1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic denervation potentiates gabaergic inhibition in the mouse neostriatum in vitro

Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease, we investigated the long-term effects of dopaminergic denervation on synaptic transmission in an in vitro slice preparation of the mouse neostriatum. In control mice, electrical stimulation elicited an antidromic potential (N1) followed by a synaptically mediated held potential (N2). In many slices, a third component (N3) was observed. Determination of the maximum stimulus intensities unveiled that in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated animals, the stimulus strength necessary to evoke a maximum N2 response was significantly higher compared to control mice. Furthermore, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreatment led to a less Frequent appearance and/or to a reduction in the amplitude of the N3 component. Application of glutamate receptor agonists and antagonists revealed two additional differences between normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. (1) Comparison of the efficacy of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 6-cyano-7-nitroquinox-aline-2,3-dione demonstrated an increase in the inhibitory effect of 6-cyano-7-nitroquinoxaline-2,3-dione in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. (2) In normal mice, removal of magnesium ions from the bathing solution invariably led to the appearance of late N-methyl-D-aspartate receptor-dependent synaptic components. There components were only slightly expressed or virtually absent in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. The described differences between the electrophysiological and pharmacological properties of evoked field potentials in slices from normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice disappeared following blockade of GABA(A) receptor-dependent inhibition by bicuculline. In normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice, bicuculline did not influence the amplitude of the N2 component, but invariably unmasked late synaptic components mediated by glutamate receptors. However, the potentiating effect of bicuculline was significantly stronger in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice compared to the controls. In the presence of bicuculline, the frequency of occurrence of the N3 component was identical in both groups. Furthermore, the apparent efficiency of 6-cyano-7-nitroquinoxaline-2,3-dione was no longer different. Application of bicuculline in the absence of magnesium ions resulted in a similar disinhibition of N-methyl-D-aspartate receptor-dependent late components as observed in the controls in the absence of bicuculline. The data demonstrate that chronic dopaminergic denervation reduces glutamate receptor-dependent synaptic excitation in the mouse neostriatum. Since differences between normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice disappear in the presence of bicuculline. we conclude that this reduction in excitability is due to a potentiation of GABA(A) receptor-dependent inhibition.