Effects of 1,2,3,4-tetrahydroisoquinoline derivatives on dopaminergic spontaneous discharge in substantia nigra neurons in rats.

1,2,3,4-Tetrahydroisoquinoline (TIQ) and its derivatives, 1-methyl-TIQ (1-MeTIQ) and 1-benzyl-TIQ (1-BnTIQ), are endogenously present in the human brain. In this study, we compared the effects of TIQ derivatives on spontaneous nigral dopaminergic discharge in rats treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the low-to-middle dose range (0.01-1 mg/kg), intravenous administration of MPTP induced a transient and potent increase in the firing rate. TIQ (0.01-30 mg/kg) had no effects, and 1-MeTIQ and 1-BnTIQ (0.01-10 mg/kg) produced a weaker increase in the firing frequency immediately after intravenous administration. Pretreatment with 1-MeTIQ (80 mg/kg, i.p.) significantly inhibited the decrease in dopaminergic spontaneous firing induced by a high dose of MPTP. The nigral induction of thiobarbituric acid-reactive substances (TBARS) by MPTP was also significantly suppressed by pretreatment with 1-MeTIQ. These results suggest that the neurotoxicity induced by TIQ derivatives is relatively weak compared to that induced by MPTP. The neuroprotective effect of 1-MeTIQ from MPTP-induced toxicity may be partially due to a decrease in free radicals, as suggested by a decrease in TBARS. This action presumably prevents cell membrane degeneration.