EFFECT OF MDL-73,745 ON ACETYLCHOLINE AND BIOGENIC-AMINE LEVELS IN RAT CORTEX

We postulate that the effect of cholinesterase inhibitors to ameliorat e the cholinergic deficit in Alzheimer's disease is related to their a bility to maintain long-lasting, non-toxic steady-state levels of acet ylcholine in cortex. We investigated the effect of the cholinesterase inhibitor, MDL 73,745 2,2-trifluoro-1-(3-trimethylsilylphenyl)ethanone ), on the extracellular levels of acetylcholine, norepinephrine, dopam ine and 5-hydroxytryptamine in the cerebral cortex of the rat by high- performance liquid chromatography coupled with electrochemical detecti on. The drug significantly increased acetylcholine levels above the ba seline 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 inhi bition and acetylcholine increase in cortex. At the 2 and 10 mg/kg dos es, the maximal cholinesterase inhibition was 64% and 77%, respectivel y, and the increase in acetylcholine release was 481% and 1016%, respe ctively. Norepinephrine and dopamine, but not 5-hydroxytryptamine leve ls, were also significantly increased by the 10 mg/kg dose. The increa ses of norepinephrine and dopamine levels reached a maximum of 124% an d 370%, respectively, and continued for a period of at least 8 h. Chol inergic side-effects were most marked at the 10 mg/kg dose but were al so noticeable at the 2 mg/kg dose in the form of fasciculations, tremo r and splay.