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

Lladò-Pelfort L, Assié MB, Newman-Tancredi A, Artigas F, Celada P.
Psychopharmacology (Berl). 2012 May;221(2):261-72. Epub 2011 Dec 3.

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, i.v. (cumulative doses; ED50 = 0.69 μg/kg, i.v.) and increased the discharge rate of 80% of mPFC pyramidal neurons in the same dose range (ED50 = 0.62 μg/kg, 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, i.p.) dose-dependently decreased extracellular 5-HT in the hippocampus and mPFC. Likewise, F13640 (0.01-2.5 mg/kg, 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.