Actions of GABAergic agents on dopamine metabolism in the nigrostriatal pathway of the rat

The gamma-aminobutyric acid (GABA) transaminase inhibitor aminoxyacetic acid, diazepam and the GABA agonists muscimol, 4,5,6,7-tetrahydroisoxazolo-[5,4-C]-pyridin-3-ol, kojic amine and SL-76002 all depressed nigrostriatal dopamine release as measured by decreased 3-methoxytyramine after parenteral administration. Experiments with intrastriatal and intranigral injections as well as parenteral injections in acutely hemisected and kainate lesioned animals demonstrated that parenteral muscimol inhibits the nigrostriatal pathway at the level of the substantia nigra. In contrast, parenteral 4,5,6,7-tetrahydroisoxazolo-[5,4-C]-pyridin-3-ol, kojic amine and aminoxyacetic acid inhibit the nigrostriatal pathway acting both within the substantia nigra and on presynaptic nigrostriatal GABA receptors in the striatum. A unique interneuronal GABA receptor also appears to be present in the striatum which is activated by intrastriatal muscimol but not 4,5,6,7-tetrahydroisoxazolo-[5,4-C]-pyridin-3-ol or kojic amine. Activation of these receptors leads to increased dopamine release in the striatum; however, this receptor population does not appear to be stimulated after parenteral administration of GABAergic agents. In summary, multiple GABA receptors appear to be present within the central nervous system which possess differential sensitivities to the GABA agonists examined; however, after parenteral administration, all GABAergics appear to depress nigrostriatal dopaminergic transmission.