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Dose-dependent desensitisation of the signalisation pathway coupled to 5-HT4 receptors following dual antidepressant administration: a study with venlafaxine

AuthorsCastro, Elena CSIC ORCID; Vidal, Rebeca CSIC ORCID; Valdizán, Elsa M. CSIC ORCID; Mostany, Ricardo; Pazos, Ángel CSIC ORCID
Issue Date2008
CitationXXX SOCESFAR 2008
AbstractVenlafaxine is an antidepressant drug for which clinical studies have suggested higher efficacy and earlier action onset than those of classical antidepressants. Although venlafaxine blocks both 5-HT and NE reuptake systems, their antidepressant effects might be due, at least in part, to adaptive changes in some 5-HT receptors. Some evidence suggests the involvement of 5-HT4 in the pathophysiology of depression. In this way, electrophysiological and behavioural data demonstrates that 5-HT4 receptor agonists show antidepressant-like effects. In addition, previous studies have described an increase of both 5-HT4 receptor density and functionality in the brain of suicide victims. The purpose of this study was to assess the long-term effects of venlafaxine (10 and 40 mg/kg/day, p.o., 21 days) on 5-HT4 receptor neurotransmission using [35S]GTP¿S binding, adenylate cyclase assays and extracellular recordings in slices of the hippocampus. Adecrease of zacopride-stimulated [35S]GTP¿S binding in striatal membranes following chronic venlafaxine treatment (% reduction = 17.1 and 58.2% (p <0.01) for 10 and 40 mg/kg respectively) was found. Consistent with [35S]GTP¿S binding studies, we also found a significant lower response in zacopride-stimulated adenylate cyclase in the same area in both 10 mg/kg (% reduction = 19.5%; ns) and 40 mg/kg (% reduction = 40.5%; p <0.05) venlafaxine-treated groups. Finally, the excitatory action on the population spike in the pyramidal cells of CA1 of 10 ¿M zacopride, an indication of 5-HT4 receptor function, was also attenuated, in a dose-dependent way, following the two doses of venlafaxine (reduction = 36.7%; p< 0.05 and 55.5%; p< 0.05, for 10 and 40 mg/kg/day respectively). In conclusion, our results demonstrate the existence of dose-dependent 5-HT4 receptor desensitisation following chronic administration of venlafaxine. Taking into account that a high dose is required to obtain a complete desensitization pattern, it is suggested that the noradrenergic component may play a relevant role in the regulation of 5-HT4 receptors by chronic NSRI drugs.
DescriptionTrabajo presentado al XXX Congreso de la Sociedad Española de Farmacología celebrado en Bilbao del 17 al 19 de septiembre de 2008.
Appears in Collections:(IBBTEC) Comunicaciones congresos
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