-N-(3-FLUORO-4-PYRIDINYL)-1H-3-METHYLINDOL-1-AMINE HYDROCHLORIDE (HP 184) - IN-VITRO SPONTANEOUS RELEASE OF ACETYLCHOLINE AND NOREPINEPHRINE

It has been shown that a single injection of N-(n-propyl)-N-(3-fluoro- 4-pyridinyl)-1H- 3-methylindol-1-amine hydrochloride) (HP 184) (0.6-4. 8 mg/kg, or 2-15 mu moles/kg, sc) reversed passive avoidance deficits in rats with combined cholinergic and noradrenergic lesions. This repo rt describes the effects of HP 184 on NE and ACh release from rat brai n slices. In contrast to 4-aminopyridine (4-AP), tyramine, or veratrid ine, HP 184 only enhanced spontaneous release and had no effect on ele ctrical stimulation (ES). Chromatographic analysis showed that the spo ntaneous release from [H-3]choline-loaded striatal slices correlated w ith increased release of ACh, not choline efflux. HP 184 also enhanced ACh spontaneous release in the absence of both extracellular calcium and functional vesicles (as defined by ES and vesamicol). In frontal c ortical slices, HP 184 caused [H-3]NE release in a calcium independent fashion different from that induced by veratridine, and was not affec ted by uptake blockers. In contrast to the cholinergic profile, the [H -3]NE release induced by HP 184 required intact storage vesicles, sinc e release was blocked by reserpine pretreatment. The results show that HP 184 can release both NE and ACh in vitro, and, coupled with the du al lesion results, suggest it may have use in diseases involving choli nergic and noradrenergic deterioration. (C) 1993 Wiley-Liss, Inc.