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Preferential in vivo action of F15599, a novel 5‐HT 1A receptor agonist, at postsynaptic 5‐HT 1A receptors
Author(s) -
LladóPelfort L,
Assié MB,
NewmanTancredi A,
Artigas F,
Celada P
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00738.x
Subject(s) - autoreceptor , microdialysis , agonist , postsynaptic potential , chemistry , 5 ht receptor , dorsal raphe nucleus , dopamine , receptor , medicine , endocrinology , serotonin , neuroscience , biology , serotonergic , biochemistry
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‐HT 1A 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 µg·kg −1 i.v and reduced that of dorsal raphe 5‐hydroxytryptaminergic neurones at doses >10‐fold higher (minimal effective dose 8.2 µg·kg −1 i.v.). Both effects were reversed by the 5‐HT 1A antagonist (±)WAY100635. F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5‐HT 1A receptors) with an ED 50 of 30 µg·kg −1 i.p., whereas it reduced hippocampal 5‐HT release (an effect dependent exclusively on 5‐HT 1A autoreceptor activation) with an ED 50 of 240 µg·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‐HT 1A receptors in PFC rather than somatodendritic 5‐HT 1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5‐HT 1A receptor agonists, which preferentially activate somatodendritic 5‐HT 1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.