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Slices of the caudate nucleus of rabbits were preincubated with 3H-choline and then superfused. Stimulation by electrical pulses at 3 Hz or by 25 mmol/l potassium elicited an increase in tritium outflow which was calcium-dependent and, in the case of electrical stimulation, tetrodotoxin-sensitive. The dopamine receptor agonist apomorphine (0.01-1 mumol/l) decreased, whereas the antagonist haloperidol increased the electrically evoked overflow of tritium. Nomifensine and cocaine, used at concentrations known to inhibit the re-uptake of dopamine, also reduced the evoked overflow of tritium, and this reduction was antagonized by haloperidol. Combined pretreatment with reserpine and alpha-methyltyrosine methylester (alpha-MT), which lowered dopamine levels by 99.5%, increased the electrically evoked overflow, as did bretylium which is shown here to block action potential-induced release of dopamine. The facilitation by haloperidol and bretylium as well as the inhibition by nomifensine and cocaine were diminished or abolished after pretreatment with reserpine plus alpha-MT. Apomorphine decreased, and haloperidol increased, the potassium-evoked overflow of tritium; the effects were not changed by tetrodotoxin. The results indicate that the striatal dopamine receptors which, when activated, depress the release of acetylcholine, are akin to the D-2 type. Endogenous dopamine also acts on the receptors as shown by several manipulations with known effects on dopaminergic transmission. A large fraction of these dopamine receptors may be located on the cholinergic axon terminals.

Slices from rabbit caudate nucleus were preincubated with [3H]dopamine and then superfused and stimulated electrically. gamma-Aminobutyric acid (10-4) and 10(-3) mol/L increased both the basal and the stimulation-evoked overflow of tritium. The effects were not changed by picrotoxin and were only slightly reduced by bicuculline. In the presence of nipecotate 10(-3) mol/L, gamma-aminobutyric acid decreased rather than enhanced the basal and the evoked overflow. The inhibition persisted in the presence of bicuculline. Muscimol did not affect, whereas baclofen decreased, the evoked overflow of tritium. Similar results obtained with synaptosomes that were stimulated by 30 mmol/L K+. The results indicate that gamma-aminobutyric acid can both facilitate and depress the release of dopamine. Facilitation occurs after entry of gamma-aminobutyric acid into the dopaminergic terminal axons, whereas inhibition if probably mediated by a receptor site located in the membrane of these terminals.

Slices of rabbit caudate nucleus were preincubated with 3H-dopamine and then superfused. 3H-dopamine and its metabolites were separated by column chromatography. The basal outflow of tritium consisted of 68% DOPAC, 21% OMDA metabolites (most of which was HVA), 6% dopamine and 5% MTA. Except for an increase in 3H-dopamine, the basal outflow was little changed by nomifensine or cocaine. Amezinium reduced the outflow of 3H-DOPAC and 3H-OMDA metabolites and increased that of 3H-dopamine and 3H-MTA; its effect was antagonized by nomifensine. Haloperidol 10(-7) M selectively enhanced the outflow of 3H-DOPAC and 3H-OMDA metabolites. At haloperidol 10(-5) M, a large increase in these two fractions was accompanied by a small increase in 3H-dopamine and 3H-MTA. Nomifensine diminished only slightly the outflow of 3H-DOPAC caused by haloperidol. The overflow of tritium elicited by electrical stimulation at 3 Hz consisted of 74% DOPAC, 15% OMDA metabolites, 10% dopamine and 0.4% MTA. Lowering the frequency reduced the overflow of total tritium and caused a decrease in the percentage of 3H-DOPAC and an increase in the percentage of 3H-dopamine. Nomifensine or cocaine greatly diminished the evoked overflow of 3H-DOPAC and 3H-OMDA compounds and increased the evoked overflow of 3H-dopamine and 3H-MTA. The effects of apomorphine and bromocriptine were similar to those caused by decreasing the stimulation frequency. The major pathways of the metabolism of previously taken up dopamine, under the conditions of our experiments, are as follows. When the neurones are at rest, dopamine metabolism is initiated by leakage of the amine into the axoplasm, where it is degraded through the aldehyde to DOPAC. Part of the DOPAC is methylated extraneuronally to HVA. Traces of MTA are formed by extraneuronal methylation of dopamine. When action potentials arrive, dopamine metabolism is initiated by exocytosis. The bulk of the extracellular dopamine is taken up back into the neurones. When the stimulation frequency is 3 Hz, most of the axoplasmic dopamine is subsequently transformed to DOPAC; little seems to be re-stored. HVA and MTA are generated essentially as during neuronal rest. When dopamine release is low (stimulation at low frequency; addition of apomorphine or bromocriptine), a larger portion seems to be re-stored, thus leading to a decrease in the percentage of DOPAC. Haloperidol, apart from its receptor blocking properties, acts on dopaminergic axons in a manner akin to the effect of reserpine.

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