DOPAMINE D-2 RECEPTOR-MEDIATED MODULATION OF THE GABAERGIC INHIBITIONOF SUBSTANTIA-NIGRA PARS RETICULATA NEURONS

Neurons of the substantia nigra pars reticulata can be readily and ful ly inhibited by endogenously released or iontophoretically applied GAB A. We have previously shown that co-application of dopamine or the D-2 -like agonist quinpirole causes a current-dependent attenuation of the inhibitory response of these neurons to GABA. To determine if the mod ulation of GABA responsiveness was mediated by activation of D-2 recep tors, effects of iontophoretic quinpirole were examined after various treatments which block or inactivate D-2 receptors, or uncouple D-2 re ceptors from their G-proteins. Results showed that the GABA-attenuatin g effect of quinpirole could be attributed to stimulation of D-2 recep tors, and not a non-specific effect of the drug, since (1) co-iontopho resis of the D-2 antagonist YM 09151-2 antagonized the GABA-modulatory effect of quinpirole, (2) prior intranigral injection of the receptor inactivator N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 50 nmol/0.5 mi one day before recording) prevented the response to quinpi role, and (3) prior intranigral injection of the G(i)-G(0)-protein ina ctivator pertussis toxin (1 mg/ml 0.9% NaCl 24 h before recording) com pletely abolished the ability of quinpirole to lessen the inhibitory r esponse to GABA. The location of the involved D-2 receptors was examin ed using selective lesioning approaches. Kainic acid lesions of the st riatonigral pathway did not prevent the ability of quinpirole to atten uate responses of pars reticulata neurons to GABA. Similarly, in previ ous studies [59], 6-hydroxydopamine lesions of the adjacent pars compa cta dopamine neurons were found not to abolish the GABA-attenuating ef fect of dopamine. Thus, it appears that the receptors mediating the re sponse are not localized to either striatonigral terminals nor to the adjacent dopamine neurons, leaving open the possibility that the respo nse is mediated by D-2 receptors located on pars reticulata neurons. C ollectively these results suggest that dendritically released dopamine may act via nigral D-2 receptors, perhaps located on pars reticulata neurons themselves, to regulate basal ganglia output from the substant ia nigra.