Alcohol consumption drives sex- and region- specific disruption of somatostatin signaling in mice.

The prefrontal cortex (PFC), which is thought to be disrupted early in the cycle of substance use and addiction [1], is comprised of a complex microcircuit of long-range glutamatergic pyramidal neurons controlled by GABAergic-expressing local inhibitory neurons [2, 3]. Somatostatin (SST)-expressing neurons are a subpopulation of these local GABAergic inhibitory cells and provide both peptidergic and GABAergic control over these PFC circuits [3, 4], and are disturbed following alcohol consumption in humans [5] and in rodent models [6, 7]. However, little is known about how endogenous SST peptide signaling is affected by alcohol. Using ex vivo electrophysiology, immunohistochemistry, in situ hybridization, and behavior, we demonstrate robust down-regulation of SST control over pyramidal output activity in the prelimbic (PL), but not infralimbic (IL), PFC after alcohol exposure. We also show this is likely mediated by changes in SST receptor expression levels and not disrupted expression or capacity for release of SST peptide, suggesting postsynaptic homeostatic changes to SST signaling following binge alcohol consumption in mice that may underlie post-alcohol dysregulation in mood. This provides insight into how voluntary alcohol consumption disrupts PFC peptide signaling and suggests a potential therapeutic target for the treatment of alcohol use disorder (AUD).