Department of Anesthesiology, Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Ave, Newark, NJ, 07103, USA.
Neuropsychopharmacology. 2019 Jul;44(8):1464-1475. doi: 10.1038/s41386-019-0378-8. Epub 2019 Mar 31.
Rostromedial tegmental nucleus (RMTg) GABA neurons exert a primary inhibitory drive onto midbrain dopamine neurons and are excited by a variety of aversive stimuli. There is, however, little evidence that the RMTg-ventral tegmental area (VTA)-nucleus accumbens shell (Acb) circuit plays a role in the aversive consequences of alcohol withdrawal. This study was performed in adult male Long-Evans rats at 48-h withdrawal from chronic alcohol drinking in the intermittent schedule. These rats displayed clear anhedonia and depression-like behaviors, as measured with the sucrose preference, and forced swimming tests. These aberrant behaviors were accompanied by a substantial increase in cFos expression in the VTA-projecting RMTg neurons, identified by a combination of immunohistochemistry and retrograde-tracing techniques. Pharmacological or chemogenetic inhibition of RMTg neurons mitigated the anhedonia and depression-like behaviors. Ex vivo electrophysiological data showed that chemogenetic inactivation of RMTg neurons reduced GABA release and accelerated spontaneous firings of VTA dopamine neurons. Finally, using a functional hemispheric disconnection procedure, we demonstrated that inhibition of unilateral RMTg, when combined with activation of D1 and D2 dopamine receptors in the contralateral (but not ipsilateral) Acb, mitigated the anhedonia and depression-like behaviors in alcohol-withdrawal rats. These data show that the integrity in the RMTg-VTA-Acb pathway in a single hemisphere is sufficient to elicit depression-like behavior during ethanol-withdrawal. Overall, the present results reveal that the RMTg-VTA-Acb pathway plays a crucial role in the depression-like behavior in animals undergoing alcohol withdrawal, further advocating the RMTg as a potential therapeutic target for alcoholism.
中脑被盖腹侧区（RMTg）GABA 神经元对中脑多巴胺神经元施加主要的抑制性驱动，并被各种厌恶刺激所兴奋。然而，几乎没有证据表明 RMTg-腹侧被盖区（VTA）-伏隔核壳（Acb）回路在酒精戒断的厌恶后果中发挥作用。这项研究是在成年雄性长耳大仓鼠慢性酒精间歇摄取 48 小时戒断后进行的。这些大鼠表现出明显的快感缺失和抑郁样行为，如蔗糖偏好和强迫游泳测试所测量的。这些异常行为伴随着 VTA 投射的 RMTg 神经元中 cFos 表达的大量增加，这是通过免疫组织化学和逆行追踪技术相结合来确定的。RMTg 神经元的药理学或化学遗传抑制减轻了快感缺失和抑郁样行为。离体电生理数据表明，RMTg 神经元的化学遗传失活减少了 GABA 的释放并加速了 VTA 多巴胺神经元的自发放电。最后，使用功能半球分离程序，我们证明了单侧 RMTg 的抑制，与对侧（但不是同侧）Acb 中的 D1 和 D2 多巴胺受体的激活相结合，减轻了酒精戒断大鼠的快感缺失和抑郁样行为。这些数据表明，单个半球中 RMTg-VTA-Acb 通路的完整性足以在乙醇戒断期间引起抑郁样行为。总的来说，目前的结果表明，RMTg-VTA-Acb 通路在经历酒精戒断的动物的抑郁样行为中起着至关重要的作用，进一步主张 RMTg 是治疗酒精中毒的潜在靶点。
