Inhibition of dopamine re-uptake: Significance for nigral dopamine neuron activity

Abstract

In the present study the effect of inhibition of the re-uptake of dopamine (DA) was analysed with respect to DA release and to the firing pattern of DA neurons in the substantia nigra (SN). Intravenous administration 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 concentration both in the SN and in the striatum, as measured by microdialysis. However, the drug failed to significantly affect the firing rate of the 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 produced a slight regularisation of the firing pattern of the nigral DA neurons without changing the firing rate of the ability of the DA neurons to fire in bursts, was found to prevent the regulatory action of GBR 12909. Pretreatment with the selective GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v., 5 min) did not significantly affect the firing 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 that a striatonigral feedback projection may serve to control the activity of nigral DA neurons not primarily by regulating the firing rate, but, preferably, by modulating the firing pattern of the neurons. In this regard, activation of somatodendritic GABAB-receptors may form the final link in this feedback inhibitory control system.

Partial depletion of dopamine in substantia nigra impairs motor performance without altering striatal dopamine neurotransmission

“…This indicates that, although dopaminergic autoinhibition unmistakably exists, it is either not significantly activated during the experimental conditions of rest and motor activity employed here, or it is counteracted by dopaminergic effects mediated by dopamine receptors other than D2 autoreceptors. This is in line with some other studies which de‐emphasize the role of somatodendritic autoreceptors for spontaneous firing activity of dopaminergic cells (Engberg et al ., 1997; Tepper et al ., 1997) as well as for striatal DA release (Bergquist et al ., 2003; Cobb & Abercrombie, 2003a) in vivo .…”

Feedback Control of Mesolimbic Somatodendritic Dopamine Release in Rat Brain

“…2 and 3). These data are consistent with previous findings using microdialysis probes in the ACB (Kalivas and Duffy, 1991; Li et al, 1996; Reith et al, 1997; Kohl et al, 1998) or other DA target regions (Carboni et al, 1989; Nomikos et al, 1990; Santiago and Westerink, 1991; Nakachi et al, 1995; Engberg et al, 1997). GBR‐12909 and nomifensine produced similar effects on synaptic DA levels in the range 10‐100 μ M (Figs.…”

Inhibition of firing rate and changes in the firing pattern of nigral dopamine neurons by γ-hydroxybutyric acid (GHBA) are specifically induced by activation of GABAB receptors

“…Functionally, activation of this GABA B -receptor-mediated input decreases DA terminal efflux in the striatum (Nissbrandt et al 1994). Furthermore, recent studies from our laboratory demonstrate that this input to the SN constitutes the final link in a striatonigral inhibitory control system (Engberg et al 1997). As discussed below, the results of the present investigation dem-616 Fig.…”