Effect of sustained administration of the 5-HT1A receptor agonist flesinoxan on rat 5-HT neurotransmission.
A short-term treatment with flesinoxan (2.5 and 5 mg/kg/day x 2 days, s.c., delivered using osmotic minipumps) decreased significantly the spontaneous firing activity of dorsal raphe serotonin (5-HT) neurons of male Sprague-Dawley rats. This firing was still decreased following 1 week of treatment with flesinoxan (5 mg/kg/day) but was back to normal after a treatment of 2 weeks. This recovery of firing was associated with a 3-fold shift to the right of the dose-response curve of the effect of the 5-HT autoreceptor agonist lysergic acid diethylamide on the firing activity of 5-HT neurons, indicating a desensitization of somatodendritic 5-HT1A autoreceptors. At the postsynaptic level, long-term treatment with flesinoxan (5 mg/kg/day x 14 days) did not modify the responsiveness of dorsal hippocampus CA3 pyramidal neurons to microiontophoretic applications of 5-HT and flesinoxan nor to endogenous 5-HT released by the electrical stimulation of the ascending 5-HT pathway, indicating an unchanged sensitivity of postsynaptic 5-HT1A receptors. Finally, in rats treated with flesinoxan for 2 weeks, the administration of the selective 5-HT1A receptor antagonist (N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohe xanecarboxamide trihydroxychloride (WAY 100635, 100 and 500 microg/kg, i.v.) did not increase the firing activity of dorsal hippocampus CA3 pyramidal neurons, thus failing to reveal an enhanced tonic activation of postsynaptic 5-HT1A receptors as for other antidepressant drugs, including the 5-HT1A receptor agonist gepirone. The marked potency and the long dissociation constant of flesinoxan for the 5-HT1A receptors may account for the latter discrepancy. In conclusion, as for selective 5-HT re-uptake inhibitors, monoamine oxidase inhibitors and 5-HT1A receptor agonists, flesinoxan produced most of the adaptive changes exerted by these antidepressant drugs on the 5-HT system.
Haddjeri
N
N
Neurobiological Psychiatry Unit, McGill University, Montréal, Québec, Canada. nhaddj@po-box.mcgill.ca
Ortemann
C
C
de Montigny
C
C
Blier
P
P
D000818:Animals; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects*; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D011725:Pyridines; D011903:Raphe Nuclei / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C056895:flesinoxan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D008238:Lysergic Acid Diethylamide