Signaling through nicotinic acetylcholine receptors (nAChRs) plays a role in cocaine reward and reinforcement, suggesting that the cholinergic system could be manipulated with therapeutics to modulate aspects of cocaine use disorder (CUD). We examined the interaction between nAChRs and cocaine reinforcement by expressing a hypersensitive β2 nAChR subunit (β2Leu9′Ser) in the ventral tegmental area of male Sprague Dawley rats. Compared to control rats, β2Leu9′Ser rats acquired (fixed ratio) intravenous cocaine self-administration faster and with greater likelihood. By contrast, β2Leu9′Ser rats were approximately equivalent to controls in their intake of cocaine on a progressive ratio schedule of reinforcement, suggesting differential effects of cholinergic signaling depending on experimental parameters. Like progressive ratio cocaine SA, β2Leu9′Ser rats and controls did not differ significantly in food SA assays, including acquisition on a fixed ratio schedule or in progressive ratio sessions. These results highlight the specific role of high-affinity, heteropentameric β2* (β2-containing) nAChRs in acquisition of cocaine SA, suggesting that mesolimbic acetylcholine signaling is active during this process.

中文翻译：

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β2* nAChR 敏感性调节雄性大鼠自我给药可卡因的获得

通过烟碱乙酰胆碱受体（nAChR）发出的信号在可卡因奖赏和强化中发挥作用，这表明胆碱能系统可以通过治疗来调节可卡因使用障碍（CUD）的各个方面。我们通过在雄性 Sprague Dawley 大鼠的腹侧被盖区表达超敏 β2 nAChR 亚基 (β2Leu9'Ser) 来研究 nAChR 与可卡因强化之间的相互作用。与对照大鼠相比，β2Leu9'Ser 大鼠更快且更有可能获得（固定比例）静脉注射可卡因自我给药。相比之下，β2Leu9'Ser 大鼠在按渐进比例强化方案摄入可卡因方面与对照组大致相当，这表明胆碱能信号传导的差异效应取决于实验参数。与渐进比例可卡因 SA 一样，β2Leu9'Ser 大鼠和对照组在食物 SA 测定中没有显着差异，包括按固定比例计划或渐进比例会话采集。这些结果强调了高亲和力、异五聚体 β2*（含 β2）nAChR 在获取可卡因 SA 中的特定作用，表明中脑边缘乙酰胆碱信号传导在此过程中活跃。