Galanin (1-15) - Fluoxetine interaction in the novel object recognition test involvement of 5-HT1A receptors in the prefrontal cortex of the rats

Galanin (1-15) [GAL(1-15)] participates in mood regulation and depression. GAL(1-15) is also able to enhance the antidepressant effects induced by Fluoxetine (FLX) in the forced swimming test through interaction between GALR1-GALR2 and 5-HT1A receptors that induced changes in the binding characteristics and mRNA of the 5-HT1AR in the hippocampus. Since the medial prefrontal cortex (mPFC) is a core region for the interaction between emotional processing and cognition with a high density of 5-HT1AR and GALR1 and GALR2, we have analyzed the binding characteristics and mRNA levels of 5-HT1AR in the mPFC after GAL(1-15)-FLX administration in the rats. GAL(1-15) increased the Kd and the Bmax of the 5HT1AR agonist binding in the mPFC as well as the mRNA levels of 5-HT1AR in mPFC. Moreover, GAL(1-15) reversed the effects of memory impairment induced by FLX(10 mg/kg) in the Novel Object Recognition task. GALR2 was involved in these effects, since the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions at behavioral level. On the contrary GAL(1-15) did not reverse the effect of FLX in the Object Location Memory task. In conclusion, our results describe an interactions between GAL(1-15) and FLX in the mPFC involving interactions at the 5-HT1AR receptor level in the plasma membrane with changes at the transcriptional level with implications also at functional level. The GALR1-GALR2-5-HT1A heteroreceptor could be postulated to be used to reverse some of the adverse effects of FLX on memory processes

Galanin(1-15) enhanced the antidepressant-like effects of escitalopram in the olfactory bulbectomy rats in the forced swimming test through 5-HT1A receptors

We previously described that Galanin (1-15) [GAL(1-15)] enhances the antidepressant-like effects induced by the SSRI Fluoxetine in the forced swimming test (FST) in naïve rats. In this work, we have analyzed in olfactory bulbectomy rats (OBX) the effect of GAL(1-15)-Escitalopram (ESC) combination in the FST and the involvement of GALR and 5-HT1A receptors in these effects. In the first set of experiments, OBX rats received three injections of ESC (10mg/Kg) (23, 5 and 1 hour) and a single injection of a threshold dose of GAL(1-15) (1nmol) and GALR2 antagonist M871 (3nmol) alone or in combination 15 minutes before the FST. Secondly, we have generated siRNA 5HT1A knockdown rats, and we have evaluated the effects of ESC and GAL(1-15) administration in the FST. One-way ANOVA followed by Fisher ́s least significant difference test was used. In the FST, GAL(1-15) (1nmol) enhanced the antidepressant-like effects of ESC, reducing immobility (p<0.05) and increasing the swimming time (p<0.05). M871 blocked the behavioural effects of GAL(1-15) in the immobility time (p<0.001) and in the swimming time (p<0.05) in the FST. Moreover, the decrease in 5-HT1AR was sufficient to block GAL(1-15) enhancement of the antidepressant-like effects mediated by ESC. Our results indicate a potent effect of the combination GAL(1-15) with SSRIs in reversed depressive symptoms in the animal model of chronic depression OBX. The results open up the possibility of using GAL(1-15) in combination with SSRIs as a novel strategy for treating depression.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. PID2020-114392RB-I00, UMA18-FEDERJA-008 and P20_00026, PI-0083-2019