The multiple effects of ketamine on electroencephalographic activity and behavior in WAG/Rij rats

The effects of ketamine, a noncompetitive antagonist at the NMDA receptor, were studied on the EEG and in the open field in a genetic animal model of generalized absence epilepsy--the WAG/Rij rat strain. Animals of this strain display spontaneous occurring generalized spike-wave discharges (SWDs) in the EEG. Ketamine was systemically administered in a dose range from 3 to 30 mg/kg. Biphasic effects of ketamine were observed in the EEG. The first phase was a dose-dependent suppression of SWDs, followed by a second phase characterized by the facilitation of SWDs. This increase was expressed first as an increased number of SWDs, and later on as a significant prolongation of individual discharges and decrease in frequency of SWDs. An obvious amplitude modulation of the discharges was also found. During the period of suppression of SWDs, a new phenomenon was observed: quasi-periodic groups of spikes or wave spikes, with an internal frequency of 4-5 Hz and a periodicity of about 5 s. That quasi-periodic activity vanished a few minutes prior to the recovery of the classical SWDs. However, a specific 5-s amplitude modulation of SWDs remained present in the recovery period. The propensity of that specific ketamine-induced activity was found to be correlated with propensity of SWDs in background EEGs of drug-free animals. Ketamine also produced a dose-related initial behavioral excitation, a decrease of muscle tone in hind quarters, followed by front quarters and head, and an absence of locomotor activity. However, the time course of the behavioral changes cannot explain the effects on the EEG. It can be concluded that ketamine has more effects on the EEG than previously assumed which cannot be explained by a simple blockade of the NMDA receptor. It is proposed that the obtained specific dynamics of SWDs' frequency may be caused by changes in the activity of the thalamo-cortical pacemaker that is generating SWDs.