Solinas Marcello, Scherma Maria, Fattore Liana, Stroik Jessica, Wertheim Carrie, Tanda Gianluigi, Fratta Walter, Goldberg Steven R
Institut de Biologie et Physiologie Cellulaires, Centre National de la Recherche Scientifique-6187, University of Poitiers, 86022 Poitiers, France.
J Neurosci. 2007 May 23;27(21):5615-20. doi: 10.1523/JNEUROSCI.0027-07.2007.
Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric alpha7 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 alpha7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-alpha7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, (1) antagonized the discriminative effects of delta-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 alpha7 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 alpha7 nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans.
大麻使用的日益增加使得寻找减少大麻滥用的药物变得极其重要。在此，我们表明同聚体α7烟碱受体是新的分子实体，可作为开发治疗大麻依赖新药的靶点。在大鼠中，全身给予选择性α7烟碱乙酰胆碱受体拮抗剂甲基lycaconitine（MLA），而非选择性异聚体非α7烟碱乙酰胆碱受体拮抗剂二氢β-刺桐啶，（1）拮抗了大麻主要活性成分δ-9-四氢大麻酚（THC）的辨别效应，（2）减少了合成大麻素CB1受体激动剂WIN55,212-2 [（R）-（+）-[2,3-二氢-5-甲基-3-[(4-吗啉基)甲基]吡咯并[1,2,3-de]-1,4-苯并恶嗪基]-(1-萘基)甲酮，甲磺酸盐]的静脉自我给药，以及（3）降低了THC诱导的伏隔核壳中的多巴胺升高。总之，我们的结果表明阻断α7烟碱受体可逆转大麻素与滥用相关的行为和神经化学效应。重要的是，MLA在不产生抑制或毒性作用的剂量下逆转了大麻素的效应，进一步表明α7烟碱拮抗剂可能是治疗人类大麻滥用的有用药物。
