NREM Delta Stimulation Following MK-801 Is a Response of Sleep Systems. Campbell, I.G. and I. Feinberg. Physiology Graduate Group, University of California, Davis, Veterans Administration Northern California System of Clinics and Dept. of Psychiatry, University of California, Davis.
APStracts 3:0173N, 1996.
We have previously shown that non-competitive blockade of the NMDA-gated cation channel with ketamine or MK-801 increases the intensity of NREM delta during subsequent sleep. This delta increase (measured as integrated amplitude in 1-4 Hz EEG) occurs in the 12 h period following i.p. injection. However, the 12 h after drug injection is also the period in which these drugs induce neurotoxic changes, raising the possibility that the increased delta represents toxic EEG slowing rather than an increase in the physiological delta waves of NREM sleep. We hypothesized that the time course of delta stimulation could be separated from the time course of neurotoxicity. We tested this hypothesis by injecting 0.3 mg/kg MK-801 at the start of the dark period (DP) and depriving rats of sleep until the onset of the light period (LP) 12 h later. There were two control groups: one received MK-801 at the start of the DP with no further manipulation and the second group received a saline injection at DP onset followed by 12 h of sleep deprivation. The dependent variable was the amount of delta integrated amplitude (IA) in the LP, whose onset was 12 h after MK-801 injection. Total IA in the light period was significantly greater in rats who received MK-801 followed by sleep deprivation than in rats who received sleep deprivation alone or MK-801 alone. This finding indicates that delta stimulation by MK-801 is maintained over 12 h of waking, indicating that the delta increase is not due to toxic EEG slowing or persisting MK-801. Instead, NMDA channel blockade by MK-801 increases the homeostatic need for delta or else directly alters sleep regulatory systems. We speculate that these effects are mediated by hypothalamic sleep centers through control of neuroendocrine pulses that produce both NREM and REM sleep. Imposing a period of waking between drug administration and sleep onset may prove a generally useful strategy for determining whether a drug affects the homeostatic need for sleep or acutely stimulates sleep systems. This strategy can also help distinguish between toxic and physiological increases in delta EEG.

Received 7 May 1996; accepted in final form 1 August 1996.
APS Manuscript Number J372-6.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 29 August 1996