Mutsuko Maekawa (1,2), Toshihiko Murayama (1), Satoshi Ono (2), Hirokazu
Narita (2) and Yasuyuki Nomura (1,*)
(1) Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
(2) Research Laboratories, Toyama Chemical Co., Ltd., Toyama 930-8508, Japan
(*) To whom correspondence should be addressed.
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 microM 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.
Keywords: T-588, Noradrenaline uptake and release, Cerebral cortical slice, Desipramine, Reserpine