High frequency stimulation (HFS) is applied to many brain regions to treat a variety of neurological disorders/diseases, yet the mechanism(s) underlying its effects remains unclear. While some studies showed that HFS inhibits the stimulated nucleus, others report excitation. In this in vitro study, we stimulated the rat globus pallidus interna (entopeduncular nucleus, EP), a commonly stimulated area for Parkinson's disease, to investigate the effect of HFS-induced elevation of extracellular potassium (K(+)(e)) on rat EP neuronal activity. Whole-cell patch-clamp recordings and [K(+)](e) measurements were obtained in rat EP brain slices before, during and after HFS. After HFS (150 Hz, 10 s), [K(+)](e) increased from 2.5-9.6+/-1.4 mM, the resting membrane potential of EP neurons depolarized by 11.1+/-2.5 mV, spiking activity was significantly depressed, and input resistance decreased by 25+/-6%. The GABA(A) receptor blocker, gabazine, did not prevent these effects. The bath perfusion of 6 or 10 mM K(+), with or without synaptic blockers, mimicked the HFS-mediated effects: inhibition of spike activity, a 20+/-9% decrease in input resistance and a 17.4+/-3.0 mV depolarization. This depolarization exceeded predicted values of elevated [K(+)](e) on the resting membrane potential. A depolarization block did not fully account for the K(+)-induced inhibition of EP neuronal activity. Taken together, our results show that HFS-induced elevation of [K(+)](e) decreased EP neuronal activity by the activation of an ion conductance resulting in membrane depolarization, independent of synaptic involvement. These findings could explain the inhibitory effects of HFS on neurons of the stimulated nucleus.