title: Effect of MDL 73,745 on acetylcholine and biogenic amine levels in rat cortex.
abstract: We postulate that the effect of cholinesterase inhibitors to ameliorate the cholinergic deficit in Alzheimer's disease is related to their ability to maintain long-lasting, non-toxic steady-state levels of acetylcholine in cortex. We investigated the effect of the cholinesterase inhibitor, MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl)ethanone), on the extracellular levels of acetylcholine, norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat by high-performance liquid chromatography coupled with electrochemical detection. The drug significantly increased acetylcholine levels above the baseline at 2 and 10 mg/kg s.c., but not at the 1 mg/kg dose. At both 2 and 10 mg/kg there was a good correlation between cholinesterase inhibition and acetylcholine increase in cortex. At the 2 and 10 mg/kg doses, the maximal cholinesterase inhibition was 64% and 77%, respectively, and the increase in acetylcholine release was 481% and 1016%, respectively. Norepinephrine and dopamine, but not 5-hydroxytryptamine levels, were also significantly increased by the 10 mg/kg dose. The increases of norepinephrine and dopamine levels reached a maximum of 124% and 370%, respectively, and continued for a period of at least 8 h. Cholinergic side-effects were most marked at the 10 mg/kg dose but were also noticeable at the 2 mg/kg dose in the form of fasciculations, tremor and splay.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-9230, USA.
authors.forename: X D
authors.initials: XD
authors.lastname: Zhu
authors.forename: E
authors.initials: E
authors.lastname: Giacobini
authors.forename: J M
authors.initials: JM
authors.lastname: Hornsperger
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000109:Acetylcholine / Q000032:analysis*; D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004298:Dopamine / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis*; D014297:Trimethylsilyl Compounds / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D002800:Cholinesterase Inhibitors; D014297:Trimethylsilyl Compounds; D012701:Serotonin; C082826:zifrosilone; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine