5-HT(4) Receptors Are Not Involved in the Effects of Fluoxetine in the Corticosterone Model of Depression

[Image: see text] Clinical and preclinical studies report the implication of 5-hydroxytryptamine 4 receptors (5-HT(4)Rs) in depression and anxiety. Here, we tested whether the absence of 5-HT4Rs influences the response to the antidepressant fluoxetine in mice subjected to chronic corticosterone administration, an animal model of depression and anxiety. Therefore, the effects of chronic administration of fluoxetine in corticosterone-treated wild-type (WT) and 5-HT(4)R knockout (KO) mice were evaluated in the open-field and novelty suppressed feeding tests. As 5-HT(1A) receptor (5-HT(1A)R) and brain-derived neurotrophic factor (BDNF) are critically involved in depression and anxiety, we further evaluated 5-HT(1A) receptor functionality by [(35)S]GTPγS autoradiography and BDNF mRNA expression by in situ hybridization techniques. We found that 5-HT(4)R KO and WT mice displayed anxiety- and depressive-like behavior following chronic administration of corticosterone, as evidenced in the open-field and novelty suppressed feeding tests. In the open-field, a decreased central activity was observed in naïve and corticosterone-treated mice of both genotypes following chronic fluoxetine administration. In the novelty suppressed feeding test, a predictive paradigm of antidepressant activity, chronic treatment with fluoxetine reverted the latency to eat in both genotypes. The antidepressant also potentiated the corticosterone-induced desensitization of the 5-HT(1A)R in the dorsal raphe nucleus. Further, chronic fluoxetine increased BDNF mRNA expression in the dentate gyrus of the hippocampus in corticosterone-treated mice of both genotypes. Therefore, our findings indicate that the behavioral effects of fluoxetine in the corticosterone model of depression and anxiety appear not to be dependent on 5-HT(4)Rs.