Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study

Abstract

1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 ,uM, decreased or abolished the spontaneous firing discharge of the principal neurones in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine DI receptor antagonist, SCH 23390(1-3 pM) did not counteract the induced inhibition of the firing rate.4 The inhibitor for the MAO A, clorgyline (30-100 gM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 gM), was applied. Lower concentrations of both drugs (300 nM-10 gM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.

Adaptive Changes in Postsynaptic Dopamine Receptors Despite Unaltered Dopamine Dynamics in Mice Lacking Monoamine Oxidase B

“…The finding that dopamine levels are unaltered in the absence of MAO B is in accord with several studies that have used a pharmacological approach to probe the role of MAO B in dopamine neurotransmission (Butcher et al, 1990 ; Kaakkola and Wurtman, 1992 ; Brannan et al, 1995 ; Mercuri et al, 1996). However, increases in dialysate dopamine levels following MAO B inhibition have also been reported (Finberg et al, 1996 ; Lamensdorf et al, 1996).…”

“…As dopamine can be catabolized by both MAO A and MAO B, the drug effect on both isoforms could produce the increase in the extracellular level of dopamine. Indeed, consistent with this hypothesis, electrophysiological studies by Mercuri et al (1996, 1997) have shown that the administration of both MAO A and MAO B inhibitors is required for the long‐term prolongation of the dopamineinduced responses in rat midbrain dopaminergic cells.…”

“…Other laboratories (Butcher et al, 1990 ; Kaakkola and Wurtman, 1992 ; Brannan et al, 1995), however, found no alteration of dopamine levels following acute administration of deprenyl. Interestingly, studies by Mercuri et al (1996, 1997) have shown that administration of MAO A or MAO B inhibitors alone caused no long‐term prolongation of dopamine‐induced electrophysiological responses (depression of firing rate and hyperpolarization) in rat midbrain dopaminergic cells and that the combined administration of MAO A and B inhibitors was required to elicit an effect. Such findings strongly suggest that the inhibition of both MAO A and B enzymes is necessary for the enhancement of dopamine neuronal activity.…”

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…All these effects are likely to be independent of nNOS inhibition or more generally of NO production and instead are a consequence of MAO B inhibitory activity possessed by 7-NI. Indeed, it has been shown that the MAO B inhibitor deprenyl decreases the spontaneous firing discharge of DA SNc and VTA cells in vitro [60] and striatal DOPAC [59].…”

A Modeling Study Suggests Complementary Roles for GABAAand NMDA Receptors and the SK Channel in Regulating the Firing Pattern in Midbrain Dopamine Neurons

“…Similarly, Chergui et al (1993) showed that bursting was blocked by the local application (iontophoresis and pressure ejection) of the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (AP-5) but not by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX) (see also Overton and Clark 1997). The duration of the excitatory postsynaptic current (EPSC) evoked by AMPA is ϳ20 ms (Bonci and Malenka 1999), whereas that evoked by NMDA is much longer lasting (Mercuri et al 1996;Overton and Clark 1997), on the order of 600 ms (Destexhe et al 1998). Glutamate affinity for AMPA receptors is lower (EC 50 ϭ 19 M) than for NMDA receptors (EC 50 ϭ 2.3 M) (Patneau and Mayer 1990), thus lower concentrations of glutamate in the cleft are required to activate NMDA receptors, which accounts at least in part for the longer duration of the activation of these receptors.…”