Noncompetitive NMDA channel blockade during waking intensely stimulates NREM delta.
We previously found that subanesthetic doses of ketamine administered during the dark (active) period (DP) in rats strongly increased the integrated amplitude of the delta (1-4 Hz) electroencephalogram (EEG) in subsequent nonrapid eye movement (NREM) sleep. Here, we injected MK-801 into adult male Sprague-Dawley rats to test the hypothesis that such delta stimulation is characteristic of drugs that noncompetitively block the cation channel gated by the N-methyl-D-aspartate (NMDA) receptor. Injections of 0.3 and 0.5 mg/kg MK-801 in the middle of the DP produced waking intoxication for approximately 3 hr. In the following light period, NREM delta integrated amplitude was markedly increased in every rat (mean 55% increase after 0.5 mg/kg). A separate control experiment with 3-hr sleep deprivation in the mid-DP showed that the delta stimulation could not be attributed to sleep loss during MK-801 intoxication. Mechanisms by which NMDA cation channel blockade might stimulate NREM delta include a compensatory (homeostatic) sleep response to the metabolic, receptor or other neuronal effects of cation channel blockade; pathologic EEG slowing caused by neurotoxicity (in which case NREM delta might provide a noninvasive index of neurotoxic vacuolization); or a persistent, direct action of the drug or its metabolites on delta-generating systems. Questions of mechanism gain interest because of the magnitude of these pharmacologic effects on the sleep EEG component (delta) thought to be correlated with brain recuperative processes. In addition, our findings add to growing evidence implicating excitatory amino acid systems in sleep regulation.
Campbell
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IG
Veterans Administration Northern California System of Clinics, Davis, USA.
Feinberg
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I
D000818:Animals; D003700:Delta Rhythm / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012894:Sleep Stages / Q000502:physiology*; D014851:Wakefulness
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate