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Work supported by grants SAF 2007-62378, FIS PI060264 and Pierre Fabre Medicament. L.L.-P. is 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. We acknowledge Veronique Ravailhe and Christelle Benas for technical assistance with microdialysis experiments and Monica Gutierrez and Veronica Paz for electrophysiological experiments.

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Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors

Publicado en:British Journal Of Pharmacology. 160 (8): 1929-1940 - 2010-08-01 160(8), DOI: 10.1111/j.1476-5381.2010.00738.x

Autores: Llado-Pelfort, L; Assie, M-B; Newman-Tancredi, A; Artigas, F; Celada, P

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Background and purpose: F15599, a novel 5-hydroxytryptamine (5-HT)(1A) receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT1A heteroreceptors. Experimental approach: In vivo single unit and local field potential recordings and microdialysis in the rat. Key results: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 mu g center dot kg-1 i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses > 10-fold higher (minimal effective dose 8.2 mu g center dot kg-1 i.v.). Both effects were reversed by the 5-HT1A antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (similar to 1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 mu g center dot kg-1 i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 mu g center dot kg-1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (+/-)WAY100635. Conclusions and implications: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT1A receptors in PFC rather than somatodendritic 5-HT1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT1A receptor agonists, which preferentially activate somatodendritic 5-HT1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.

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