INHIBITION OF [H-3] DOPAMINE UPTAKE INTO RAT STRIATAL SLICES BY QUATERNARY N-METHYLATED NICOTINE METABOLITES

The effects of quaternary N-methylated nicotine derivatives were examined on in vitro uptake of [H-3]dopamine ([H-3]DA) in rat striatal slices. Striatal slices were incubated with a 10-mu-M concentration of the following compounds: N-methylnicotinium, N-methylnoricotinium, N-methylcotininium, N,N'-dimethylnicotinium and N'-methylnicotinium salts. The results clearly indicated that significant (60%) inhibition of [H-3]DA uptake occurred with those compounds possessing a N-methylpyridinium group; whereas, compounds that were methylated at the N'-pyrrolidinium position were less effective or exhibited no inhibition of [H-3]DA uptake. The results suggest that high concentrations of quaternary N-methylated nicotine metabolites which are structurally related to the neurotoxin MPP+, and which may be formed in the CNS, may protect against Parkinson's Disease and explain the inverse relationship between smoking and Parkinsonism reported in epidemiologic studies.