Inhibition of [³H]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 [³H]dopamine ([³H]DA) in rat striatal slices. Striatal slices were incubated with a 10 μM concentration of the following compounds: N-methylnicotinium, N-methylnornicotinium, N-methylcotininium, N,N′ -dimethylnicotinium and N′ -methylnicotinium salts. The results clearly indicated that significant (60%) inhibition of [³H]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 [³H]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.