LAUSR

ABSTRACT The pharmacological treatment of major depression is mainly based on drugs elevating serotonergic (5‐HT) activity. Specifically, selective 5‐HT reuptake inhibitors, including Fluoxetine (FLX), are the most commonly used for treatment of major depression. However, the understanding of the mechanism of action of FLX beyond its effect of elevating 5‐HT is limited. The interaction between serotoninergic system and neuropeptides signaling could be a key aspect. We examined the ability of the neuropeptide Galanin(1–15) [GAL(1–15)] to modulate the behavioral effects of FLX in the forced swimming test (FST) and studied feasible molecular mechanisms. The data show that GAL(1–15) enhances the antidepressant‐like effects induced by FLX in the FST, and we demonstrate the involvement of GALR1/GALR2 heteroreceptor complex in the GAL(1–15)‐mediated effect using in vivo rat models for siRNA GALR1 or GALR2 knockdown. Importantly, 5‐HT1A receptors (5HT1A‐R) also participate in the GAL(1–15)/FLX interactions since the 5HT1AR antagonist WAY100635 blocked the behavioral effects in the FST induced by the coadministration of GAL(1–15) and FLX. The mechanism underlying GAL(1–15)/FLX interactions affected the binding characteristics as well as the mRNA levels of 5‐HT1A‐R specifically in the dorsal hippocampus while leaving unaffected mRNA levels and affinity and binding sites of this receptor in the dorsal raphe. The results open up the possibility to use GAL(1–15) as for a combination therapy with FLX as a novel strategy for treatment of depression. HIGHLIGHTSGAL(1–15) enhances the antidepressant‐like effects induced by Fluoxetine.5‐HT1A receptors participate in the GAL(1–15)/FLX interactions.GAL(1–15)/FLX interactions affected binding and 5‐HT1AR mRNA levels in hippocampus.