Preferential in vivo action of F15599, a novel 5-HT(1A) receptor agonist, at postsynaptic 5-HT(1A) receptors.

Abstract

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 microg x kg(-1) i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 microg x kg(-1) i.v.). Both effects were reversed by the 5-HT(1A) antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (approximately 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 microg x 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 microg x 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.

• Authors: L Lladó-Pelfort, M-B Assié, A Newman-Tancredi, F Artigas, P Celada
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 160 Issue 8 Pg. 1929-40 (Aug 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20649591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
• Antidepressive Agents
• Antipsychotic Agents
• Autoreceptors
• Cyclohexanes
• Dopamine Antagonists
• Piperazines
• Piperidines
• Pyrimidines
• Serotonin 5-HT1 Receptor Agonists
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Receptor Agonists
• WAY 101363
• Receptor, Serotonin, 5-HT1A
• Serotonin
• Dopamine

Topics

• Action Potentials
• Animals
• Antidepressive Agents (pharmacology)
• Antipsychotic Agents (pharmacology)
• Autoreceptors (agonists, metabolism)
• Brain (cytology, drug effects, metabolism)
• Cyclohexanes (pharmacology)
• Dopamine (metabolism)
• Dopamine Antagonists (pharmacology)
• Dose-Response Relationship, Drug
• Hippocampus (drug effects, metabolism)
• Injections, Intraperitoneal
• Male
• Microdialysis
• Piperazines (pharmacology)
• Piperidines (administration & dosage, pharmacology)
• Prefrontal Cortex (drug effects, metabolism)
• Pyramidal Cells (drug effects, metabolism)
• Pyrimidines (administration & dosage, pharmacology)
• Raphe Nuclei (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptor, Serotonin, 5-HT1A (metabolism)
• Serotonin (metabolism)
• Serotonin 5-HT1 Receptor Agonists
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Receptor Agonists (administration & dosage, pharmacology)
• Synapses (drug effects, metabolism)
• Time Factors