Pearson Anna C, Kimmey Blake A, Taormina Madison B, Holden William M, Ostroumov Alexey
Department of Pharmacology & Physiology, Georgetown University, Washington, DC 20057, USA.
Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20057, USA.
bioRxiv. 2025 Jul 26:2025.07.22.666200. doi: 10.1101/2025.07.22.666200.
Identifying shared neural mechanisms influenced by diverse classes of drugs of abuse is essential for understanding addiction and for developing broad-spectrum treatments for substance use disorders. Previous studies indicate that many drugs of abuse increase dopamine output from the ventral tegmental area (VTA) by altering the balance of excitatory and inhibitory inputs onto dopamine neurons, thereby promoting maladaptive plasticity within reward circuits. Here, we demonstrate in rats that acute injections of morphine and cocaine, but not saline, disrupt chloride homeostasis in VTA GABA neurons. This disruption is characterized by a depolarized GABA reversal potential, impaired chloride extrusion, and posttranslational downregulation of the potassium chloride cotransporter KCC2. Although previous studies linked drug-induced posttranslational downregulation of KCC2 in the VTA to glucocorticoid receptor activation, we found that a glucocorticoid receptor antagonist did not prevent cocaine- and morphine-induced disruption of chloride homeostasis. Instead, our data show that dopamine receptor activation is both necessary and sufficient for these alterations. Notably, chloride homeostasis remains impaired 30 days after volitional morphine self-administration, indicating long-lasting plasticity. These findings complement previous work on nicotine and alcohol, suggesting a shared mechanism of inhibitory plasticity in the VTA following drug exposure. Given that chloride dysregulation in VTA GABA neurons influences downstream circuit function and promotes maladaptive behaviors associated with drug use, we propose KCC2 as a promising therapeutic target for substance use disorders.
识别受多种滥用药物影响的共同神经机制，对于理解成瘾以及开发针对物质使用障碍的广谱治疗方法至关重要。先前的研究表明，许多滥用药物通过改变多巴胺神经元上兴奋性和抑制性输入的平衡，增加腹侧被盖区（VTA）的多巴胺输出，从而促进奖赏回路内的适应不良可塑性。在此，我们在大鼠中证明，急性注射吗啡和可卡因而非生理盐水，会破坏VTA中GABA能神经元的氯离子稳态。这种破坏的特征是GABA反转电位去极化、氯离子外排受损以及氯化钾共转运体KCC2的翻译后下调。尽管先前的研究将VTA中药物诱导的KCC2翻译后下调与糖皮质激素受体激活联系起来，但我们发现糖皮质激素受体拮抗剂并不能阻止可卡因和吗啡诱导的氯离子稳态破坏。相反，我们的数据表明多巴胺受体激活对于这些改变既是必要的也是充分的。值得注意的是，在自愿吗啡自我给药30天后，氯离子稳态仍然受损，表明存在持久的可塑性。这些发现补充了先前关于尼古丁和酒精的研究，提示药物暴露后VTA中存在抑制性可塑性的共同机制。鉴于VTA中GABA能神经元的氯离子失调会影响下游回路功能并促进与药物使用相关的适应不良行为，我们提出KCC2作为物质使用障碍的一个有前景的治疗靶点。
