Midbrain KCC2 downregulation: Implications for stress-related and substance use behaviors

Stress-related and substance use disorders are both characterized by disruptions in reward-related behaviors, and these disorders are often comorbid with one another. Recent investigations have identified a novel mechanism of inhibitory plasticity induced by both stress and substance use within the ventral tegmental area (VTA), a key region in reward processing. This mechanism involves the neuron-specific potassium chloride cotransporter isoform 2 (KCC2), which is essential in modulating inhibitory signaling through the regulation of intracellular chloride (Cl^-) in VTA GABA neurons. Experiences, such as exposure to stress or substance use, diminish KCC2 expression in VTA GABA neurons, leading to abnormal reward-related behaviors. Here, we review literature suggesting that KCC2 downregulation contributes to irregular dopamine (DA) transmission, impacting multiple reward circuits and promoting maladaptive behaviors. Activating KCC2 restores canonical GABA functioning and reduces behavioral deficits in preclinical models, leading us to advocate for KCC2 as a target for therapies aimed at alleviating and mitigating various stress-related and substance use disorders.