Examining Sex Differences in Response to NMDAR Antagonist MK‐801 on Sleep Architecture and Brain Function Using Electroencephalography in Rats

Abstract

Accumulating evidence suggests glutamatergic hypofunction is one underlying factor in the pathology of schizophrenia. Administration of N-methyl-D-aspartate receptor (NMDAR) antagonists induces psychotomimetic-like symptoms in healthy humans and has emerged as a pharmacological model for symptoms of schizophrenia in animals. MK-801, an NMDAR antagonist, is frequently used to disrupt cognition and induce hyperlocomotion, modelling the cognitive and positive symptoms of schizophrenia, respectively. However, despite significant contributions of these models to surrounding literature, there are vast sex differences in the symptomology of schizophrenia in the human population that are underrepresented in animal models. Evidence suggests that prevalence and severity of negative and cognitive symptoms may be greater in males relative to females. Furthermore, sleep disturbances are underappreciated symptoms of schizophrenia, and sex differences in these have also been reported. Applying a translational biomarker approach that can be readily implemented in human subjects, present studies used polysomnography and quantitative electroencephalography (qEEG) measures to determine if NMDAR antagonists can reveal sex differences on sleep and brain function in animals similar to those reported in the human population. EEG surface electrodes and wireless transmitters were implanted in male and female Sprague-Dawley rats. EEG's were recorded for 24 hours in freely moving rats from their homecage. MK-801 (males: 0.056-0.56 mg/kg, sc; females: 0.03-0.3 mg/kg, sc) was administered 2 hours into the light cycle. Recordings were manually scored into wake, rapid eye movement (REM), and non-REM sleep, and qEEG spectral power was evaluated during waking epochs only. Activity counts were also simultaneously recorded. Consistent with previous literature, MK-801 induced hyperlocomotion, increased time awake, and decreased both NREM and REM sleep. Females were more sensitive than males to all of these measures, showing longer duration and magnitude of effects. Furthermore, MK-801 induced profound dose-dependent increases on both low and high gamma power in male rats. Interestingly, no comparable dose-dependent increases in gamma power were found in female rats across a full log unit dose range. Gamma power is highly sensitive to glutamate function, and abnormalities have been associated with cognitive impairment and psychotic symptoms in patients with schizophrenia. This is the first report, to our knowledge, of a blunted response to MK-801's effects in female rats compared to males despite increased sensitivity to all other reported measures. Ultimately, EEG revealed sex-related differences in NMDAR function which may correspond with prevalence/severity of symptoms of schizophrenia in humans. This may overall strengthen the validity of using NMDAR antagonism in preclinical model to experimentally induce schizophrenia-like symptoms.