Presynaptic effects of tetrahydropapaveroline on striatal dopaminergic neurons

The effects of tetrahydropapaveroline (THP) on dopamine (DA) neurons were studied in superfused rabbit neostriatal tissue slices prelabeled with [3H]DA. In this preparation the depolarization-induced overflow of 3H[DA] and its metabolites was totally inhibited when the calcium concentration of the superfusion solution was decreased to 1/10 (0.13 mM). In this tissue THP, similarly to haloperidol (0.03 μM), enhanced the stimulation-evoked overflow of radioactive products in a concentration-dependent manner (1-100 μM), and antagonized the inhibitory effects of apomorphine and bromocriptine on the overflow of DA; both actions of THP were fully reversible after 90 min of washout. In addition, THP (3-10 μM) produced a parallel shift to the right in the dose-response curves for the effects of apomorphine in inhibiting the stimulation-evoked overflow of DA. These results indicate that at low concentrations (≤10 μM), THP facilitates the release of DA acting as a competitive agonist of presynaptic DA receptors. At higher concentrations (30-100 μM), not only was this effect largely exaggerated, but in addition, the drug induced an increase in the basal efflux of 3H and of 3,4-[3H]dihydroxyphenylacetic acid. Moreover, at these high concentrations (30-100 μM) THP reduced considerably the basal efflux and the stimulation-evoked overflow of 3H-O-methylated metabolites, an effect most likely due to inhibition of the enzyme cathechol-O-methyltransferase. The differential effects of 1 μM benzotropine and 10 μM THP on the metabolism of [3H]DA released under basal and stimulated conditions, plus the fact that 1 μM benzotropine did not prevent the enhancement in transmitter overflow induced by THP, suggest that at 10 μM or less, THP does not block the neuronal uptake of DA in striatal dopaminergic neurons.