Dopamine D2, receptor-mediated modulation of the GABAergic inhibition of substantia nigra pars reticulata neurons.

Neurons of the substantia nigra pars reticulata can be readily and fully inhibited by endogenously released or iontophoretically applied GABA. We have previously shown that co-application of dopamine or the D2-like agonist quinpirole causes a current-dependent attenuation of the inhibitory response of these neurons to GABA. To determine if the modulation of GABA responsiveness was mediated by activation of D2 receptors, effects of iontophoretic quinpirole were examined after various treatments which block or inactivate D2 receptors, or uncouple D2 receptors from their G-proteins. Results showed that the GABA-attenuating effect of quinpirole could be attributed to stimulation of D2 receptors, and not a non-specific effect of the drug, since (1) co-iontophoresis of the D2 antagonist YM 09151-2 antagonized the GABA-modulatory effect of quinpirole, (2) prior intranigral injection of the receptor inactivator N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 50 nmol/0.5 ml one day before recording) prevented the response to quinpirole, and (3) prior intranigral injection of the Gi-Go-protein inactivator pertussis toxin (1 mg/ml 0.9% NaCl 24 h before recording) completely abolished the ability of quinpirole to lessen the inhibitory response to GABA. The location of the involved D2 receptors was examined using selective lesioning approaches. Kainic acid lesions of the striatonigral pathway did not prevent the ability of quinpirole to attenuate responses of pars reticulata neurons to GABA. Similarly, in previous studies [59], 6-hydroxydopamine lesions of the adjacent pars compacta dopamine neurons were found not to abolish the GABA-attenuating effect of dopamine. Thus, it appears that the receptors mediating the response are not localized to either striatonigral terminals nor to the adjacent dopamine neurons, leaving open the possibility that the response is mediated by D2 receptors located on pars reticulata neurons. Collectively these results suggest that dendritically released dopamine may act via nigral D2 receptors, perhaps located on pars reticulata neurons themselves, to regulate basal ganglia output from the substantia nigra.