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NEUROPHARMACOLOGY

Effects of the Potential Antidepressant OPC-14523 [1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone Monomethanesulfonate] a Combined and 5-HT_1A Ligand: Modulation of Neuronal Activity in the Dorsal Raphe Nucleus

Department of Psychiatry, McGill University, Montréal, Québec, Canada (J.E.B., G.D.); and Laboratory of Neuropharmacology and Neurochemistry, University of Claude Bernard Lyon I, Institut National de la Santé et de la Recherche Médicale, Lyon, France (N.H.)

OPC-14523 (OPC; [1-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate)] is a novel compound with high affinity for and 5-HT_1A receptors as well as for the 5-HT transporter. OPC has previously been shown to produce antidepressant-like effects in animal models of depression. This project set out to determine the effect of OPC on serotonergic neurotransmission and to shed light on its mechanism(s) of action. In an electrophysiological model of in vivo extracellular recordings in anesthetized rats, a 2-day treatment (1 mg/kg/day) with OPC induced a significant increase in dorsal raphe nucleus (DRN) putative 5-HT neurons' firing activity. This increase was blocked by the coadministration of NE-100 [N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine], a selective ₁ antagonist (10 mg/kg/day). Furthermore, after 2-day treatments with OPC, the 5-HT_1A autoreceptor response was altered, as demonstrated by the dramatically reduced response to an increase of endogenous 5-HT induced by the acute administration of paroxetine (500 µg/kg, i.v.). However, the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (4 µg/kg, i.v.) maintained its ability to decrease 5-HT firing activity, an effect that was reversible by the subsequent administration of the 5-HT_1A antagonist WAY 100635 [N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexanecarboxamide] (100 µg/kg, i.v.). As 8-OH-DPAT has been shown to act preferentially through postsynaptic 5-HT_1A receptors, our data suggests that this effect of OPC is mediated primarily by the 5-HT_1A autoreceptor. The decreased response of the 5-HT_1A autoreceptor to paroxetine was not blocked by the coadministration of NE-100 indicating that ₁ receptors are not involved in this effect. Thus, both and 5-HT_1A receptors play a role in the "antidepressant-like" effects produced by OPC, which is in keeping with previously published behavioral data. In addition, the current series of experiments suggest that OPC might have potential as an antidepressant with a rapid onset of action compared with selective serotonin reuptake inhibitor treatments, which initially suppress the firing activity of putative 5-HT neurons and require at least 2 to 3 weeks to restore the firing activity to baseline neuronal firing activity through a desensitization of the 5-HT_1A autoreceptor.

Address correspondence to: Dr. Guy Debonnel, Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: guy.debonnel{at}mcgill.ca

This article has been cited by other articles:

				J. E. Bermack and G. Debonnel Effects of OPC-14523, a combined sigma and 5-HT1a ligand, on pre- and post-synaptic 5-HT1a receptors J Psychopharmacol, January 1, 2007; 21(1): 85 - 92. [Abstract] [PDF]