Brief Communications
Nicotinic ₇ Receptors as a New Target for Treatment of Cannabis Abuse

Marcello Solinas,^1,2 Maria Scherma,^2,4 Liana Fattore,⁵ Jessica Stroik,² Carrie Wertheim,² Gianluigi Tanda,³ Walter Fratta,⁴ and Steven R. Goldberg²

¹Institut de Biologie et Physiologie Cellulaires, Centre National de la Recherche Scientifique-6187, University of Poitiers, 86022 Poitiers, France, ²Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, and ³Psychobiology Section, Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, ⁴B. B. Brodie Department of Neuroscience, University of Cagliari, 09024 Cagliari, Italy, and ⁵Institute of Neuroscience, National Research Council, Consiglio Nazionale delle Ricerche Italy, 09024 Cagliari, Italy

Correspondence should be addressed to Steven R. Goldberg, Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224. Email: sgoldber{at}intra.nida.nih.gov

Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric ₇ nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective ₇ nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-₇ nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, (1) antagonized the discriminative effects of -9-tetrahydrocannabinol (THC), the main active ingredient in cannabis, (2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone, mesylate salt], and (3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of ₇ nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to ₇ nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans.

Key words: abuse; acetylcholine receptor; cannabinoids; dopamine; behavior; nucleus accumbens

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Received Jan. 4, 2007; revised March 28, 2007; accepted April 17, 2007.

Correspondence should be addressed to Steven R. Goldberg, Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224. Email: sgoldber{at}intra.nida.nih.gov

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