Examining MK‐801‐Induced Changes on EEG in Ovariectomized Female Rats with and without 17β‐Estradiol

Abstract

Schizophrenia affects 1% of the human population. Despite similar lifetime prevalence in males and females, >75% of patients diagnosed between 45‐50 years of age are female, an age range that corresponds with the menopause transition. Additionally, perimenopausal and postmenopausal women exhibit heightened symptom severity, risk of relapse, and poorer treatment response to some antipsychotic medications including olanzapine. Because decreased circulating estrogen is a physiological change associated with menopause, this suggests a strong relationship between estrogen decline and schizophrenia. Administration of N‐methyl‐D‐aspartate receptor (NMDAR) antagonists 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, respectively. Moreover, electroencephalography (EEG) studies provide a cross‐species, translational biomarker to examine normal and aberrant brain function. MK‐801 has been found to induce excessive increases in high frequency gamma power using EEG which corresponds with cognitive disruptions and positive symptoms. However, few preclinical studies using NMDAR antagonists examine the influence of hormones including 17β‐estradiol (E2) that are known to impact symptomatology and treatment response. Using surface electrodes and wireless EEG transmitters, we have previously shown age‐related differences in response to MK‐801 between 3 and 12 month old ovary‐intact female rats. Unlike humans, ovary‐intact female rats undergo estropause at around 12 months of age and, paradoxically, may experience a persistent estrus phase maintaining elevated levels of estradiol. This suggests estradiol may have protected against MK‐801‐induced disruptions. To directly test the hypothesis that E2 depletion influences NMDAR function, we are examining the effects of MK‐801 (0.03‐0.18 mg/kg, sc) in 3 month old ovariectomized (Ovx; a rodent model of surgical menopause) female Sprague‐Dawley rats. Preliminary data suggest Ovx rats display altered sensitivity to MK‐801‐induced elevations in gamma power compared to ovary‐intact, age‐matched rats. Additionally, we are evaluating E2 through administration via implanted silastic capsules containing 25% E2 and 75% cholesterol, a well‐established method of tonic delivery (Ovx+E rats). Results from these ongoing studies will be presented. We hypothesize there will be heightened sensitivity to NMDAR antagonist‐induced elevations in gamma power in Ovx rats relative to Ovx+E rats. Moreover, we hypothesize that olanzapine will be less effective in attenuating MK‐801‐induced elevations in gamma power in the OVX rats. Ultimately, these studies aim to establish a relationship between estradiol, NMDAR function, and antipsychotic‐like activity that inform menopause‐related differences in patients with schizophrenia and can be pursued in the development novel antipsychotic medications.