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

Br J Pharmacol. 2010 Aug;160(8):1929-40. doi: 10.1111/j.1476-5381.2010.00738.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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