SITE AND RECEPTOR MECHANISM OF MK801 DELTA STIMULATION

描述（改编自申请人摘要）：现有证据表明

DESCRIPTION (Adapted from applicant's abstract): Current evidence indicates that the homeostatic (recuperative) processes of sleep are proportional to the amount of high amplitude, slow (delta) EEG within NREM sleep. The investigator has discovered that blockade of the cation channel gated by the NMDA subpopulation of GluRs during waking intensely stimulates NREM delta during subsequent sleep. The investigator has now demonstrated this effect with spectral as well as period analysis and shown that MK-801-induced changes in NREM and REM spectra closely parallel those of sleep deprivation, the most potent physiological sleep stimulus. In addition to its significance for sleep research, this NDP provides a novel, highly reliable model for in vivo studies of the effects of GluR perturbations on cortical electrophysiology. Glutamate, the main excitatory neurotransmitter, plays a central role in normal brain function and in pathological conditions including excitotoxicity and, possibly, schizophrenia. The investigator's research will identify the neural structures that can produce NDP in response to microinjection of MK-801 and the competitive NMDA antagonist CPPene. Sites for injection include highly plastic limbic structures that respond acutely to channel blockade with hypermetabolism and have high densities of NMDA receptors, structures implicated in NREM sleep regulation, and structures involved in the circuits that generate EEG oscillations. These studies will be the first systematic investigation of changes in quantified sleep (and waking) EEG following bilateral NMDA receptor blockade in specific brain structures. They are not a random search for any sleep EEG effects but are aimed at duplicating with microinjection the highly reliable NDP the investigator found with systemic administration of MK-801. The investigator's research could provide new insights into systemic GluR physiology, mechanisms of sleep homeostasis, NREM sleep abnormalities in schizophrenia and depression, and the NMDA (PCP) model of schizophrenia. It might also lead to the development of a novel class of hypnotics that stimulates a more physiological sleep EEG.