The Effects of T-588, a Novel Cognitive Enhancer, on Noradrenaline Uptake and Release in Rat Cerebral Cortical Slices

Abstract

Previously, we reported that (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N, N-diethylamino)-ethoxy]ethanol hydrochloride (T-588), a novel cognitive enhancer, stimulated noradrenaline (NA) release from rat cerebral cortical slices. In this study, we investigated the effects of T-588 on NA uptake and release, compared to the effects of desipramine, a blocker of the NA carrier on the plasma membrane. Both T-588 and desipramine caused dose-dependent inhibition of [³H]NA uptake into the slices. Addition of 3 mM T-588 stimulated [³H]NA release from the prelabeled slices even in the presence of 10 μM desipramine, which inhibited NA uptake completely. Tyramine, which accelerates NA carrier-mediated release, also stimulated [³H]NA release, and tyramine-stimulated release was inhibited by desipramine. These findings indicated that T-588-stimulated NA release was not mediated by 1) inhibition of reuptake or 2) reverse transport mediated by NA carriers. Reserpine, which interacts with the intracellular vesicular transport system, increased [³H]NA efflux from slices. High K⁺-, not T-588-, stimulated [³H]NA release was shifted upward by reserpine. These findings suggest that T-588 evokes NA release by a mechanism similar to that induced by reserpine. T-588 might act as a cognitive enhancer via neurotransmitter release in the brain.