-1-(BENZO[B]THIOPHEN-5-YL)-2-[2-(N,N-DIETHYLAMINO) ETHOXY]ETHANOL HYDROCHLORIDE (T-588), A NOVEL COGNITIVE ENHANCER, ON NORADRENALINE RELEASE IN RAT CEREBRAL CORTICAL SLICES

We investigated the effects of -1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-di ethylamino) ethoxy]ethanol hydrochloride (T-588), a novel cognitive en hancer, on noradrenaline (NA) release from rat cerebral cortical slice s in vitro. Addition of T-588 in an assay mixture stimulated [H-3]NA r elease from prelabeled slices in the presence or absence of extracellu lar CaCl2, and in the presence of the Ca2+/calmodulin antagonists N-(6 -aminohexyl)-5-chloro-1-naphthalenes and trifluoperazine. T-588 stimul ated NA release with a time lag of about 1 min, and the high level of release was maintained for at least 10 min, whereas maximal KCl-evoked NA release was observed within 1 min after the addition of KCl, and t he effect declined subsequently. The effect of T-588 was reversible (p retreatment with T-588 showed no effect on NA release after two washes by centrifugation). We also compared the effects of T-588 and N ethyl maleimide (NEM), a sulfhydryl alkylating agent known to stimulate neur otransmitter release in several types of cells. The addition of NEM st imulated NA release irreversibly from the slices in a Ca2+-independent manner, and the effect of NEM, but not that of T-588, was inhibited b y the simultaneous addition of dithiothreitol, a sulfhydryl group redu cing agent. The addition of T-588, which stimulated NA release by itse lf, inhibited the NA release by 0.6 mM NEM, although the effect of T-5 88 was additive in the presence of 0.2 mM NEM. These findings suggest that T-588 stimulates NA release from rat cerebral cortical slices in a Ca2+- and calmodulin-independent manner, possibly via an NEM sensiti ve factor(s), although the mechanism of the effects of T-588 seems to be different from that of NEM. (C) 1997 Elsevier Science Inc.