Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Neuropsychopharmacology. 2022 Nov;47(12):2123-2131. doi: 10.1038/s41386-022-01357-7. Epub 2022 Jun 18.
The lateral habenula (LHb) is an epithalamic nuclei that has been shown to signal the aversive properties of ethanol. The present study tested the hypothesis that activity of the LHb is required for the acquisition and/or expression of dependence-induced escalation of ethanol drinking and somatic withdrawal symptoms. Male Sprague-Dawley rats completed 4 weeks of baseline drinking under a standard intermittent access two-bottle choice (2BC) paradigm before undergoing 2 weeks of daily chronic intermittent ethanol (CIE) via vapor inhalation. Following this CIE exposure period, rats resumed 2BC drinking to assess dependence-induced changes in voluntary ethanol consumption. CIE exposed rats exhibited a significant increase in ethanol drinking that was associated with high levels of blood alcohol and a reduction in somatic symptoms of ethanol withdrawal. However, despite robust cFos activation in the LHb during ethanol withdrawal, chemogenetic inhibition of the LHb did not alter either ethanol consumption or somatic signs of ethanol withdrawal. Consistent with this observation, ablating LHb outputs via electrolytic lesions of the fasciculus retroflexus (FR) did not alter the acquisition of somatic withdrawal symptoms or escalation of ethanol drinking in CIE-exposed rats. The LHb controls activity of the rostromedial tegmental nucleus (RMTg), a midbrain nucleus activated by aversive experiences including ethanol withdrawal. During ethanol withdrawal, both FR lesioned and sham control rats exhibited similar cFos activation in the RMTg, suggesting that RMTg activation during ethanol withdrawal does not require LHb input. These data suggest that, at least in male rats, the LHb is not necessary for the acquisition or expression of escalation of ethanol consumption or expression of somatic symptoms of ethanol withdrawal. Overall, our findings provide evidence that the LHb is dispensable for some of the negative consequences of ethanol withdrawal.
外侧缰核（LHb）是一种丘脑核，已被证明可发出乙醇的厌恶性信号。本研究检验了以下假设：即 LHb 的活动是获得和/或表达依赖诱导的乙醇饮用量增加和躯体戒断症状所必需的。雄性 Sprague-Dawley 大鼠在标准间歇双瓶选择（2BC）范式下进行 4 周的基线饮酒后，通过蒸气吸入进行 2 周的每日慢性间歇乙醇（CIE）暴露。在经历了 CIE 暴露期后，大鼠恢复 2BC 饮酒以评估依赖诱导的自愿性乙醇消耗变化。CIE 暴露的大鼠表现出显著的乙醇饮用量增加，这与高血液酒精水平和乙醇戒断的躯体症状减少有关。然而，尽管在乙醇戒断期间 LHb 中出现了强烈的 cFos 激活，但 LHb 的化学遗传抑制并未改变乙醇消耗或乙醇戒断的躯体迹象。与这一观察结果一致，通过对折返束（FR）进行电解消融来破坏 LHb 的输出，并未改变 CIE 暴露大鼠躯体戒断症状的获得或乙醇饮用量的增加。LHb 控制着中脑核 rostromedial tegmental nucleus（RMTg）的活动，该核在包括乙醇戒断在内的厌恶性体验中被激活。在乙醇戒断期间，FR 消融和假手术对照大鼠的 RMTg 中均出现类似的 cFos 激活，这表明 RMTg 在乙醇戒断期间的激活不需要 LHb 的输入。这些数据表明，至少在雄性大鼠中，LHb 对于获得或表达乙醇消耗的增加或乙醇戒断的躯体症状的表达并非必需。总的来说，我们的研究结果提供了证据表明，LHb 在某些乙醇戒断的负面后果中是可有可无的。
