Effects of OPC-14523,a combined sigma and 5-HT 1a ligand,on pre- and post-synaptic 5-HT 1a receptors

OPC-14523 (OPC) is a novel compound with high affinity for sigma and 5-HT_1A receptors that shows ‘antidepressant-like’ effects in animal models of depression. We have previously demonstrated that OPC produces an increase in 5-HT neurotransmission and a decreased response of 5-HT neurons to the acute administration of paroxetine in the DRN, an effect that appears to be mediated by OPC’s 5-HT_1A receptor affinity. The current study sets out to investigate more specifically the effects of OPC on 5-HT_1A pre- and post-synaptic receptors, to assess whether it acts as an agonist or antagonist. Using an electrophysiological model of in vivo extracellular recordings in anaesthetized rats, the effects of OPC was assessed on pre-synaptic DRN 5-HT_1A autoreceptors and post-synaptically on hippocampal 5-HT_1A receptors of CA₃ pyramidal neurons. OPC applied by microiontophoresis, produced a significant decrease in the firing activity of 5-HT neurons of the DRN and of quisqualate-activated CA₃ pyramidal neurons of the dorsal hippocampus. The effects of OPC on 5-HT_1A receptors were significantly reduced by the co-application of the 5-HT_1A antagonist WAY-100635. In addition, the effects of OPC were not blocked by the injection of the sigma antagonists NE-100 or haloperidol. Therefore, OPC is acting as an agonist on both pre- and post-synaptic 5-HT_1A receptors. The current findings combined with previous data on OPC suggest a pharmacological profile that warrants further investigation.