Brunke O R, Bonauto S M, Boshak E M, Rauch M J, Weera M M
Department of Psychology, Tufts University, Medford, MA.
Neuroscience Program, Graduate School of Biomedical Sciences, Tufts University, Boston, MA.
bioRxiv. 2025 May 28:2025.05.23.655819. doi: 10.1101/2025.05.23.655819.
Avoidance coping following stress exposure predicts heightened alcohol drinking. Similarly, blunted sensitivity to the aversive effects of alcohol facilitates increased drinking. However, the relationship between stress exposure, coping mechanism, and sensitivity to alcohol's aversive effects is unknown. In rats, predator odor stress increases alcohol intake in animals that show persistent avoidance of stress-paired stimuli, termed "Avoiders". Here, we tested the hypothesis that Avoider rats have blunted sensitivity to alcohol's aversive effects using an alcohol-induced conditioned taste aversion (CTA) paradigm. After a single conditioning session, Non-Avoider rats acquired alcohol-induced CTA while Avoiders did not. Male rats across all groups eventually acquired alcohol CTA after four conditioning sessions. However, in females, only Non-Avoiders acquired alcohol-induced CTA. In male Non-Avoider rats, a single CTA-inducing dose of alcohol increased cFos expression in the lateral habenula (LHb), an important nucleus in aversion signaling. In male Avoiders, the same dose of alcohol decreased LHb cFos expression. cFos expression in the lateral hypothalamus (LH), which provides glutamatergic inputs to the LHb, was also diminished by alcohol in male Avoider rats. In females, alcohol had no effect on cFos cell counts in the LHb. However, in the LH, alcohol diminished cFos expression in female Non-Avoiders. Collectively, these findings suggest that stressed Avoider rats are hyposensitive to alcohol's aversive effects, which may facilitate their heightened alcohol drinking after stress. Sex- and stress group-specific differences in LH and LHb recruitment highlight these regions as candidates for mediating stress-induced changes in alcohol behaviors.
应激暴露后的回避应对方式预示着饮酒量的增加。同样，对酒精厌恶效应的敏感性降低也会促使饮酒量增加。然而，应激暴露、应对机制与对酒精厌恶效应的敏感性之间的关系尚不清楚。在大鼠中，捕食者气味应激会增加那些持续回避应激配对刺激的动物（称为“回避者”）的酒精摄入量。在此，我们使用酒精诱导的条件性味觉厌恶（CTA）范式来检验回避者大鼠对酒精厌恶效应敏感性降低这一假说。经过单次条件训练后，非回避者大鼠获得了酒精诱导的CTA，而回避者大鼠则没有。所有组的雄性大鼠在经过四次条件训练后最终都获得了酒精CTA。然而，在雌性大鼠中，只有非回避者获得了酒精诱导的CTA。在雄性非回避者大鼠中，单次诱导CTA剂量的酒精会增加外侧缰核（LHb）中cFos的表达，LHb是厌恶信号传导中的一个重要核团。在雄性回避者中，相同剂量的酒精会降低LHb中cFos的表达。外侧下丘脑（LH）为LHb提供谷氨酸能输入，酒精也会降低雄性回避者大鼠LH中的cFos表达。在雌性大鼠中，酒精对LHb中cFos细胞计数没有影响。然而，在LH中，酒精会降低雌性非回避者的cFos表达。总的来说，这些发现表明，处于应激状态的回避者大鼠对酒精的厌恶效应反应迟钝，这可能促使它们在应激后饮酒量增加。LH和LHb募集的性别及应激组特异性差异突出了这些区域作为介导应激诱导酒精行为变化候选区域的可能性。
