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

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 GABA(A) (IPSCs) receptors. 2. Dopamine reversibly reduced the amplitude of GABA(A) IPSCs by up to 48% with an IC₅₀ value of 3.4 ± 0.8 μM. The dopamine D₂ receptor agonist quinpirole, but not the D₁ receptor agonist SKF 82958, also inhibited GABA(A) 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 GABA(A) IPSCs by up to 70% with an IC₅₀ value of 0.6 ± 0.1 μM. 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 ± 0.03 μM. 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 ± 9.4 μM). 4. Dopamine and muscarine both increased the paired-pulse ratio of GABA(A) 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 ± 0.4 μM). 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.