Sharma Rishi, Chischolm Abigail, Parikh Meet, Thakkar Mahesh
Harry S. Truman Memorial Veterans Hospital and Department of Neurology, University of Missouri, Columbia, Missouri, USA.
Alcohol Clin Exp Res (Hoboken). 2024 May;48(5):827-842. doi: 10.1111/acer.15295. Epub 2024 Mar 29.
Binge drinking, characterized by heavy episodic alcohol consumption, poses significant health hazards and increases the likelihood of developing an alcohol use disorder (AUD). Given the growing prevalence of this behavior and its negative consequences, there is a need to explore novel therapeutic targets. Accumulating evidence suggests that cholinergic interneurons (CIN) within the shell region of the nucleus accumbens (NAcSh) play a critical role in reward and addiction. However, their specific involvement in binge alcohol administration remains unclear. We hypothesized that CIN in the NAcSh regulates binge alcohol consumption.
To test this hypothesis, we used male ChAT-cre mice expressing Cre-recombinase in cholinergic neurons. We performed chemogenetic manipulation using Designer Receptor Exclusively Activated by Designer Drugs (DREADD) to examine the activity, and genetic ablation of CIN in the NAcSh to examine the amount of alcohol consumed in mice exposed to binge alcohol consumption using the 4-Days Drinking-in-Dark (DID) paradigm. The impact of CIN manipulations in the NAcSh on sucrose self-administration was used to control for taste and caloric effects. Additionally, in a separate group of mice, c-Fos immunofluorescence was employed to verify chemogenetic activation or inhibition. Histological and immunohistochemical techniques were used to verify microinfusion sites, DREADD expression in CINs, and genetic ablation.
We found that, while chemogenetic activation of CIN in the NAcSh caused a significant increase in alcohol consumption, chemogenetic inhibition or genetic ablation of CIN significantly reduced the amount of alcohol consumed without affecting sucrose self-administration. The chemogenetic inhibition caused a significant reduction, whereas activation caused a significant increase, in the number of c-Fos-labeled CIN in the NAcSh.
Our findings highlight the crucial involvement of CIN in the NAcSh in modulating binge alcohol consumption, suggesting that targeting these neurons could serve to modify alcohol-related behaviors.
暴饮，其特征为大量间歇性饮酒，会带来重大健康危害，并增加患酒精使用障碍（AUD）的可能性。鉴于这种行为的患病率不断上升及其负面后果，有必要探索新的治疗靶点。越来越多的证据表明，伏隔核壳区（NAcSh）内的胆碱能中间神经元（CIN）在奖赏和成瘾中起关键作用。然而，它们在暴饮酒精中的具体作用仍不清楚。我们假设NAcSh中的CIN调节暴饮酒精的摄入量。
为了验证这一假设，我们使用了在胆碱能神经元中表达Cre重组酶的雄性ChAT-cre小鼠。我们使用仅由设计药物激活的设计受体（DREADD）进行化学遗传操作以检查活性，并对NAcSh中的CIN进行基因消融，以使用4天暗箱饮酒（DID）范式检查暴露于暴饮酒精的小鼠的酒精摄入量。通过NAcSh中CIN操作对蔗糖自我给药的影响来控制味觉和热量效应。此外，在另一组小鼠中，采用c-Fos免疫荧光来验证化学遗传激活或抑制。使用组织学和免疫组织化学技术来验证微量注射部位、CINs中的DREADD表达以及基因消融。
我们发现，虽然NAcSh中CIN的化学遗传激活导致酒精摄入量显著增加，但CIN的化学遗传抑制或基因消融显著减少了酒精摄入量，而不影响蔗糖自我给药。化学遗传抑制导致NAcSh中c-Fos标记的CIN数量显著减少，而激活则导致显著增加。
我们的研究结果突出了NAcSh中的CIN在调节暴饮酒精摄入量方面的关键作用，表明靶向这些神经元可能有助于改变与酒精相关的行为。
