NREM delta stimulation following MK-801 is a response of sleep systems

J Neurophysiol. 1996 Dec;76(6):3714-20. doi: 10.1152/jn.1996.76.6.3714.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Delta Rhythm*
  • Dizocilpine Maleate / pharmacokinetics
  • Dizocilpine Maleate / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Half-Life
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Sleep Deprivation / physiology
  • Sleep Stages / drug effects*
  • Stimulation, Chemical

Substances

  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate