| First Author | Kimmey BA | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | PubMed ID | 31806759 |
| Mgi Jnum | J:286682 | Mgi Id | MGI:6388233 |
| Doi | 10.1073/pnas.1911446116 | Citation | Kimmey BA, et al. (2019) 5-HT2A receptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area. Proc Natl Acad Sci U S A |
| abstractText | 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-HT2AR) agonists can treat stress- and alcohol-related disorders, but the neural substrates are ill-defined. Thus, we reasoned that 5-HT2AR 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-HT2AR agonist TCB-2 ex vivo via functional enhancement of the potassium-chloride cotransporter KCC2. The signaling pathway linking 5-HT2AR 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-HT2AR agonists at the neuronal and circuit levels of brain reward circuitry. |
