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-HT1A Ligand: Modulation of Neuronal Activity in the Dorsal Raphe Nucleus

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-HT1A 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-(2phenylethoxy)phenyl)-thylamine], a selective 1 antagonist (10 mg/kg/day). Furthermore, after 2-day treatments with OPC, the 5-HT1A 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 g/kg, i.v.). However, the 5-HT1A agonist 8-hydroxy-2-(din-propylamino)tetralin (8-OH-DPAT) (4 g/kg, i.v.) maintained its ability to decrease 5-HT firing activity, an effect that was reversible by the subsequent administration of the 5-HT1A antagonist WAY 100635 [N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexanecarboxamide] (100 g/kg, i.v.). As 8-OH-DPAT has been shown to act preferentially through postsynaptic 5-HT1A receptors, our data suggests that this effect of OPC is mediated primarily by the 5-HT1A autoreceptor. The decreased response of the 5-HT1A 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-HT1A receptors play a role in the “antidepressantlike” 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-HT1A autoreceptor. An enormous amount of evidence suggests the involvement of the serotonin system in the pathophysiology of depression (Delgado, 2000). Electrophysiological data demonstrates that representatives from all classes of antidepressants, after long-term treatments and through various mechanisms, increase 5-HT neurotransmission (Chaput et al., 1991; Blier and de Montigny, 1994). For example, acute treatments with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) lead to decreased firing activity of 5-HT neurons in the dorsal raphe nucleus (DRN), but as treatment continues, the 5-HT neurons regain normal firing activity due to desensitization of the 5-HT1A somatodendritic autoreceptor. This desensitization has been proposed as the adaptive change that explains the delayed enArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.104.066472. ABBREVIATIONS: 5-HT, serotonin; 5-HT1A, 5-hydroxytryptamine1A; SSRI, selective serotonin reuptake inhibitor; DRN, dorsal raphe nucleus; 4-IBP, 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide; OPC, OPC-14523; OPC-14523, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy3,4-dihydro-2-quinolinone monomethanesulfonate; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; NE-100, N,N-dipropyl-2-(4-methoxy-3(2-phenylethoxy)phenyl)-thylamine; WAY-100635, N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexanecarboxamide. 0022-3565/04/3102-578–583$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 310, No. 2 Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics 66472/1156437 JPET 310:578–583, 2004 Printed in U.S.A. 578 at A PE T Jornals on N ovem er 3, 2017 jpet.asjournals.org D ow nladed from hancement of 5-HT-mediated neurotransmission, which is consistent with the clinical onset of action of SSRIs (Chaput et al., 1986; Blier et al., 1988; Blier and de Montigny, 1994). The existence of receptors was initially reported by Martin et al. (1976). The existence of at least two receptors, denoted 1 and 2, is now accepted (Quirion et al., 1987, 1992). ligands have been implicated in the pathophysiology of depression or have been proposed as potential antidepressants. ligands such as SA-4503 [1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride], ( )-pentazocine, DTG [1,3-di-(2-tolyl)guanidine], and JO-1784 [( )-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-11-ethyl-but-3-en-1-ylamine hydrochloride] have been shown to produce antidepressant-like effects in behavioral models of depression such as the forced swimming test, the tail suspension test, and in clinical trials (Matsuno et al., 1996; Kinsora et al., 1998; Pande et al., 1998; Ukai et al., 1998; Akunne et al., 2001; Urani et al., 2001). We previously demonstrated that the ligands 4-IBP and ( )-pentazocine produce an increase in the basal firing activity of 5-HT neurons of the DRN after short-term (2 days) and long-term (21 days) treatments (Bermack and Debonnel, 2001). The effects of ( )-pentazocine were blocked by the coadministration of the selective 1 antagonist NE-100, whereas those of 4-IBP were blocked by the coadministration of the nonselective antagonist haloperidol but not NE-100 (Bermack and Debonnel, 2001). OPC is a novel compound with high affinities for and 5-HT1A receptors and with 5-HT reuptake inhibitory activities (Tottori et al., 2001). Similar to other ligands, OPC yielded antidepressant-like effects in animal models of depression (Tottori et al., 2001). Interestingly, the immobility time was reduced in the forced swimming test after a single dose of OPC, and the daily administration for 7 days enhanced this effect (Tottori et al., 2001). Thus, the purpose of this study was to assess the effect of acute and short-term treatments with OPC on DRN neurotransmission using an electrophysiological model of extracellular recordings of putative 5-HT neurons from the DRN. Furthermore, we assessed the effect of the treatments with OPC on the response of the 5-HT1A somatodendritic autoreceptors since OPC has high affinity for 5-HT1A receptors, and this could have relevance to its potential antidepressant properties. Materials and Methods Animals. Experiments were performed in male Sprague-Dawley rats (Charles River, St. Constant, Québec) weighing 250 to 300 g. Rats were housed under standard laboratory conditions including 12 h light/dark cycle and free access to food and water. Acute Treatments. For the acute treatments, once a putative 5-HT neuron was identified and recorded for approximately 1 min, saline or OPC were administered intravenously via the tail vein during electrophysiological recording. Five rats were tested for each dose studied with one injection administered per rat. Short-Term Treatments. Animals were anesthetized with halothane for the subcutaneous implantation of osmotic minipumps (Durect Corporation, Cupertino, CA) placed in the back of the animal. The minipumps delivered a dose of 1 mg/kg/day OPC-14523 dissolved in 5% ethanol and distilled water. A separate series of rats were implanted with two pumps simultaneously, one containing OPC and the other containing NE-100 (10 mg/kg/day). The duration of all treatments was 2 days. The control groups were treated with minipumps filled with 5% ethanol and distilled water. Electrophysiological experiments were performed with the minipump(s) on