Fu Yixin, Li Wenfu, Mai Yunlin, Guan Junhao, Ding Ruxuan, Hou Jiawei, Chen Bingqing, Cao Guoxin, Sun Shizhu, Tang Ying, Fu Rao
Department of Anatomy, School of Medicine, Sun Yat-Sen University, Shenzhen 518106, China.
Clinical Skills Training Center, School of Medicine, Sun Yat-Sen University, Shenzhen 518106, China.
Int J Mol Sci. 2024 Mar 2;25(5):2933. doi: 10.3390/ijms25052933.
Alcohol use disorders (AUDs) frequently co-occur with negative mood disorders, such as anxiety and depression, exacerbating relapse through dopaminergic dysfunction. Stress-related neuropeptides play a crucial role in AUD pathophysiology by modulating dopamine (DA) function. The rostromedial tegmental nucleus (RMTg), which inhibits midbrain dopamine neurons and signals aversion, has been shown to increase ethanol consumption and negative emotional states during abstinence. Despite some stress-related neuropeptides acting through the RMTg to affect addiction behaviors, their specific roles in alcohol-induced contexts remain underexplored. This study utilized an intermittent voluntary drinking model in mice to induce negative effect behavior 24 h into ethanol (EtOH) abstinence (post-EtOH). It examined changes in pro-stress (, , ) and anti-stress (, , , , ) neuropeptide-coding genes and analyzed their correlations with aversive behaviors. We observed that adult male C57BL/6J mice displayed evident anxiety, anhedonia, and depression-like symptoms at 24 h post-EtOH. The laser-capture microdissection technique, coupled with or without retrograde tracing, was used to harvest total ventral tegmental area (VTA)-projecting neurons or the intact RMTg area. The findings revealed that post-EtOH consistently reduced and levels while elevating levels in these neuronal populations. Notably, RMTg and levels counteracted ethanol consumption and depression severity, while levels were indicative of the mice's anxiety levels. Together, these results underscore the potential role of stress-related neuropeptides in the RMTg in regulating the negative emotions related to AUDs, offering novel insights for future research.
酒精使用障碍（AUDs）常与焦虑和抑郁等负性情绪障碍同时出现，通过多巴胺能功能障碍加剧复发。应激相关神经肽通过调节多巴胺（DA）功能在AUD病理生理学中起关键作用。嘴内侧被盖核（RMTg）抑制中脑多巴胺神经元并发出厌恶信号，已被证明在戒酒期间会增加乙醇摄入量和负性情绪状态。尽管一些应激相关神经肽通过RMTg发挥作用影响成瘾行为，但它们在酒精诱导情境中的具体作用仍未得到充分探索。本研究利用小鼠间歇性自愿饮酒模型，在乙醇（EtOH）戒断24小时（戒断EtOH后）诱导负性效应行为。研究了促应激（ 、 、 ）和抗应激（ 、 、 、 、 ）神经肽编码基因的变化，并分析了它们与厌恶行为的相关性。我们观察到成年雄性C57BL/6J小鼠在戒断EtOH后24小时表现出明显的焦虑、快感缺失和抑郁样症状。激光捕获显微切割技术结合或不结合逆行追踪，用于收集投射到腹侧被盖区（VTA）的全部神经元或完整的RMTg区域。研究结果显示，戒断EtOH后，这些神经元群体中的 和 水平持续降低，而 水平升高。值得注意的是，RMTg中的 和 水平抵消了乙醇摄入量和抑郁严重程度，而 水平则表明了小鼠的焦虑水平。总之，这些结果强调了RMTg中应激相关神经肽在调节与AUDs相关的负性情绪中的潜在作用，为未来研究提供了新的见解。
