The generation of drugs with therapeutic properties against depression presenting a shorter onset of action is a critical issue. In this regard, the development of 5-HT4 receptor agonists has been suggested as a novel pharmacological target to get faster acting antidepressants. Modifications in hippocampal BDNF expression and 5-HT4 receptor-associated adenylate cyclase desensibilization have been identified as changes related to antidepressant efficacy. The aim of this study was to analyze in rats the modification of these process as well as the behavioural effects induced by the treatment with the 5-HT4 receptor partial agonist RS67333 (1.5 mg/kg/day s.c.) during two short periods of administration (3 and 7 days). The 3 day-treatment resulted in a tendency to the increase of expression of BDNF mRNA only in the CA3 area of the rat hippocampus: 7 days of treatment were required to obtain a significant upregulation of BDNF mRNA in the dentate gyrus (140.8%, p<0.05) and CA1 field (172.6%, p<0.05). In a similar manner, RS67333 only desensitized the 5-HT4 receptor-coupled adenylate cyclase in the group subjected to the 7 day regimen compared to control (Emax 84.1% vs 135.1% respectively, p<0.05). Regarding behavioural studies, RS67333 was effective in the forced swimming test following 3 days of administration. However, at least 7 days of treatment were required to obtain a complete behavioural response in two validated paradigms (novelty-feeding suppressed and reversion of corticosterone-induced anhedonia) to predict chronic antidepressant response. The SSRI antidepressant (10 mg/kg) was only effective in these paradigms following a chronic (14 or 21 days) administration. These results suggest that 7 days are required with this 5-HT4 receptor agonist to elicit hippocampal neuroplastic changes associated with a fully positive behavioural effect. On the other hand, these results confirm that 5-HT4 receptor agonism is an encouraging strategy for the development of antidepressants with a shorter onset of action.

Ministerio de Ciencia, Innovación y Tecnología (SAF-07/61862) ; Fundación Alicia Koplowitz and Fundación de Investigacion Médica Mutua Madrileña.

Peer Reviewed