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Major depression is the largest contributor to global disability by years lived with disability. Selective serotonergic reuptake inhibitors, including fluoxetine (FLX), are the most commonly used antidepressant for the treatment of major depression. However, they are effective for remission in only 30% of patients. Recently, we observed that the N-terminal fragment of Galanin [GAL(1-15)] enhanced the antidepressant effects of FLX in naïve animals. In this work, we have analyzed in an animal model of depression, the olfactory bulbectomy (OBX) rats, the effect of GAL(1-15) on FLX-mediated responses in the forced swimming test (FST) and the sucrose preference test (SPT), tests related with despair and anhedonic behaviours. We have also studied the corticosterone levels in OBX rats after the coadministration of GAL(1-15)+FLX. Groups of rats received a subchronic pattern of FLX(10mg/Kg) alone or in combination with GAL(1-15)(1nmol)15min before the tests. Blood samples for corticosterone assay were collected 1h after the treatments. One-way ANOVA followed by Fisher ́s least significant difference test was used. Our results show that GAL(1-15) decreases the immobility time by 50% (p

Galanin N-terminal fragment (1-15) [GAL(1-15)] modulates the antidepressant effects induced by the 5-HT1A receptor (5-HT1AR) agonist in the forced swimming test (FST) and the binding characteristics and mRNA levels of 5-HT1AR in the dorsal hippocampus and dorsal raphe (DR). Recently, we observed that GAL(1-15) enhanced the antidepressant-like effects induced by Fluoxetine (FLX) in the FST. In this work, we have studied whether the effects of GAL(1–15) on FLX action were mediated via 5-HT1AR, analyzing the effect of the 5-HT1AR antagonist WAY100635 in this effect and if the binding characteristics and mRNA levels of 5-HT1AR in the DR and dorsal hippocampus are modified by GAL(1-15)+FLX. Groups of rats (n=6-8) received three injections of sc FLX(10mg/kg) and 15 minutes before the FST a single icv injection of GAL(1-15) (1nmol) and 5HT1AR antagonist WAY100635(6nmol) icv alone or in combination. We also analyzed the effects of GAL(1-15)+FLX in the binding characteristics of the 5-HT1AR agonist [H3]-8-OH-DPAT and 5-HT1A mRNA levels in the DR, CA1 and Dentate Gyrus (DG). WAY100635 significantly blocked the reduction in immobility time (p

We have described that Galanin N-terminal fragment (1-15) [GAL(1-15)] is associated with depressive effects and also modulates the antidepressant effects induced by the 5-HT1A receptor (5-HT1AR) agonist 8-OH-DPAT in the forced swimming test (FST). Importantly, the mechanism underlying this action involved interactions at the receptor level in the plasma membrane with changes also at the transcriptional level. Thus, GAL(1–15) affected the binding characteristics as well as the mRNA levels of 5-HT1AR in the dorsal hippocampus and dorsal raphe (DR). Recently, we observed that GAL(1-15) enhanced the antidepressant-like effects induced by Fluoxetine (FLX) in the FST. In view of this, we have studied whether the effects of GAL(1–15) on FLX action were mediated via 5-HT1AR, analyzing the effect of the 5-HT1AR antagonist WAY100635 in the GAL(1-15)-mediated effect in the FST. We have also determined the binding characteristics and mRNA levels of 5-HT1AR in the DR and dorsal hippocampus after GAL(1-15)-FLX administration. To study if the effects of GAL(1-15) on FLX action were mediated via the 5HT1AR, groups of rats (n=6-8 rats per groups) received three subcutaneous injections (sc) of FLX(10mg/kg) and 15 minutes before the FST a single intracerebroventricular injection (icv) of GAL(1-15) (1nmol) and 5HT1AR antagonist WAY100635(6nmol) icv alone or in combination. In the second set of experiments, we analyzed the effects of the three injections of sc FLX or Vehicle and a single icv injection of GAL(1-15) or aCSF and sacrified 30 min later to analyze the binding characteristics of the 5-HT1AR agonist [H3]-8-OH-DPAT and 5-HT1A mRNA levels in sections of the DR and Dorsal Hippocampus, specifically in the Ammon’s horn 1 (CA1) and Dentate Gyrus (DG). The results confirmed that the 5HT1AR participates in this interaction as the 5HT1AR antagonist WAY100635 (6nmol) significantly blocked the reduction in immobility time (p

The selective serotonergic (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 5-HT system and neuropeptides signaling could be a key aspect. The neuropeptide Galanin(1-15) [GAL(1-15)], induced a strong depression-like and anxiogenic-like effects in the forced swimming test (FST), the tail suspension test, the open field and the light/dark test. The GALR1-GALR2 heteroreceptor complexes in the dorsal hippocampus and in the dorsal raphe were involved in these effects. We have analyzed the effect of GAL(1–15) on FLX-mediated responses in the FST. We tested the involvement of GALR in the GAL(1–15) effect with the selective GALR2 antagonist M871 and using siRNA GALR2 or GALR1 knockdown rats. Groups of rats received three injections of sc FLX(2.5mg/Kg) or FLX(10mg/Kg) and a single icv injection of a threshold dose of GAL(1-15)(1nmol) 15 minutes before the FST. In a second set of experiments, we determined the involvement of GALR1 and GALR2 in the effect of GAL(1-15) on FLX-mediated action. Groups of rats received three injections of sc FLX(10mg/kg), a single icv injection of GAL(1-15) (1nmol) and the GALR2 antagonist M871 (3nmol) icv alone or in combination. Also, in siRNA GALR1 or GALR2 knockdown rats we coadministered FLX(10mg/Kg) and GAL(1-15)(1nmol). The coadministration of sc FLX(2.5mg/Kg) and icv injection of GAL(1-15)(1nmol) induced antidepressant-like effects with a significant decrease in the immobility (p