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