Presynaptic dopamine D2 and muscarine M3 receptors inhibit excitatory and inhibitory transmission to rat subthalamic neurones in vitro

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Abstract
1 Whole-cell patch-clamp recordings were made from subthalamic nucleus (STN) neurones in brain slices from rats. Stimulation with bipolar electrodes evoked synaptic currents mediated by glutamate (EPSCs) and GABAA (IPSCs) receptors. 2 Dopamine reversibly reduced the amplitude of GABAA IPSCs by up to 48% with an IC50 value of 3.4 ± 0.8μm. The dopamine D2 receptor agonist quinpirole, but not the D1 receptor agonist SKF 82958, also inhibited GABAA IPSCs. This effect was completely reversed by the D2 receptor antagonist sulpiride but not by SCH 23390, a D1 antagonist. 3 Muscarine reversibly reduced the amplitude of GABAA IPSCs by up to 70 % with an IC50 value of 0.6 ± 0.1μm. Inhibition of IPSCs by muscarine was completely blocked by scopolamine (10 μm), a muscarinic receptor antagonist. The M3 muscarinic receptor antagonist 4-DAMP effectively reversed muscarine-induced inhibition of IPSCs with an IC50 of 0.11 ± 0.03μm. Although the M1 receptor antagonist pirenzepine also reversed the inhibition of IPSCs by muscarine, this effect was only observed at relatively high concentrations (IC50=21.7 ± 9.4μm). 4 Dopamine and muscarine both increased the paired-pulse ratio of GABAA IPSCs. Neither agent produced sustained changes in postsynaptic holding current. 5 Glutamate EPSCs were also inhibited reversibly by dopamine (by up to 29 %; IC50= 16 ± 3 μm) and muscarine (by up to 41 %; IC50=1.0 ± 0.4μm). However, both agents were more potent and efficacious for reducing GABA IPSCs compared with glutamate EPSCs. 6 These results suggest that the most significant effect of dopamine and muscarine in the STN is to reduce inhibitory synaptic input by acting at presynaptic dopamine D2 and muscarinic M3 receptors, respectively.