N-methylation of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsolinol, in rat brains: in vivo microdialysis study.

Abstract

N-Methylation of (R)-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-salsolinol] derived from dopamine was proved by in vivo microdialysis study in the rat brain. The striatum was perfused with (R)-salsolinol and N-methylated compound was identified in the dialysate using HPLC and electrochemical detection with multichanneled electrodes. N-Methylation of (R)-salsolinol was confirmed in three other regions of the brain, the substantia nigra, hypothalamus, and hippocampus. In the substantia nigra, the amount of N-methylated (R)-salsolinol was significantly larger than in the other three regions. These results indicate that around dopaminergic neurons, particularly in the substantia nigra, (R)-salsolinol was methylated into N-methyl-(R)-salsolinol, which has a chemical structure similar to that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the selective dopaminergic neurotoxin. N-Methylation of tetrahydroisoquinolines and beta-carbolines have already been proven to increase their toxicity to dopaminergic neurons and N-methylation might be an essential step for these alkaloids to increase their toxicity. On the other hand, after perfusion of (R)-salsolinol, release of dopamine and 5-hydroxytryptamine was observed and inhibition of monoamine oxidase was indicated. (R)-Salsolinol and its derivatives may be candidates for being dopaminergic neurotoxins.