Effects of 1-cyclohexyl- and 1-cyclohexyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline on dopaminergic spontaneous discharge in nigral neurons of rats

• Low to middle dose of MPTP increased transient nigral spontaneous firing frequency.
• 1-cHex-TIQ increase firing frequency than MPTP, but it diminished by N-propargylation.
• 1-cHex-N-proTIQ antagonized MPTP-induced firing loss with dose dependent manner.
• One of antagonizing mechanisms of 1-cHex-N-proTIQ will cause by TBARS depression.

1,2,3,4-Tetrahydroisoquinoline (TIQ) and some of its derivatives, such as 1-benzyl-TIQ and 1-methyl-TIQ, are endogenously present in human brain and are thought to contribute to induction or prevention of Parkinson’s disease. In the present study, we estimated the effects of the artificially synthesized TIQ derivatives 1-cyclohexyl-TIQ (1-cHex-TIQ) and 1-cyclohexyl-N-propargyl-TIQ (1-cHex-N-proTIQ) on spontaneous nigral dopaminergic discharge in rats. Low to middle doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced a transient and significant, but not relatively potent, increase in the firing rate, followed by a sustained decrease with higher doses. 1-cHex-TIQ increased the firing frequency at low and high doses. In contrast, 1-cHex-N-proTIQ had no effects on spontaneous firing. Although intraperitoneal pretreatment with 1-cHex-TIQ did not inhibit this MPTP-induced decrease in firing, pretreatment with 1-cHex-N-proTIQ significantly depressed this decreased firing in a dose-dependent and long-lasting manner. Selegiline, a monoamine oxidase type B inhibitor that is used as a therapeutic drug for Parkinson’s disease, also significantly inhibited the decrease in dopaminergic spontaneous firing induced by MPTP, but the effect was transient. These results suggest that although the decrease in firing induced by 1-cHex-TIQ is clearly more potent compared to that induced by MPTP, its effect is eliminated by adding an N-propargyl functional group. The antagonizing effect of 1-cHex-N-proTIQ on MPTP-induced firing loss may be exerted by a different mechanism than that of selegiline.