期刊
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
卷 15, 期 5, 页码 631-643出版社
OXFORD UNIV PRESS
DOI: 10.1017/S1461145711000782
关键词
Adenylate cyclase; BDNF; hippocampus; neurogenesis; serotonin
资金
- Ministerio de Ciencia e Innovacion, Spain
- Plan Nacional sobre Drogas
- Ministerio de Sanidad
- Fundacion Alicia Koplowitz, Spain
- Ministerio de Ciencia e Innovacion [SAF-07/61862]
- Fundacion Alicia Koplowitz
- Fundacion de Investigacion Medica Mutua Madrilena
- Faes Farma, S.A.
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, beta-catenin, AKT and 5-HT4 receptor functionality. RS67333 treatment up-regulated hippocampal cell proliferation, beta-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.
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