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Stress is known to alter GABAergic signaling in the ventral tegmental area (VTA), and this inhibitory plasticity is associated with increased alcohol self-administration. In humans, serotonin 2A receptor (5-HTR) agonists can treat stress- and alcohol-related disorders, but the neural substrates are ill-defined. Thus, we reasoned that 5-HTR pharmacotherapies may ameliorate the stress-induced dysregulated inhibitory VTA circuitry that contributes to subsequent alcohol abuse. We found that acute stress exposure in mice compromised GABA-mediated inhibition of VTA GABA neurons corresponding with increased ethanol-induced GABAergic transmission. This stress-induced inhibitory plasticity was reversible by applying the 5-HTR agonist TCB-2 ex vivo via functional enhancement of the potassium-chloride cotransporter KCC2. The signaling pathway linking 5-HTR activation and normalization of KCC2 function was dependent on protein kinase C signaling and phosphorylation of KCC2 at serine 940 (S940), as mutation of S940 to alanine prevented restoration of chloride transport function by TCB-2. Through positive modulation of KCC2, TCB-2 also reduced elevated ethanol-induced GABAergic signaling after stress exposure that has previously been linked to increased ethanol consumption. Collectively, these findings provide mechanistic insights into the therapeutic action of 5-HTR agonists at the neuronal and circuit levels of brain reward circuitry.

5-HT 2A receptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area

5-HT _2A receptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area