Dopamine-derived endogenous 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-methyl-(R)-salsolinol, induced parkinsonism in rat: Biochemical, pathological and behavioral studies

Dopamine-derived 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydrosisopuinoline (salsolinol, Sal) and related compounds were examined for their selective neurotoxicity to dopamine neurons by injection into the rat striatum. Among salsolinol analogs examined, only N-methyl-(R)-salsolinol (NM(R)Sal) induced behavioral changes very similar to those in Parkinson's disease: hypokinesia, stiff tail, limb twitching at rest and postural abnormality. Biochemical analysis showed that after NM(R)Sal injection, NM(R)Sal itself and its oxidation product, 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion (DMDHIQ(+)) accumulated in the striatum, and also in the substantia nigra definite amount of DMDHIQ(+) was detected. Dopamine and noradrenaline were reduced in the striatum and more markedly in the substantia nigra, whereas serotonin and its metabolite were not affected. Morphological analysis revealed selective reduction of tyrosine hydroxylase (TH)-containing neurons in the substantia nigra after continuous NM(R)Sal administration in the striatum. These results demonstrate the selective cytotoxicity of NM(R)Sal to the dopamine neurons in the substantia nigra, and the possible involvement of this 6,7-dihydroxyisoquinoline in the pathogenesis of Parkinson's disease is discussed.