Chronic alcohol withdrawal-associated increases in VTA Hcrtr1 expression are associated with heightened nociception and anxiety-like behavior in female rats.

Alcohol withdrawal is characterized by various symptoms that include pain and negative affect in the absence of the drug. The neural underpinnings of these behaviors are not entirely understood, but orexin has emerged as a candidate target for the treatment of substance use disorders. Here, we explored changes in orexin system-related gene expression in brain regions important for mediating reward and stress, including the ventral tegmental area (VTA) and extended amygdala (including the central amygdala, nucleus accumbens shell, and bed nucleus of the stria terminalis), in adolescent and adult female Wistar rats following chronic alcohol exposure. We observed higher numbers of Hcrtr1- (orexin receptor 1)-expressing neurons in the VTA of adolescent and adult female rats during withdrawal from chronic alcohol exposure. The number of Hcrt1+ VTA neurons was negatively correlated with thermal sensitivity in adolescent female rats and anxiety-like behavior in adult female rats. These data suggest that chronic alcohol effects on orexin receptor expression in the VTA are related to specific behaviors that manifest during withdrawal, highlighting potential avenues for targeting alcohol withdrawal-associated behaviors across development.