title: 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.
authors: Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain.
authors: Jesús
authors: J
authors: Pascual-Brazo
authors: Elena
authors: E
authors: Castro
authors: Alvaro
authors: A
authors: Díaz
authors: Elsa M
authors: EM
authors: Valdizán
authors: Fuencisla
authors: F
authors: Pilar-Cuéllar
authors: Rebeca
authors: R
authors: Vidal
authors: Begoña
authors: B
authors: Treceño
authors: Angel
authors: A
authors: Pazos
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D009434:Neural Pathways / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000814:Aniline Compounds; D000928:Antidepressive Agents; D009419:Nerve Tissue Proteins; D010880:Piperidines; C107826:RS 67333