Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior
Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior
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DOI：
10.1007/s00213-008-1375-5
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发表时间：
2009-03-01
影响因子：
3.4
通讯作者：
Engel, Jorgen
中科院分区：
文献类型：
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作者：
Kuzmin, Alexander;Jerlhag, Elisabet;Engel, Jorgen
对乙醇中枢作用的敏感性部分取决于脑烟碱乙酰胆碱受体 (nAChR) 的亚基组成。因此，腹侧被盖区（VTA）施用烟碱亚基特异性拮抗剂α-芋螺毒素MII（α CtxMII，α（3）β（2）*，β（3）*，α（6）*）的效果与全身美加明（MEC，nAChR的变构负调节剂），二氢-β-赤霉素（DH beta E， α(4)β(2)*) 和甲基利卡乌头碱 (MLA, α(7)*) 阐明 nAChR 的不同亚基在大鼠乙醇剥夺后操作性乙醇自我给药和乙醇消耗的复发样激活中的参与。在接受操作性口服自我给药乙醇训练的大鼠 (FR = 1) 中研究了药物的作用。对于乙醇剥夺，训练有素的动物要经历 10 天的乙醇剥夺期。 α CtxMII 通过植入的永久性颅内插管直接注入 VTA，而 MEC、DH beta E 和 MLA 则进行全身给药。α CtxMII 减少了操作性乙醇的自我给药，并阻止了剥夺诱导的类似复发的乙醇消耗。 MEC 减少了操作性乙醇的自我施用并抑制了剥夺引起的酒精消耗的增加。 DH beta E 在较低剂量范围内不会改变乙醇的自我给药，但会在较高剂量（4 mg/kg）时抑制乙醇摄入，尽管这种作用可能是非特异性的。 MLA 未能阻止剥夺后的自我饮酒和复发样饮酒行为。我们的结果表明，nAChR 参与了大鼠操作性酒精自我给药和复发样饮酒行为的调节。我们的观察结果支持这样的工作假设：nAChR α(3)β(2)*、β(3) 和/或 α(6)* 受体亚基的系统活性选择性配体可能对治疗酒精中毒具有治疗价值。
The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, alpha-conotoxin MII (alpha CtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-beta-erythroidine (DH beta E, alpha(4)beta(2)*), and methyllycaconitine (MLA, alpha(7)*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats.The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. alpha CtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DH beta E, and MLA were administered systemically.alpha CtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DH beta E did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation.Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism.