Modulation of neuroplasticity pathways and antidepressant-like behavioural responses following the short-term (3 and 7 days) administration of the 5-HT4 receptor agonist RS67333

Abstract

It has been recently suggested that activation of 5-HT₄ receptors might exert antidepressant-like effects in rats after 3 d treatment, suggesting a new strategy for developing faster-acting antidepressants. We studied the effects of 3 d and 7 d treatment with the 5-HT₄ receptor partial agonist RS67333 (1.5 mg/kg.d) in behavioural tests of chronic efficacy and on neuroplastic-associated changes, such as adult hippocampal neurogenesis, expression of CREB, BDNF, β-catenin, AKT and 5-HT₄ receptor functionality. RS67333 treatment up-regulated hippocampal cell proliferation, β-catenin expression and pCREB/CREB ratio after 3 d treatment. This short-term treatment also reduced immobility time in the forced swim test (FST), together with a partial reversion of the anhedonic-like state (sucrose consumption after chronic corticosterone). Administration of RS67333 for 7 d resulted in a higher increase in the rate of hippocampal cell proliferation, a significant desensitization of 5-HT₄ receptor-coupled adenylate cyclase activity and a more marked increase in the expression of neuroplasticity-related proteins (BDNF, CREB, AKT): these changes reached the same magnitude as those observed after 3 wk administration of classical antidepressants. Consistently, a positive behavioural response in the novelty suppressed feeding (NSF) test and a complete reversion of the anhedonic-like state (sucrose consumption) were also observed after 7 d treatment. These results support the antidepressant-like profile of RS67333 with a shorter onset of action and suggest that this time period of administration (3-7 d) could be a good approximation to experimentally predict the onset of action of this promising strategy.

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

“…The development of new antidepressants is therefore of considerable importance (Wong et al, 2010), and understanding the mechanisms underlying the delayed onset should offer insights into new approaches. Recent studies as well as our present results indicate that 5-HT4 receptor agonists are faster acting than SSRIs (Lucas et al, 2007;Pascual-Brazo et al, 2012;Tamburella et al, 2009). Although a 7-day treatment with fluoxetine or RS67333 induced antidepressant-like activity in the TST and ST, only the 5-HT 4 agonist RS67333 resulted in anxiolytic-like activity in the OF and the EPM.…”

“…Indeed, administration of 5-HT 4 agonists induced similar molecular and behavioral changes as common antidepressants in rodents (Bockaert et al, 2008;Lucas et al, 2007;Pascual-Brazo et al, 2012). Depressed-like state in the olfactory bulbectomy or chronic mild stress model was completely abolished after 10-14 days of RS67333 treatment in rats, suggesting a more rapid response mechanism in comparison with classical antidepressants (Lucas et al, 2007).…”

“…Moreover, a recent study in rats reported that the behavioral and neurogenic (proliferation of newborn cells) effects of the 5-HT 4 receptor agonist RS67333 occur after short-term administration (3-7 days depending on the paradigm) (Pascual-Brazo et al, 2012). Thus, we also investigated whether subchronic RS67333 treatment induced a rapid onset of behavioral effects.…”

“…Depressed-like state in the olfactory bulbectomy or chronic mild stress model was completely abolished after 10-14 days of RS67333 treatment in rats, suggesting a more rapid response mechanism in comparison with classical antidepressants (Lucas et al, 2007). A positive behavioral response in the Novelty-Suppressed Feeding (NSF) test in rat, a complete reversion of anhedonic-like state (sucrose consumption), and an increase in swimming behavior in defeated mice in the forced swim test were also observed after a short period of RS67333 treatment (Gomez-Lazaro et al, 2012;Pascual-Brazo et al, 2012). In addition to behavioral data, and in agreement with a previous report from Lucas et al (2007), a recent study performed in naive rats confirmed that a short period of treatment with RS67333 increased the number of newborn cells in the dentate gyrus (DG) (Pascual-Brazo et al, 2012).…”

“…A positive behavioral response in the Novelty-Suppressed Feeding (NSF) test in rat, a complete reversion of anhedonic-like state (sucrose consumption), and an increase in swimming behavior in defeated mice in the forced swim test were also observed after a short period of RS67333 treatment (Gomez-Lazaro et al, 2012;Pascual-Brazo et al, 2012). In addition to behavioral data, and in agreement with a previous report from Lucas et al (2007), a recent study performed in naive rats confirmed that a short period of treatment with RS67333 increased the number of newborn cells in the dentate gyrus (DG) (Pascual-Brazo et al, 2012). These results are interesting because hippocampal neurogenesis has been implicated in some of the behavioral effects of antidepressants in adult rodents (David et al, 2009;Santarelli et al, 2003).…”