Journal of Neurophysiology, Vol 76, Issue 6 3714-3720, Copyright © 1996 by APS
NREM delta stimulation following MK-801 is a response of sleep systems
I. G. Campbell and I. Feinberg
Physiology Graduate Group, University of California, Davis 95616, USA.
1. We have previously shown that noncompetitive blockade of the
N-methyl-D-aspartate (NMDA)-gated cation channel with ketamine or
Dizocilpine maleate (MK-801) increases the intensity of
non-rapid-eye-movement (NREM) delta during subsequent sleep. This delta
increase [measured as integrated amplitude (IA) in 1- to 4-Hz
electroencephalogram (EEG)] occurs in the 12-h period following
intraperitoneal 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. 2. 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. 3. There were two control groups: one received MK-801 at the start
of the DP with no further manipulation, and the second received a saline
injection at DP onset followed by 12 h of sleep deprivation. The dependent
variable was the amount of delta IA in the LP, whose onset was 12 h after
MK-801 injection. Total IA in the LP was significantly greater in rats that
received MK-801 followed by sleep deprivation than in rats that received
sleep deprivation alone or MK-801 alone. 4. 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
rapid-eye-movement sleep. 5. 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.
