Monoamine oxidase inhibition causes a long-term prolongation of the dopamine-induced responses in rat midbrain dopaminergic cells

Abstract

The way monoamine oxidase (MAO) modulates the depression of the firing rate and the hyperpolarization of the membrane caused by dopamine (DA) on rat midbrain dopaminergic cells was investigated by means of intracellular recordings in vitro. The cellular responses to DA, attributable to the activation of somatodendritic D2/3 autoreceptors, were prolonged and did not completely wash out after pharmacological blockade of both types (A and B) of MAO. On the contrary, depression of the firing rate and membrane hyperpolarization induced by quinpirole (a direct D2 receptor agonist) were not affected by MAO inhibition. Furthermore, although the inhibition of DA reuptake by cocaine and nomifensine caused a short-term prolongation of DA responses, the combined inhibition of MAO A and B enzymes caused a long-term prolongation of DA effects. Moreover, the effects of DA were not largely prolonged during the simultaneous inhibition of MAO and the DA reuptake system. Interestingly, the actions of amphetamine were not clearly augmented by MAO inhibition. From the present data it is concluded that the termination of DA action in the brain is controlled mainly by MAO enzymes. This long-term prolongation of the dopaminergic responses suggests a substitutive therapeutic approach that uses MAO inhibitors and DA precursors in DA-deficient disorders in which continuous stimulation of the dopaminergic receptors is preferable.

Fig. 1.

Pargyline prolongation of DA responses.A, The bath application of DA (30 μm) produced a reversible hyperpolarization and inhibition of firing. Thebar indicates the period of DA application. A long-term prolongation of the DA-induced hyperpolarization and inhibition (DA was applied for the same period of control) was observed when pargyline 10 μm was superfused on the cells for 30 min. The subsequent application of sulpiride (300 nm) antagonized the prolonged response to DA application. B, The inhibitory effects of quinpirole (100 nm) were not affected by the superfusion of pargyline (10 μm) for 30 min. Note that in this and the following figures the speed of the chart was changed at the points indicated (see x underneath) to show individual action potentials. Full amplitude of the action potential was not reproduced because of the limited frequency of the pen recorder.

Fig. 2.

Long-term prolongation of the DA-responses in pargyline and effects of the combined perfusion of DA uptake blockers.a, Plot of the firing rate (percentage of control) versus time in control condition and after a treatment with pargyline (10 μm). Note that pargyline produced an enduring DA-induced firing inhibition. The bar illustrates the DA washout starting point. Note that the firing remained depressed even after 160 min of DA washout. In b, the previous graph was superimposed with two other graphs to observe the different changes in DA responses caused by pargyline alone or in combination with cocaine (3 μm) and nomifensine (10 μm). Data were obtained from 4–10 determinations. Error bars represent SEM.

Fig. 6.

Effects of pargyline on amphetamine-induced responses. A, Control response to amphetamine.B, After pargyline application (30 min), the membrane hyperpolarization and the inhibition of firing caused by amphetamine were slightly potentiated.

Fig. 3.

Effects of clorgyline on the DA-induced responses.A, Control response to DA application. B, Long-term prolongation of DA-induced inhibition after clorgyline treatment. Note that sulpiride was able to restore the control firing discharge of the cells, indicating a protracted activation of the somatodendritic D2-like autoreceptors.

Fig. 4.

Effects of deprenyl on DA-induced responses.A, The superfusion of DA induced a reversible inhibition of this principal cell. B, After the bath application of deprenyl the depressant effect of DA was potentiated. This long-lasting inhibition was antagonized by sulpiride (100 nm).

Fig. 5.

Effects of DA uptake inhibitors on DA-induced responses. Aa, Potentiation of the DA responses by cocaine (3 μm) and prevention of the pargyline-induced long-term prolongation of DA inhibition. Ab, The graph shows the cocaine-induced short-term prolongation of the inhibitory period caused by DA (each point represents four to six determinations).Ac, Prevention of the long-term prolongation of the DA-induced inhibition in the presence of cocaine (3 μm).Ba, Potentiation of DA responses by nomifensine. In the presence of pargyline plus nomifensine the long-term prolongation of the DA-induced inhibitory effect caused by pargyline was not observed.Bb, The graph shows the nomifensine-induced short-term prolongation of the DA-induced inhibitory period (each point represents four to five determinations). Bc, Prevention of the long-term prolongation of the DA-induced inhibition in the presence of nomifensine (10 μm). Note that the graphs inAc and Bc are shown superimposed in Figure 2b.