Effect of 2-(4-phenylpiperidino)cyclohexanol (AH 5183) on the veratridine-induced increase in acetylcholine synthesis by rat hippocampal tissue.
The intent of this study was to determine whether the drug 2-(4-phenylpiperidino)cyclohexanol (AH 5183 or vesamicol) might inhibit the veratridine-induced increase in acetylcholine (ACh) synthesis by reducing the veratridine-induced activation of a detergent-soluble choline-O-acetyltransferase (EC 2.3.1.6; ChAT) fraction associated with a vesicle-bound store of ACh. When minces of rat hippocampal tissue were loaded with [14C]choline and subsequently depolarized with veratridine, an increase in the synthesis of [14C]ACh occurred that could be abolished by L-AH 5183 (75 nM). When minces were depolarized with veratridine in the presence of L-AH 5183 (75 nM), the depolarization-induced activation of a detergent-soluble ChAT fraction associated with a vesicle-bound store of ACh was blocked. Conversely, the veratridine-induced activation of a water-soluble ChAT fraction believed to be cytosolic was not. AH 5183 also blocked the repletion of the vesicle-bound store with newly synthesized ACh following veratridine-induced depletion of ACh, a result that appeared to be mediated by an effect on the synthesis of ACh at the vesicular surface. These results suggest that veratridine depolarization of rat hippocampal nerve terminals stimulates the synthesis of ACh by activating a detergent-soluble fraction of ChAT closely associated with synaptic vesicle release sites. ACh synthesis and transport at the vesicular surface may be influenced by a common AH 5183-sensitive regulatory protein.
Carroll
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PT
Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock 79430.
Ivy
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MT
D000109:Acetylcholine / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D002794:Choline / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D007552:Isotonic Solutions / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009286:Naphthylvinylpyridine / Q000494:pharmacology; D017830:Octoxynol; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology*; D014702:Veratrine / Q000031:analogs & derivatives*
D007552:Isotonic Solutions; C051865:Krebs-Ringer solution; D010880:Piperidines; D009286:Naphthylvinylpyridine; C006189:vesamicol; D011092:Polyethylene Glycols; D014701:Veratridine; D017830:Octoxynol; D007770:L-Lactate Dehydrogenase; D002795:Choline O-Acetyltransferase; D014702:Veratrine; D010622:Phencyclidine; D002794:Choline; D000109:Acetylcholine