INHIBITION OF DOPAMINE REUPTAKE - SIGNIFICANCE FOR NIGRAL DOPAMINE NEURON ACTIVITY

In the present study the effect of inhibition of the re-uptake of dopa mine (DA) was analysed with respect to DA release and to the firing pa ttern of DA neurons in the substantia nigra (SN). Intravenous administ ration of GBR 12909 (0.5-8 mg/kg), a specific and potent inhibitor of DA re-uptake, was found to dose-dependently increase the DA concentrat ion both in the SN and in the striatum, as measured by microdialysis. However, the drug failed to significantly affect the firing rate of th e nigral DA neurons. In contrast, GBR 12909 dose-dependently induced a regularisation of the firing pattern, concomitant with a reduction in burst activity. An acute hemisection of the brain, which by itself pr oduced a slight regularisation of the firing pattern of the nigral DA neurons without changing the firing rate or the ability of the DA neur ons to fire in bursts, was found to prevent the regulatory action of G BR 12909. Pretreatment with the selective GABA(B)-receptor antagonist CGP 35348 (200 mg/kg, i.v., 5 min) did not significantly affect the fi ring rate, the regularity of the DA neurons, or their ability to fire in bursts. However, CGP 35348 markedly antagonised the ability of GBR 12909 to induce pacemaker-like firing or a decrease in burst activity of the nigral DA neurons. The results of the present study suggest tha t a striatonigral feedback projection may serve to control the activit y of nigral DA neurons not primarily by regulating the firing rate, bu t, preferably, by modulating the firing pattern of the neurons. In thi s regard, activation of somatodendritic GABA(B)-receptors may form the final link in this feedback inhibitory control system. (C) 1997 Wiley -Liss, Inc.