Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in rats

Authors

  • R Vidal,

    1. Instituto de Biomedicina y Biotecnología (IBBTEC) (UC-CSIC-IDICAN), Santander, Cantabria
    2. Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain
    3. CIBERSAM, Ciber de Salud Mental, Instituto Carlos III, Spain
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  • EM Valdizan,

    1. Instituto de Biomedicina y Biotecnología (IBBTEC) (UC-CSIC-IDICAN), Santander, Cantabria
    2. Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain
    3. CIBERSAM, Ciber de Salud Mental, Instituto Carlos III, Spain
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  • MT Vilaró,

    1. Departamento de Neuroquímica y Neurofarmacología, Instituto de Investigaciones Biomédicas de Barcelona, CSIC-IDIBAPS, Barcelona, Spain
    2. CIBERNED, Ciber de Enfermedades Neurodegenerativas, Instituto Carlos III, Spain
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  • A Pazos,

    1. Instituto de Biomedicina y Biotecnología (IBBTEC) (UC-CSIC-IDICAN), Santander, Cantabria
    2. Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain
    3. CIBERSAM, Ciber de Salud Mental, Instituto Carlos III, Spain
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  • E Castro

    Corresponding author
    1. Instituto de Biomedicina y Biotecnología (IBBTEC) (UC-CSIC-IDICAN), Santander, Cantabria
    2. Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain
    3. CIBERSAM, Ciber de Salud Mental, Instituto Carlos III, Spain
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Elena Castro, Department of Physiology and Pharmacology, School of Medicine, Cardenal Herrera Oria s/n, University of Cantabria, 39011 Santander, Spain. E-mail: castroe@unican.es

Abstract

BACKGROUND AND PURPOSE The 5-HT4 receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT4 receptor-mediated signalling events.

EXPERIMENTAL APPROACH The effects of 21 days treatment (p.o.) with high (40 mg·kg−1) and low (10 mg·kg−1) doses of venlafaxine, were evaluated at different levels of 5-HT4 receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg−1, 21 days) was also evaluated on 5-HT4 receptor density.

KEY RESULTS Treatment with a high dose (40 mg·kg−1) of venlafaxine did not alter 5-HT4 mRNA expression, but decreased the density of 5-HT4 receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg−1) while it was attenuated in rats treated with 40 mg·kg−1 of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT4 receptor density.

CONCLUSIONS AND IMPLICATIONS Our data indicate a functional desensitization of 5-HT4 receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake.

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