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Chronic fluoxetine regulates both 5-HT1A receptor functionality and hippocampal b-catenin pathway in an animal model of depression

AuthorsPascual-Brazo, Jesús CSIC; Rodríguez-Gaztelumendi, A. CSIC ORCID; Ruiz, I.; Pilar-Cuéllar, Fuencisla CSIC ORCID; Pazos, Ángel CSIC ORCID; Díaz, Álvaro CSIC ORCID
Issue Date2008
PublisherJohn Wiley & Sons
CitationFundamental and Clinical Pharmacology 22(s2): 89 (2008)
AbstractIn the last years, brain neurogenesis has received much attention regarding the molecular mechanisms by which anti-depressants exert their therapeutic effect: in this regard, the b-catenin pathway plays a crucial role in cell proliferation and fate of adult hippocampal stem/progenitor cells (AHPs). On the other hand, 5-HT neurotransmission, classically involved in anti-depressant-induced responses, appears to play a relevant role in brain plasticity. Because of that, the goal of this study was to analyze both the hippocampal expression of b-catenin (immunoblotting, total cell hippocampal lisates) and the density and functionality of brain 5-HT1A receptors ([3H]OH-DPAT and [35S]GTPcS autoradiography) in an animal model of depression, as well as its regulation by the chronic administration of the serotonin re-uptake inhibitor (SSRI) fluoxetine (10 mg/kg/day, 14 days; s.c.). The animal model of bilateral olfactory bulbectomy in rat (OB) resembles many neurochemical and structural features observed in human depression. Chronic fluoxetine fully attenuated hyperactivity in the >open-field> test in the OB + fluoxetine group (P < 0.01 vs. OB + vehicle) whereas had no effect in sham-operated animals. Regarding Western blot assays, a reduction of b-catenin expression was found in the hippocampal lisates from OB animals. Chronic fluoxetine treatment resulted in a significant increase (P < 0.05 vs. non-treated groups) of b-catenin expression in both experimental groups. No changes were found in OB rats in hippocampus either in receptor density or in 8-OH-DPAT-induced stimulation of [35S]GTPcS binding in hippocampus and dorsal raphe nucleus (DRN). Chronic fluoxetine significantly reduced the level of 8-OH-DPAT-induced stimulation of [35S]GTPcS binding in both sham-operated and OB animals, in areas such as dentate gyrus (169.2, 26.7 vs. 272.5, 45.0 in shamoperated, P < 0.05; 128.6, 14.5 vs. 300.7, 84.3 in OB animals, P < 0.05) and DRN. These findings support a role for the regulation of neuro-proliferative pathways in the mechanism of action of fluoxetine, raising the question of the involvement of 5-HT mediated mechanisms in these modifications.
DescriptionTrabajo presentado al EPHAR 2008 Congress celebrado en Manchester.
Appears in Collections:(IBBTEC) Artículos
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