DOPAMINE-DERIVED ENDOGENOUS THYL-6,7-DIHYDROXY-1,2,3,4-TETRAHYDROISOQUINOLINE, N-METHYL-(R)-SALSOLINOL, INDUCED PARKINSONISM IN RAT - BIOCHEMICAL, PATHOLOGICAL AND BEHAVIORAL-STUDIES

Dopamine-derived thyl-6,7-dihydroxy-1,2,3,4-tetrahydrosisopuinoline (s alsolinol, Sal) and related compounds were examined for their selectiv e 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 injectio n, NM(R)Sal itself and its oxidation product, 1,2-dimethyl-6,7-dihydro xyisoquinolinium ion (DMDHIQ(+)) accumulated in the striatum, and also in the substantia nigra definite amount of DMDHIQ(+) was detected. Do pamine and noradrenaline were reduced in the striatum and more markedl y in the substantia nigra, whereas serotonin and its metabolite were n ot affected. Morphological analysis revealed selective reduction of ty rosine hydroxylase (TH)-containing neurons in the substantia nigra aft er continuous NM(R)Sal administration in the striatum. These results d emonstrate the selective cytotoxicity of NM(R)Sal to the dopamine neur ons in the substantia nigra, and the possible involvement of this 6,7- dihydroxyisoquinoline in the pathogenesis of Parkinson's disease is di scussed.