title: Compared effects of two vesicular acetylcholine uptake blockers, AH5183 and cetiedil, on cholinergic functions in Torpedo synaptosomes: acetylcholine synthesis, choline transport, vesicular uptake, and evoked acetylcholine release.
abstract: We examined the effects of two drugs, AH5183 and cetiedil, demonstrated to be potent inhibitors of acetylcholine (ACh) transport by isolated synaptic vesicles on cholinergic functions in Torpedo synaptosomes. AH5183 exhibited a high specificity toward vesicular ACh transport, whereas cetiedil was shown to inhibit both high-affinity choline uptake and vesicular ACh transport. Choline acetyltransferase was not affected by either drug. High external choline concentrations permitted us to overcome cetiedil inhibition of high-affinity choline transport, and thus synthesis of [14C]ACh in treated preparations was similar to that in controls. We then tested evoked ACh release in drug-treated synaptosomes under conditions where ACh translocation into the vesicles was blocked. We observed that ACh release was impaired only in cetiedil-treated preparations; synaptosomes treated with AH5183 behaved like the controls. Thus, this comparative study on isolated nerve endings allowed us to dissociate two steps in drug action: upstream, where both AH5183 and cetiedil are efficient blockers of the vesicular ACh translocation, and downstream, where only cetiedil is able to block the ACh release process.
authors.affiliation: Département de Neurochimie, CNRS, Gif-sur-Yvette, France.
authors.forename: Y M
authors.initials: YM
authors.lastname: Gaudry-Talarmain
authors.forename: M F
authors.initials: MF
authors.lastname: Diebler
authors.forename: S
authors.initials: S
authors.lastname: O'Regan
mesh_terms: D000109:Acetylcholine / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002794:Choline / Q000378:metabolism* / Q000494:pharmacology; D004557:Electric Organ / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009467:Neuromuscular Depolarizing Agents; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014101:Torpedo / Q000378:metabolism*
chemical_list: D001381:Azepines; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; D000001:Calcimycin; C006189:vesamicol; C006955:cetiedil; D010622:Phencyclidine; D002794:Choline; D000109:Acetylcholine