Abstract

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 σ 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 σ₁ 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 σ₁ receptors are not involved in this effect. Thus, both σ 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.