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In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat

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Abstract

Rationale

F13640 (befiradol) is a novel 5-HT1A receptor agonist with exceptional selectivity vs. other receptors and binding sites. It shows analgesic activity in animal models and is currently developed for human use.

Objectives

Given the potential dual role of the serotonergic system in pain, through the modulation of ascending signals in spinal cord and their emotional processing by corticolimbic areas, we examined the in vivo activity of F13640 at somatodendritic autoreceptors and postsynaptic 5-HT1A heteroreceptors in medial prefrontal cortex (mPFC).

Methods

In vivo single unit recordings and intracerebral microdialysis in the rat.

Results

F13640 reduced the activity of dorsal raphe serotonergic neurons at 0.2–18.2 μg kg−1, i.v. (cumulative doses; ED50 = 0.69 μg kg−1, i.v.) and increased the discharge rate of 80% of mPFC pyramidal neurons in the same dose range (ED50 = 0.62 μg kg−1, i.v.). Both effects were reversed by the subsequent administration of the 5-HT1A receptor antagonist (±)WAY100635. In microdialysis studies, F13640 (0.04–0.63 mg kg−1, i.p.) dose-dependently decreased extracellular 5-HT in the hippocampus and mPFC. Likewise, F13640 (0.01–2.5 mg kg−1, i.p.) dose-dependently increased extracellular DA in mPFC, an effect dependent on the activation of postsynaptic 5-HT1A receptors in mPFC. Local perfusion of F13640 in mPFC (1–1,000 μM) also increased extracellular DA in a concentration-dependent manner. Both the systemic and local effects of F13640 were prevented by prior (±)WAY100635 administration.

Conclusions

These results indicate that, upon systemic administration, F13640 activates both 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors in prefrontal cortex with a similar potency. Both activities are likely involved in the analgesic properties of the compound.

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Abbreviations

DA:

Dopamine

DR:

Dorsal raphe nucleus

F13640:

[(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone Fumaric acid salt

mPFC:

Medial prefrontal cortex

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Acknowledgements

This work was supported by grants SAF 2007–62378, FIS PI060264, FIS PI09/1245 (PN I + D + I 2008–2011, ISCIII-Subdirección General de Investigación y Fomento de la Investigación), Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM and Pierre Fabre Médicament. L.L.-P. was supported by a JAE fellowship from CSIC. P.C. is supported by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya. L.L-P. and P.C. declare no conflict of interest. F.A. received lecture fees from Pierre Fabre Médicament. A.N.-T. and M.B.A. were employees of Pierre Fabre Médicament at the time of realization of the studies and were involved in the experimental design and microdialysis data interpretation. We acknowledge Véronique Ravailhe and Christelle Benas for technical assistance with microdialysis experiments and Mónica Gutiérrez and Verónica Paz for electrophysiological experiments.

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  1. Adrian Newman-Tancredi

    Present address: NeuroAct Communication, Castres, France

Authors and Affiliations

  1. Department of Neurochemistry and Neuropharmacology, Institut d’Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Rosselló 161, 6th floor, 08036, Barcelona, Spain

    Laia Lladó-Pelfort, Francesc Artigas & Pau Celada

  2. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain

    Laia Lladó-Pelfort, Francesc Artigas & Pau Celada

  3. Neurobiology Division 2, Centre de Recherches Pierre Fabre, Castres, France

    Marie-Bernadette Assié & Adrian Newman-Tancredi

  4. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Francesc Artigas & Pau Celada

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  1. Laia Lladó-Pelfort
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  2. Marie-Bernadette Assié
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Correspondence to Pau Celada.

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Lladó-Pelfort, L., Assié, MB., Newman-Tancredi, A. et al. In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat. Psychopharmacology 221, 261–272 (2012). https://doi.org/10.1007/s00213-011-2569-9

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