The mechanism of NIK-247, a novel cholinesterase inhibitor, modulating release of endogenous neurotransmitter from brain slices of rats

• Published in: Japanese Journal of Pharmacology Vol. 58; no. suppl.2; p. 374
• Main Authors: Ishii, Yutaka, Sumi, Takahiko
• Format: Journal Article
• Language: English
• Published: The Japanese Pharmacological Society 1992
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)49615-7

We reported that NIK-247 enhances the basal release of endogenous monoamine selectively from rat brain slices without affecting K^+ -evoked release. In the present experiments, we studied the mechanism of NIK-247-induced increase in basal release of endogenous DA, and examined the effects of NIK-247 on the veratridine-evoked release of DA and GABA from rat striatal slices. Stimulation by NIK-247 (1x10^-4 M) of the basal release of DA was independent of Na^+ in the medium, and was enhanced synergistically by nomifensine (1x10^-5 M). NIK-247 (1x10^-4 ～1x10^-6 M) induced a dose-dependent inhibition of the veratridine (5x10^-6 M) evoked release of DA and GABA. Amitriptyline (1x10^-4 M) and imipramine (1x10^-4 M), tricyclic antidepressants, enhanced the basal release of DA, and inhibited the veratridine- but not K^+ -evoked release of DA and GABA. These results indicate that NIK-247 enhances the basal release of monoamines through activation of a carrier mediated mechanism of release and inhibits the veratridine-evoked transmitter release by blocking Na^+ channels. These effects of NIK-247 are similar to those of tricyclic antidepressants.