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Keywords:

  • HP 184;
  • 4-AP;
  • tyramine;
  • veratridine

Abstract

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 μmoles/kg, sc) reversed passive avoidance deficits in rats with combined cholinergic and noradrenergic lesions. This report describes the effects of HP 184 on NE and ACh release from rat brain slices. In contrast to 4-aminopyridine (4-AP), tyramine, or veratridine, HP 184 only enhanced spontaneous release and had no effect on electrical stimulation (ES). Chromatographic analysis showed that the spontaneous release from [3H]choline-loaded striatal slices correlated with 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 cortical slices, HP 184 caused [3H]NE release in a calcium independent fashion different from that induced by veratridine, and was not affected by uptake blockers. In contrast to the cholinergic profile, the [3H]NE release induced by HP 184 required intact storage vesicles, since release was blocked by reserpine pretreatment. The results show that HP 184 can release both NE and ACh in vitro, and, coupled with the dual lesion results, suggest it may have use in diseases involving cholinergic and noradrenergic deterioration. © 1993 wiley-Liss, Inc.