Mouse parasubthalamic neurons drive alcohol drinking escalation and behavioral disinhibition.

Corticotropin-releasing factor (CRF, encoded by ) signaling is thought to play a critical role in the development of excessive alcohol drinking and the emotional and physical pain associated with alcohol withdrawal. Here, we investigated the parasubthalamic nucleus (PSTN) as a potential source of CRF relevant to the control of alcohol consumption, affect, and nociception in mice. We identified PSTN neurons as a neuronal subpopulation that exerts a potent and unique influence on behavior by promoting not only alcohol but also saccharin drinking, while PSTN neurons are otherwise known to suppress consummatory behaviors. Furthermore, PSTN neurons are causally implicated in the escalation of alcohol and saccharin intake produced by chronic intermittent ethanol (CIE) vapor inhalation, a mouse model of alcohol use disorder. In contrast to our predictions, the ability of PSTN neurons to increase alcohol drinking is not mediated by CRF signaling. Moreover, the pattern of behavioral disinhibition and reduced nociception driven by their activation does not support a role of negative reinforcement as a motivational basis for the concomitant increase in alcohol drinking. Finally, silencing expression in the PSTN slowed down the escalation of alcohol intake in mice exposed to CIE and accelerated their recovery from withdrawal-induced mechanical hyperalgesia. Altogether, our results suggest that PSTN neurons may represent an important node in the brain circuitry linking alcohol use disorder with sweet liking and novelty seeking.