830. Galanin(1-15) and Naltrexone: A novel approach for alcohol use disorder in rats, involving the mesolimbic system

Abstract

Abstract Background Alcohol Use Disorder (AUD) is one of the most prevalent psychiatric conditions and represents a major public health burden worldwide. Despite available pharmacotherapies, including naltrexone (NTX)—a mu-opioid receptor (MOR) antagonist—therapeutic efficacy remains limited due to side effects and significant interindividual variability in treatment response. The neuropeptide galanin (GAL) and its fragments have been implicated in the modulation of alcohol intake and reward mechanisms. The N-terminal fragment GAL(1–15) exhibits distinct neurobiological and behavioral effects from the full-length peptide our previous studies demonstrated that GAL(1–15) decreases both alcohol-seeking behavior and consumption. In this study, we investigated whether combining GAL(1–15) with NTX could synergistically suppress alcohol-reinforced behaviors and explored the underlying neurobiological mechanisms. Aims & Objectives The main objective was to assess the effect of combined GAL(1–15) and NTX administration on alcohol-seeking and consumption behaviors in rats. We also aimed to determine the involvement of the GAL receptor subtype GALR2 and to evaluate the role of the mesolimbic reward system and opioid signaling in mediating these effects. Specifically, we examined whether this combination alters locomotor activity, dopamine release in the dorsal striatum, and the expression of key transcriptional markers in reward-related brain regions. Method Adult male rats were treated with GAL(1–15), NTX, or their combination. To assess motivation for alcohol, we employed an operant self-administration paradigm, and the role of GALR2 was evaluated using the selective antagonist M871. Alcohol preference and voluntary intake were measured using the two-bottle choice test. Locomotor activity and stereotyped behaviors, along with dopamine release in the dorsal striatum following alcohol injections, were assesse. Finally, quantitative PCR analyses were performed to evaluate transcriptional changes in c-Fos, MOR, pro-opiomelanocortin (POMC), and dopamine receptor genes (D1R and D2R) across the ventral tegmental area (VTA), nucleus accumbens (NAc), and hypothalamus. Results Co-administration of GAL(1–15) and NTX significantly reduced alcohol self-administration and voluntary consumption compared with either compound alone. These effects were reversed by GALR2 blockade with M871, confirming receptor-specific mediation. The combination also attenuated alcohol-induced locomotor activity and stereotyped behaviors. Dopamine release in the dorsal striatum was markedly decreased following GAL(1–15)+NTX treatment, indicating modulation of striatal dopaminergic signaling. At the transcriptional level, the combination reduced c-Fos and MOR expression in the VTA and NAc, while also altering POMC and dopamine receptor gene expression, consistent with dampened mesolimbic activity. Discussion & Conclusions These findings demonstrate that GAL(1–15) enhances the efficacy of NTX in reducing alcohol-seeking and alcohol-induced behaviors, likely through a synergistic modulation of the mesolimbic dopaminergic and opioid systems via GALR2 receptor interactions. The combination not only suppressed alcohol consumption but also normalized neurochemical and transcriptional markers associated with reward and reinforcement. Targeting galaninergic signaling in conjunction with established opioid antagonists may therefore represent a novel pharmacological strategy for improving AUD outcomes and minimizing relapse risk. Further preclinical and translational studies are warranted to validate this combinatory approach for clinical use. PID2020-114392RB-I00/AEI/10.13039/501100011033;PID2024-156923OB-I00, EXP2022/008766; 2025I009 and PPRO-B4-2024-010.