Together our data are consistent with the

Together, our data are consistent with the idea that the antidepressant-like effect of a low dose of galanin administration in the DRN would be mediated by the activation of local GAL2. To support this hypothesis, we set an additional experiment to evaluate whether the antidepressant-like effect of galanin would be blocked by the infusion of a selective GAL2 antagonist in the DRN. We showed that previous intra-DRN infusion of M871, a GAL2 antagonist, counteracted the antidepressant-like effect of galanin in rats. GAL2 involvement in mediating antidepressant-like effects has been previously demonstrated. For example, mice that over-express GAL2 receptors exhibited an antidepressant-like phenotype in the FST [30]. Moreover, J18, a new systemically active galanin analog that binds preferentially to GAL2 induced an antidepressant-like effect in the tail suspension test [31], similarly to what was observed with the intracerebroventricular infusion of the GAL2 agonist AR-M1896 [3]. It is important to note that chronic administration of fluoxetine up-regulated GAL2, but not GAL1, in the DRN [14]. Notwithstanding, Mazarati and co-workers [32] found that injection of the GAL2 agonist galanin 2–11 (also called AR-M1896) in the DRN increased 5-HT concentrations in the DRN and in the hippocampus. These results raise the possibility that the antidepressant-like effect of AR-M1896 observed in the present study could involve the activation of serotonergic neurons in the DRN. Although we did not infuse either galanin or galanin agonists in a particular subregion of the DRN, our histology showed that most microinjections reached the mid-caudal dorsal raphe. Swimming stress increased c-Fos Rizatriptan Benzoate sale in some caudal dorsal and caudal ventral parts of DRN [33,34], thus suggesting the involvement of this subregion in FST-elicited behaviors. The activation of 5-HT neurons in the interfascicular part of DRN (DRI) at the caudal level leads to an increase of 5-HT in limbic regions concomitant with antidepressant-like effects in the FST [35]. The DRI is anatomically related to the median raphe, which, based on Deakin and Graeff’s theory, constitutes an important nucleus in the neurobiology of depression and stress related behaviors [36,37]. Based on the aforementioned evidence, it is possible that galanin, by activating GAL2 receptors in the DRI, might increased 5-HT in the dorsal hippocampus, preventing the behavioral consequences of stress elicited during the FST. Further studies are necessary to address this question. Another possible scenario concerns the increasing number of evidence that galanin effects may be conveyed by complex agonistic and antagonistic interactions of different G protein-coupled receptors [38,39]. Of importance to the present study, the existence of GAL1/5HT1A and GAL2/5-HT1A complexes in the DRN of rats have been demonstrated [40]. Then, the antidepressant-like effect resulting from activation of GAL2 receptors might involve a complex interaction with 5-HT1A receptors. Supporting this idea, the injection of 8-OH-DPAT in the DRN decreased immobility time in rats exposed to the FST [41]. Finally, although the predictive validity of the rat FST to detect antidepressant-like effect is generally accepted, it is still under discussion if immobility time in the paradigm represents a behavioral despair or a passive coping [42,43]. However, changes in immobility time are consistent and easily reproduced, allowing the detection of mechanisms related to the antidepressant effect induced by different classes of drugs. Based on that, the results of the present study have to be interpreted in the light of the limitation of using the FST as the only read out the drug-induced behavioral effects. Nevertheless, it provides additional evidence about galanin involvement in depression neurobiology that can be further confirmed in additional experiments.
Conclusions In summary, our results showed that infusion of galanin or of a GAL2 ligand in the DRN of rats decrease immobility time in the FST. Previous infusion of a GAL2 antagonist in the DRN blocked the antidepressant-like effect of galanin. Altogether, our results suggest that the antidepressant-like effect of galanin infusion is possibly mediated by GAL2 receptors in the DRN. Our results are in accordance with previous data suggesting that GAL2 selective agonists should be considered as a potentially new therapy for mood disorders.