1-benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous neurotoxic compound, disturbs the behavioral and biochemical effects of L-DOPA: In vivo and ex vivo studies in the rat

摘要

Environmental factors and endogenously produced toxins, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), are considered to be involved in the pathogenesis of Parkinson's disease (PD). In this study, we investigated the impact of single and multiple 1BnTIQ (25 and 50 mg/kg i.p.) administration on l-DOPA-induced changes in the rate of dopamine and serotonin metabolism in the rat brain. Additionally, using in vivo microdialysis, we measured the impact of acute and multiple 1BnTIQ administrations on l-DOPA-induced dopamine release in the striatum. These data were compared with results from behavioral tests in which we measured the effect of 1BnTIQ and l-DOPA on locomotor activity. Finally, we determined the effect of the repeated administration of 1BnTIQ on the l-DOPA-induced elevation of caspase-3 activity in the hippocampus. An ex vivo neurochemical study indicated that both acute and chronic 1BnTIQ injections strongly inhibited l-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. In contrast, in vivo microdialysis studies suggested that the differences in 1BnTIQ's effects are dependent on the type of treatment. A single dose of 1BnTIQ intensified the elevation of dopamine release induced by l-DOPA administration (～1,300 %; P < 0.01), while multiple administrations of 1BnTIQ significantly enhanced the basal dopamine levels while partially diminishing the effects of l-DOPA injection (~200 %; P < 0.01). Additionally, we found that chronic administration of 1BnTIQ completely blocked the l-DOPA-induced increase in caspase-3 activity in the hippocampus. These findings indicate that both acute and chronic administrations of 1BnTIQ disturbs the behavioral and biochemical effects of l-DOPA in the rat. The data presented from ex vivo and in vivo studies clearly suggest that 1BnTIQ's effects may be connected with the inhibition of DAT and/or COMT activity in the brain. Furthermore, elevated endogenous levels of 1BnTIQ may pose a serious risk in PD patients undergoing l-DOPA therapy.