Dopaminergic mechanisms in the subthalamic nucleus (STN) are implicated in the pathophysiology of Parkinson's disease. Here, electrophysiological responses of STN neurons to dopamine (DA) were investigated by using whole-cell patch-clamp recordings in the rat brain slice preparation. Under current-clamp, DA depolarized membrane potential and increased the frequency of spontaneous action potentials of STN neurons. Under voltage-clamp, DA (3-300 μM) produced a reversible concentration-dependent inward current (I D A ; 6-40 pA) with an EC 5 0 of 13 μM. This DA-induced current had a negative slope conductance which reversed at -102 mV. It was partially reduced by barium and by superfusion with an elevated concentration of extracellular K + . Moreover, TTX and glutamate receptor antagonists (CNQX and AP5) did not significantly affect the DA responses, indicating that I D A is not dependent upon afferent synaptic activity in the STN. Quinpirole, a D 2 receptor agonist, mimicked the DA action more effectively than did the D 1 agonist SKF-38393. The D 2 antagonist sulpiride, but not the D 1 antagonist SCH-23390, blocked responses induced by DA. Intracellular application of G-protein inhibitor GDP-β-S also suppressed I D A . GTP-γ-S, added to the pipette solution, evoked a sustained inward shift in the absence of DA. These results suggest that DA increases the activity of STN neurons via activation of G-protein-coupled D 2 -like receptors which reduce a K + conductance.