Galanin N-terminal fragment (1− 15) reduces alcohol seeking and alcohol relapse in rats: Involvement of mesocorticolimbic system

Alcohol Use Disorder (AUD) is among the most prevalent mental illnesses, and due to the low efficacy of the current medication, it is essential to find new biological targets that could modulate alcohol consumption. Since Galanin (1−15) [GAL(1−15)] produces a loss of motivational behaviour by an artificial reinforcer and decreases the preference an alcohol consumption in a voluntary alcohol intake, we have studied the role of GAL(1−15) in alcohol-seeking behaviour and the involvement of the corticomesolimbic system as well as the role of GAL(1−15) in context-induced alcohol relapse. In rats, we have studied GAL(1−15)-effects on alcohol-seeking in self-administration, in fixed-ratio (FR1) and progressive-ratio (PR), and the involvement of GAL receptors using siRNA GALR1 or GALR2 knockdown animals. We have analysed the transcriptional changes of C-Fos, dopamine receptors, GAL receptors and 5HT1A receptors in the corticomesolimbic system. Also, we have examined the effect of GAL(1−15) in context-induced alcohol relapse. GAL(1−15) substantially reduced alcohol-seeking behaviour in the operant self-administration model in an FR1 protocol and at the breaking point in a PR schedule. GALR1and GALR2 were involved in these effects, as indicated by the analysis by GALR2 antagonist and GALR1 and GALR2 knockdown animals. Notably, the mechanism of GAL(1−15)-mediated actions involved changes in C-Fos, Dopamine receptors and 5HT1A expression in the ventral tegmental area, accumbens nucleus and prefrontal cortex. Significantly, GAL(1−15) reduced the context-induced alcohol relapse. These results open up the possibility to use GAL(1−15) as a novel strategy in AUD. This work was supported by grants awarded by Spanish Ministry of Economy PID2020-114392RB-100, PDC2021-121566-100 and by Junta de Andalucía P20-00026-R and PI-0083-2019. Partial funding for open access charge: Universidad de Málaga