Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Addict Biol. 2022 Mar;27(2):e13147. doi: 10.1111/adb.13147.
Disruption of neuronal chloride ion (Cl ) homeostasis has been linked to several pathological conditions, including substance use disorder, yet targeted pharmacotherapies are lacking. In this study, we explored the potential of serotonin 2A receptor (5-HT R) agonism to reduce alcohol consumption in male wild-type C57Bl/6J mice and to ameliorate alcohol-induced inhibitory plasticity in the midbrain. We found that administration of the putative 5-HT R agonist TCB-2 attenuated alcohol consumption and preference but did not alter water or saccharin consumption. We hypothesized that the selective behavioural effects of TCB-2 on alcohol drinking were due, at least in part, to effects of the agonist on ventral tegmental area (VTA) neurocircuitry. Alcohol consumption impairs Cl transport in VTA GABA neurons, which acts as a molecular adaptation leading to increased alcohol self-administration. Using ex vivo electrophysiological recordings, we found that exposure to either intermittent volitional alcohol drinking or an acute alcohol injection diminished homeostatic Cl transport in VTA GABA neurons. Critically, in vivo TCB-2 administration normalized Cl transport in the VTA after alcohol exposure. Thus, we show a potent effect of alcohol consumption on VTA inhibitory circuitry, in the form of dysregulated Cl homeostasis that is reversible with agonism of 5-HT Rs. Our results provide insight into the potential therapeutic action of 5-HT R agonists for alcohol abuse.
神经元氯离子（Cl-）内环境稳态的破坏与多种病理状况有关，包括物质使用障碍，但缺乏靶向药物治疗。在这项研究中，我们探讨了血清素 2A 受体（5-HT R）激动剂减少雄性野生型 C57Bl/6J 小鼠饮酒量和改善酒精诱导的中脑抑制性可塑性的潜力。我们发现，假定的 5-HT R 激动剂 TCB-2 的给药可减少酒精的消耗和偏好，但不改变水或糖精的消耗。我们假设 TCB-2 对酒精饮用的选择性行为效应至少部分归因于激动剂对腹侧被盖区（VTA）神经回路的影响。酒精消耗会损害 VTA GABA 神经元中的 Cl-转运，这是一种分子适应，导致酒精自我给药增加。使用离体电生理记录，我们发现，间歇性自愿饮酒或急性酒精注射暴露会降低 VTA GABA 神经元中的内稳态 Cl-转运。至关重要的是，体内 TCB-2 给药可在酒精暴露后使 VTA 中的 Cl-转运正常化。因此，我们展示了酒精消耗对 VTA 抑制性回路的强烈影响，其形式为 Cl-内环境稳态失调，5-HT R 激动剂可逆转这种失调。我们的结果为 5-HT R 激动剂治疗酒精滥用提供了潜在的治疗作用的见解。
