Early socially isolated rats of both sexes reduce alcohol consumption and seeking by the Galanin (1-15) and naltrexone combination.

Background: Alcohol Use Disorder (AUD) is a psychiatric condition whose severity can be amplified by social factors, such as social isolation, particularly during adolescence, which exacerbates development of AUD in adulthood. Our previous studies have demonstrated that the Galanin (1-15) fragment [GAL (1-15)] reduces alcohol seeking and consumption. Furthermore, the combination of GAL (1-15) with Naltrexone (NTX)-an approved but moderately effective treatment for AUD- potentiates reduced alcohol intake and seeking behavior, showing interaction with the opioid system. Objective: Previous studies on the effects of GAL (1-15) on AUD have been conducted mainly in male animals, leaving the effects on females largely unexplored despite the well-established sex differences in alcohol use disorder. Therefore, this study introduces early-life social isolation as a critical environmental vulnerability factor for adult alcohol abuse and evaluates these mechanisms in female subjects for the first time. Specifically, we investigate the combined effects of GAL (1-15)+NTX on alcohol consumption and seeking in male and female adolescent-isolated rats, along with associated changes in mesolimbic gene expression. Methods: In socially isolated male and female rats, we evaluated GAL (1-15)+NTX in terms of voluntary alcohol intake (two-bottle choice) and reward-seeking behavior (self-administration). We analyzed transcriptional changes in C-Fos, MOR, dopamine and galanin receptors in the ventral tegmental area and nucleus accumbens. Results: Social isolation moderately increased ethanol intake and operant alcohol responding in both sexes. GAL (1-15)+NTX significantly reduced operant responding in isolated rats of both sexes, but reduced alcohol consumption only in males, with no significant effect in females at the tested doses. These effects were associated with alterations in C-Fos, MOR and dopamine receptor expression, suggesting that there is an association between molecular changes related to the mesolimbic and opioid systems and the observed reduction in alcohol-seeking behavior and consumption, even in a model of early social isolation. Conclusion: These findings suggest that GAL (1-15)+NTX could be explored further as a potential strategy in AUD research, particularly in socially vulnerable contexts.