A 7 days treatment with the 5-HT4 receptor agonist RS67333 is required to obtain a complete antidepressant-like response in animal models

Abstract

In the last years, new drugs are being developed to obtain antidepressant-like effects with a shor ter onset of action, such as partial agonists of 5-HT4 receptors. According to the neurogenic hypothesis of depression, the antidepressant effect could be due to increased proliferation and neurotrophic factors in hippocampus. The aim of this study was to analyze neuroplasticrelated changes as BrdU incorporation, BDNF mRNA expression, transcription factors as β-catenin and CREB, all correlated with behavioural tests. The 5-HT4 receptor partial agonist RS67333 (1.5 mg/kg/da y s.c.) was administered for 3 or 7 days to Sprague-Dawley rats. RS67333 was effective in the forced swimming test following 3 and 7 days. However, 7 days were required to obtain antidepressant-like response in the novelty-suppressed feeding and corticosterone-induced anhedonia. BrdU and β-catenin immunolabelling were increased after 3 and 7 days. BDNF mRNA expression was increased in CA3 of the hippocampus (28%, p<0.01) after 3 days, while 7 days increased in CA1 (73%, p<0.01) and DG (53%, p<0.01). Similarly, RS67333 only desensitized the 5-HT4 receptor-coupled adenylate cyclase after 7 days compared to control (Emax 84% vs 135% respectively, p<0.05). CREB (40%, p<0.05), and pCREB (83%, p<0.05) were only significantly increased after 7 days treatment, while pCREB/CREB ratio was increased aft er both 3 days (93%, p<0.05) and 7 days (84%, p<0.05). These results suggest that 7 days of RS67333treatment arerequired to elicit hippocampal neuroplastic changes associated to fully positivebehavioural effects, confirming that 5-HT4 receptor agonism is an encouraging strategy for the development of faster acting antidepressants.