A Role for Galanin N-Terminal Fragment (1–15) in Anxiety- and Depression-Related Behaviors in Rats

BACKGROUND: Galanin (GAL) plays a role in mood regulation. In this study we analyzed the action of the active N-terminal fragment [GAL(1–15)] in anxiety- and depression-related behavioral tests in rats. METHODS: The effect of GAL(1–15) was analyzed in the forced swimming test, tail suspension test, open field test, and light/dark test. The proximity of GAL(1) and GAL(2) receptors was examined with the proximity ligation assay (PLA). We tested the GAL receptors involved in GAL(1–15) effects with the GAL(2) receptor antagonist M871 and with an in vivo model of siRNA GAL(2) receptor knockdown or siRNA GAL(1) receptor knockdown rats. The effects of GAL(1–15) were also studied in the cell line RN33B. RESULTS: GAL(1–15) induced strong depression-like and anxiogenic-like effects in all the tests. These effects were stronger than the ones induced by GAL. The involvement of the GAL(2) receptor was demonstrated with M871 and with the siRNA GAL(2) receptor knockdown rats. The PLA indicated the possible existence of GAL(1) and GAL(2) heteroreceptor complexes in the dorsal hippocampus and especially in the dorsal raphe nucleus. In the siRNA GAL(1) receptor knockdown rats the behavioral actions of GAL(1–15) disappeared, and in the siRNA GAL(2) receptor knockdown rats the reductions of the behavioral actions of GAL(1–15) was linked to a disappearance of PLA. In the cell line RN33B, GAL(1–15) decreased 5-HT immunoreactivity more strongly than GAL. CONCLUSIONS: Our results indicate that GAL(1–15) exerts strong depression-related and anxiogenic-like effects and may give the basis for the development of drugs targeting GAL(1) and GAL(2) heteroreceptor complexes in the raphe-limbic system for the treatment of depression and anxiety.