Intranasal Galanin(1–15) influences depression- and anxiety-related behaviors through sex-dependent mechanisms in rats

BACKGROUND: Major depressive disorder affects more women than men, possibly due to sex-specific biological and environmental factors. Previous studies have shown that Galanin, as well as specific fragments of it, such as Galanin 1-15 [GAL(1-15)], play a crucial role in modulating depression in animal models by acting on brain regions like the hippocampus and dorsal raphe nuclei. Until now, its effects had only been studied in male rats, where GAL(1-15) produces depressive and anxiogenic behaviors in behavioral tests. This study analyzes, for the first time, the effects of GAL(1-15) on female rats and compares the expression of galaninergic and serotonergic genes between males and females to understand sex-dependent mechanisms in depression. METHODS: For this purpose, the effect of GAL(1-15) administered intranasally in female rats was assessed, using validated behavioral tests for depression: the Forced Swim Test (FST) and the Tail Suspension Test (TST), as well as the anxiety behavior test: the Open Field Test (OFT). Furthermore, the expression of galaninergic genes (GAL, GALR1, GALR2, GALR3) and the 5-HT1A receptor was compared in untreated male and female rats using qPCR in key brain regions implicated in depressive disorder: the dorsal raphe nucleus (DR), the dorsal hippocampus, and the prefrontal cortex (PFC). RESULTS: We demonstrated that GAL(1-15) intranasally administered in female rats strongly produced depressive behavior in the FST as well as in the TST. Moreover, in the anxiety test, intranasal GAL(1-15) at high doses produced anxiety behavior in the OFT. In addition, the qPCR study revealed that naïve female rats exhibited increased expression of the galaninergic system and 5-HT1A receptor compared to naïve male rats in the DR, dorsal hippocampus, and PFC, several nuclei implicated in depression. CONCLUSIONS: These results demonstrate the existence of sexual dimorphism in the galangergic system.These findings on sex-specific neurobiological variations are crucial for advancing toward more precise therapies tailored to the specific characteristics of each sex in the treatment of depression.