Recent studies investigated an interaction between MK-801 and morphine-induced analgesia which originates in spinal and supraspinal subcortical areas of the CNS, particularly in the periaqueductal gray. Interactive effects between MK-801 and morphine-induced cortical EEG that coincides with behavior generated in mesolimbic areas have not been demonstrated. The present study first investigated an acute interaction between MK-801 and morphine-induced effects on cortical EEG and EEG spectral parameters in rat. Rats were administered one of five doses of MK-801 (0.003-0.3 mg/kg, i.p.) prior to morphine (3 mg/kg, i.v.), or MK-801 (0.1 mg/kg, i.p.) prior to an increasing cumulative morphine dose over a period of 120 minutes (5-120 mg/kg, i.v.). MK-801 pretreatment produced a significant dose-response effect and increased morphine-induced global spectral power (mV{dollar}\sp2{dollar}/Hz), duration of morphine-induced high voltage slow wave EEG bursts and latency to sleep onset. MK-801 significantly decreased morphine-induced mean frequency, mobility, complexity and edge frequency, and shifted the relative distribution of total power as a function of frequency band to lower frequencies, increasing power in the 0-5 Hz range. Significant interaction effects were found for all spectral parameters except peak frequency. Pretreatment with MK-801 shifted the cumulative morphine dose-response curve for total power to the left and for complexity to the right. The results demonstrated that MK-801 potentiates morphine-induced effects on EEG and EEG spectral parameters quantitatively in rat brain and produces qualitative changes in the EEG response to morphine. A potential interaction between MK-801 and morphine tolerance and dependence was further investigated. Rats were treated for seven days with morphine alone or with morphine and MK-801. Control groups received chronic MK-801 alone or saline. On day eight all rats received morphine alone followed by naloxone. An additional group received chronic morphine alone, followed by MK-801 on day eight prior to morphine and naloxone. Co-treatment significantly accelerated the development of tolerance to morphine-induced total power and latency to sleep onset. MK-801 co-treatment decreased, where chronic morphine alone increased, the excitatory response to morphine. Chronic co-administration had no effect on the EEG and behavioral response to naloxone precipitated morphine withdrawal, but acute MK-801 in morphine tolerant animals prevented the behavioral signs of morphine withdrawal. The results support recent reports that chronic morphine treatment produces supersensitivity to glutamate in the rat cortex and alteration in mesolimbic dopamine levels which are modulated by glutaminergic activity. In conclusion, acute co-treatment with MK-801 significantly potentiates morphine-induced EEG, EEG spectral parameters and behavior, and attenuates the behavioral signs of withdrawal from morphine following chronic morphine administration. Chronic co-treatment, furthermore, accelerates the development of tolerance to morphine-induced effects on these parameters.