The effects of T-588, a novel cognitive enhancer, on noradrenaline uptake and release in rat cerebral cortical slices.
Previously, we reported that (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)-ethoxy]e thanol 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.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
M
M
Maekawa
T
T
Murayama
S
S
Ono
H
H
Narita
Y
Y
Nomura
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D002122:Calcium Chloride / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology; D004048:Diethylamines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism* / Q000493:pharmacokinetics*; D011189:Potassium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000008:administration & dosage / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D014439:Tyramine / Q000037:antagonists & inhibitors / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D004048:Diethylamines; D013876:Thiophenes; C082372:T 588; D011189:Potassium Chloride; D012110:Reserpine; D002122:Calcium Chloride; D003891:Desipramine; D009638:Norepinephrine; D014439:Tyramine