P.1.c.059 Electrophysiological properties of the triple reuptake inhibitor SEP 225289 on monoaminergic neurons

Abstract

SEP 225289 reduced the firing rate of NE, DA and 5-HT neurons through the activation of 2, D2 and 5-HT1A autoreceptors, respectively. The predominant inhibitory effect of SEP 225289 was detected in the LC while it produces only a partial decrease in VTA DA and DRN 5-HT neuronal activities. The unexpected moderate inhibitory effect of SEP 225289 in the DRN is not due to a lesser degree of reuptake blockade of 5-HT than for NE because it is similarly effective in prolonging the recovery of firing of pyramidal neurons following 5-HT and NE applications. It is thus possible that noradrenergic and/or dopaminergic inputs innervating the DRN produce excitatory influence on 5-HT neurons thereby limiting the inhibitory effect of SEP 225289 in the DRN. The observation that SEP 225289 activates the firing of 5-HT neurons in the presence of the 5-HT1A receptor antagonist WAY 100635 is consistent with this hypothesis. Supported by funding from SEPRACOR Inc.