Ostroumov, A. | Search bioRxiv

bioRxiv2025

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 characterized by a depolarized GABAA 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.

neuroscience↗

bioRxiv2024

Dynamic Changes in Chloride Homeostasis Coordinate Midbrain Inhibitory Network Activity during Reward Learning

The ability to associate environmental stimuli with positive outcomes is a fundamental form of learning. While extensive research has focused on the response profiles of midbrain dopamine neurons during associative learning, less is known about learning-mediated changes in the afferents that shape their responses. We demonstrate that during critical phases of learning, anion homeostasis in midbrain GABA neurons - a primary source of input to dopamine neurons - is disrupted due to downregulation of the chloride transporter KCC2. This alteration in GABA neurons preferentially impacted lateral mesoaccumbal dopamine pathways and was not observed after learning was established. At the network level, learning-mediated KCC2 downregulation was associated with enhanced synchronization between individual GABA neurons and increased dopamine responses to reward-related stimuli. Conversely, enhancing KCC2 function during learning reduced GABA synchronization, diminished relevant dopamine signaling, and prevented cue-reward associations. Thus, circuit-specific adaptations in midbrain GABA neurons are crucial for forming new reward-related behaviors.

neuroscience↗