Adolescent social isolation promotes oxycodone consumption and augments mu opioid receptor responsiveness in the ventral pallidum.

Exposure to adversity during adolescence augments vulnerability to opioid use disorders in adulthood, yet the neurobiological mechanisms underlying this risk remain incompletely understood. The ventral pallidum (VP) is a region highly implicated in reward valuation and is sensitive to both stress and opioid modulation. Here, we examined whether adolescent social isolation (aSI) alters consumption of oxycodone and mu-opioid receptor (MOR) mediated inhibition of dopamine release in the VP. Male and female rats were exposed to aSI or group housing during adolescence (aGH) and assessed in adulthood for oxycodone consumption and pallidal dopamine release using ex vivo fast-scan cyclic voltammetry (FSCV). aSI increased oxycodone intake, with females consuming significantly more oxycodone than males. While aSI did not alter baseline dopamine release, MOR activation with DAMGO or oxycodone produced greater inhibition of dopamine release in aSI females, but not males, indicating a sex-specific enhancement of MOR functional responsivity following aSI. Pallidal enkephalin abundance was not affected by aSI, suggesting that aSI induces receptor-level regulation rather than changes in the endogenous ligand. Together, these findings indicate that aSI produces enduring, sex-specific alterations in MOR modulation of dopamine in the VP. These effects may underlie maladaptive behaviors observed in adulthood, and aid in the understanding of how stress in adolescence serves as a risk factor for opioid use disorder.