Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA.
Center for Drug & Alcohol Programs, Medical University of South Carolina, Charleston, SC, 29425, USA.
Neuropsychopharmacology. 2019 Oct;44(11):1896-1905. doi: 10.1038/s41386-019-0406-8. Epub 2019 May 6.
Acute withdrawal from alcohol is associated with a number of unpleasant symptoms that play an important role in preventing recovery and long-term abstinence. Considerable research has focused on the role that neuropeptide systems and the amygdala play in mediating affective symptoms of acute withdrawal, but promising preclinical findings have not translated successfully into the clinic. The rostromedial tegmental nucleus (RMTg) has been implicated in both fear and anxiety. In addition, RMTg neurons exert inhibitory control over midbrain dopamine neurons, the activity of which are suppressed during acute withdrawal. Thus, we hypothesized that the RMTg may play a role in mediating symptoms of acute withdrawal. Using a chronic ethanol vapor exposure paradigm that renders rats physically dependent on ethanol, we observed significant withdrawal-induced enhancement of cFos expression in the RMTg. This was accompanied by a significant increase in somatic symptoms and a decrease in reward sensitivity as measured by intracranial self-stimulation (ICSS). Both measures followed a similar time course to RMTg cFos expression with peak symptom severity occurring 12 h following cessation of ethanol exposure. Heightened anxiety-like behavior was also observed in withdrawn rats at this same time point. RMTg inhibition had no effect on somatic signs of withdrawal or withdrawal-induced changes in reward sensitivity, but significantly attenuated withdrawal-induced anxiety-like behavior. Together, these data demonstrate that the RMTg plays a distinct role in the negative affective state associated with acute withdrawal and may therefore be critically involved in the neurobiological mechanisms that promote relapse during early stages of recovery.
急性酒精戒断与许多不愉快的症状有关，这些症状在预防康复和长期戒除方面起着重要作用。大量研究集中在神经肽系统和杏仁核在介导急性戒断的情感症状方面的作用，但有希望的临床前发现并没有成功转化为临床应用。穹窿脚吻侧核（RMTg）在恐惧和焦虑中都有涉及。此外，RMTg 神经元对中脑多巴胺神经元发挥抑制性控制，这些神经元在急性戒断期间的活动受到抑制。因此，我们假设 RMTg 可能在介导急性戒断症状中发挥作用。使用一种慢性乙醇蒸气暴露范式，使大鼠对乙醇产生身体依赖性，我们观察到 RMTg 中 cFos 表达在戒断后显著增强。这伴随着躯体症状的显著增加和颅内自我刺激（ICSS）测量的奖励敏感性下降。这两个测量都与 RMTg cFos 表达的相似时间过程相关，最大症状严重程度发生在乙醇暴露停止后 12 小时。在同一时间点，也观察到戒断大鼠出现焦虑样行为加剧。RMTg 抑制对戒断后的躯体症状或戒断引起的奖励敏感性变化没有影响，但显著减轻了戒断引起的焦虑样行为。总之，这些数据表明 RMTg 在与急性戒断相关的负面情感状态中起着独特的作用，因此可能与恢复早期促进复发的神经生物学机制密切相关。
