Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties

The effect of single and multiple 1-methyl-1,2,3,4-tetrahydroisoquinoline ( 1MeTIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) administration on concentrations of dopamine and its metabolites: homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT) in three brain areas was studied HPLC with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidativ e and O-methylation pathways was assessed by calculation of the ratio of ap propriate metabolites to dopamine concentration. In addition, the spontaneo us and apomorphine-stimulated locomotor activity, and muscle rigidity was s tudied after acute administration of 1MeTIQ and 1BnTIQ. We have found that 1MeTIQ did not change the level of dopamine and HVA in all investigated str uctures both after a single and chronic administration. However, the levels of intermediary dopamine metabolites, DOPAC and 3MT, were distinctly affec ted. The level of DOPAC was strongly depressed (by 60-70%) while the level of extraneuronal matabolite 3MT was significantly elevated (by 170-200%). I n contrast to 1MeTIQ, 1BnTIQ depressed the level of dopamine (by approximat ely 60%) and increased the level of total metabolite, HVA. (by 40%) especia lly in the striatum, but the levels of DOPAC and 3MT remained unchanged. Th e paper has shown that 1MeTIQ and 1BnTIQ produced different effects on dopa mine catabolism. Potential neuroprotective compound 1MeTIQ did not change t he rate of total dopamine catabolism, it strongly inhibited the monoamine o xidase (MAO)-dependent catabolic pathway and significantly activated the ca techol-O-methyltransferase (COMT)-dependent O methylation. In contrast 1BnT IQ, a compound with potential neurotoxic activity, produced the significant increase of the rate of dopamine metabolism with strong activation of the oxidative MAO-dependent catabolic pathway. Interestingly, both compounds pr oduced similar antidopaminergic functional effects: antagonism of apomorphi ne hyperactivity and induction of muscle rigidity. The results may explain the biochemical basis of the neuroprotective and of the neurotoxic properti es endogenous brain tetrahydroisoquinoline derivatives.