Cocaine and Morphine Converge to Disrupt Chloride Homeostasis in Ventral Tegmental Area GABA Neurons

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 characterised by a depolarised GABA A 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 D1/D5 receptor activation is both necessary and sufficient for these alterations. Notably, chloride homeostasis remains impaired for several weeks 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 behaviours associated with drug use, we propose KCC2 as a promising therapeutic target for substance use disorders.