Center for Social and Affective Neuroscience, BKV, Linköping University, Linköping, S-581 85, Sweden.
Psychosomatic Medicine Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, China.
Br J Pharmacol. 2020 Oct;177(19):4516-4531. doi: 10.1111/bph.15210. Epub 2020 Aug 14.
Alcohol and nicotine use disorders are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of μ and κ-opioid receptors to nicotine-induced escalation of alcohol self-administration in rats.
Chronic nicotine was tested on alcohol self-administration and motivation to obtain alcohol. We then tested the effect of the κ antagonist CERC-501 and the preferential μ receptor antagonist naltrexone on basal and nicotine-escalated alcohol self-administration. To probe μ or κ receptor adaptations, receptor binding and G-protein coupling assays were performed in reward-related brain regions. Finally, dopaminergic activity in response to alcohol was examined, using phosphorylation of DARPP-32 in nucleus accumbens as a biomarker.
Nicotine robustly induced escalation of alcohol self-administration and motivation to obtain alcohol. This was blocked by naltrexone but not by CERC-501. Escalation of alcohol self-administration was associated with decreased DAMGO-stimulated μ receptor signalling in the ventral tegmental area (VTA) and decreased pDARPP-32 in the nucleus accumbens shell in response to alcohol.
Collectively, these results suggest that nicotine contributes to escalate alcohol self-administration through a dysregulation of μ receptor activity in the VTA. These data imply that targeting μ rather than κ receptors may be the preferred pharmacotherapeutic approach for the treatment of alcohol use disorder when nicotine use contributes to alcohol consumption.
酒精和尼古丁使用障碍通常同时存在。酒精和尼古丁都可以激活与奖赏相关的大脑区域中的阿片系统，导致慢性暴露后阿片信号发生适应性变化。这些适应性变化对共病的潜在作用目前尚不清楚。在这里，我们研究了μ和κ阿片受体在大鼠尼古丁诱导酒精自我给药增加中的作用。
在酒精自我给药和获取酒精的动机方面测试了慢性尼古丁。然后，我们测试了κ拮抗剂 CERC-501 和选择性μ受体拮抗剂纳曲酮对基础和尼古丁递增的酒精自我给药的影响。为了探究μ或κ受体的适应性，在与奖赏相关的脑区中进行了受体结合和 G 蛋白偶联测定。最后，使用伏隔核中 DARPP-32 的磷酸化作为生物标志物，检测了多巴胺能活性对酒精的反应。
尼古丁强烈诱导酒精自我给药和获取酒精的动机增加。纳曲酮可阻断这种作用，但 CERC-501 则不能。酒精自我给药的增加与腹侧被盖区（VTA）中 DAMGO 刺激的μ受体信号降低以及酒精刺激下伏隔核壳中的 pDARPP-32 减少有关。
综上所述，这些结果表明，尼古丁通过 VTA 中μ受体活性的失调促进酒精自我给药的增加。这些数据表明，当尼古丁的使用促进酒精的摄入时，针对μ受体而不是κ受体可能是治疗酒精使用障碍的首选药物治疗方法。
