Antidepressant-like responses to the combined sigma and 5-HT(1A) receptor agonist OPC-14523
Tottori K, Miwa T, Uwahodo Y, Yamada S, Nakai M, Oshiro Y, Kikuchi T, Altar CA.
Research Institute of Pharmacological and Therapeutical Development,
Otsuka Pharmaceutical Co., Ltd,
463-10 Kagasuno 771-0192,
Kawauchi-cho Tokushima, Japan
Neuropharmacology 2001 Dec;41(8):976-988


The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC(50)=47-56nM), the 5-HT(1A) receptor (IC(50)=2.3nM), and the 5-HT transporter (IC(50)=80nM). OPC-14523 inhibited the in vitro reuptake of 3H-5-HT (IC(50)=27nM), but it showed very weak inhibitory activity on 3H-NE and 3H-DA reuptake. OPC-14523 did not inhibit MAO A or B activities or muscarinic receptors. A single oral administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimming test (FST) with rats (ED(50)=27mg/kg) and mice (ED(50)=20mg/kg) without affecting the general locomotor activity. In contrast, fluoxetine and imipramine each required at least four days of repeated dosing to show this activity. The acute activity of OPC-14523 was blocked by pretreatment with the sigma receptor antagonist NE-100 or the selective 5-HT(1A) receptor antagonist WAY-100635. The induction of flat body posture by OPC-14523 was blocked by the selective 5-HT(1A) receptor antagonist NAN-190, and forebrain 5-HT biosynthesis was attenuated by OPC-14523 at behaviorally effective doses. In contrast, OPC-14523, unlike fluoxetine, failed to inhibit 5-HT reuptake at oral doses below 100mg/kg. Thus, the acute antidepressant-like action of OPC-14523 is achieved by the combined stimulation of sigma and 5-HT(1A) receptors without inhibition of 5-HT reuptake in vivo.
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