Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden.
Addict Biol. 2020 Sep;25(5):e12807. doi: 10.1111/adb.12807. Epub 2019 Jul 10.
Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small effect sizes, and improved treatments are needed. Smoking and AUD share heritability and are pharmacologically associated, since drug-induced dopamine (DA) output in nucleus accumbens (nAc) involves nicotinic acetylcholine receptors (nAChRs) in both cases. Smoking therapy agents, such as the partial nAChR agonist varenicline or the DA/noradrenaline transporter inhibitor bupropion, could potentially also be used for AUD. To investigate this hypothesis, the effects of varenicline, bupropion, or a combination of the two on nAc DA levels, ethanol intake, and the alcohol deprivation effect (ADE) were examined. In vivo microdialysis showed that varenicline (1.5 mg/kg) and bupropion (2.5, 5, or 10 mg/kg) elevated nAc DA levels and that the combination produced additive effects. Five days treatment with varenicline, bupropion, or the combination did not suppress ethanol consumption, as compared with vehicle-treated control. However, combined administration of varenicline and bupropion completely blocked the ADE when readministering ethanol following 14 days of abstinence. Since ADE is considered highly predictive for the clinical outcome in man, our data suggest that the combination of varenicline and bupropion could be a promising treatment for AUD.
酒精使用障碍（AUD）对健康有害，并导致早产死亡。不幸的是，现有的药理学和非药理学治疗方法的效果较小，需要改进的治疗方法。吸烟和 AUD 具有遗传相关性，并且在药理学上相关，因为在这两种情况下，药物诱导的伏隔核（nAc）中的多巴胺（DA）输出都涉及烟碱型乙酰胆碱受体（nAChRs）。吸烟治疗剂，如部分 nAChR 激动剂伐仑克林或多巴胺/去甲肾上腺素转运体抑制剂安非他酮，也可能用于 AUD。为了验证这一假设，研究了伐仑克林、安非他酮或两者联合应用对 nAc DA 水平、乙醇摄入和酒精剥夺效应（ADE）的影响。体内微透析显示，伐仑克林（1.5mg/kg）和安非他酮（2.5、5 或 10mg/kg）可升高 nAc DA 水平，且联合用药具有相加作用。与接受载体治疗的对照组相比，5 天的伐仑克林、安非他酮或联合治疗并没有抑制乙醇的消耗。然而，在 14 天的禁欲后重新给予乙醇时，联合使用伐仑克林和安非他酮完全阻断了 ADE。由于 ADE 被认为对人类的临床结果具有高度预测性，我们的数据表明，伐仑克林和安非他酮的联合应用可能是 AUD 的一种有前途的治疗方法。
