Efforts to develop adjuvant therapies for the treatment of Parkinson's disease (PD) have led to interest in drugs that could mimic the therapeutic effects of lesion or deep brain stimulation of the subthalamic nucleus (STN). Extracellular single unit recordings were conducted to determine whether noncompetitive NMDA receptor blockade, suggested to have potential as an adjuvant treatment in PD, attenuates rate increases and firing pattern changes observed in the STN in a rodent model of PD. Systemic administration of the noncompetitive NMDA antagonist MK801 to rats with unilateral dopamine cell lesions did not significantly alter burstiness or interspike interval coefficient of variation, although mean firing rate decreased by a modest 20% with 50% of neurons showing decreases in rate >15% and spike train power in the 3-8-Hz (theta) range was reduced. MK801, combined with the D1 dopamine agonist SKF 38393 in intact rats or administered alone in lesioned rats, also significantly reduced incidence of multisecond (2-60 s) periodic oscillatory activity. Amantadine, a drug currently used as an adjuvant agent in PD whose beneficial effects are commonly attributed to its noncompetitive NMDA antagonist properties, had effects that contrasted with those of MK801. In both intact and lesioned animals, amantadine significantly increased STN firing rates and total spike train power in the 8-50-Hz range and did not alter spike power in the 3-8-Hz range or multisecond oscillatory activity. These observations show that an effective noncompetitive NMDA antagonist such as MK801 induces modest change in STN activity in 6-hydroxydopamine (6-OHDA)-lesioned rats, with the most notable effect on multisecond periodicities in firing rate and theta frequency total spike power. Amantadine's effects differed from MK801's, raising questions about its primary mechanism of action and the role in PD pharmacotherapy of the STN rate increases induced by this drug.