Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor subtype 5 (mGlu5) demonstrate anxiolytic-like and antidepressant-like effects yet concern regarding adverse effect liability remains. Functional coupling of mGlu5 with ionotropic N-methyl-D-aspartate receptors (NMDARs) represents a potential mechanism through which full inhibition leads to adverse effects, as NMDAR inhibition can induce cognitive impairments and psychotomimetic-like effects. Recent development of “partial” mGlu5 NAMs, characterized by submaximal but saturable levels of blockade, may represent a novel development approach to broaden the therapeutic index of mGlu5 NAMs. This study compared the partial mGlu5 NAM, M-5MPEP, with the full mGlu5 NAM, VU0424238 on sleep, cognition, and brain function alone and in combination with a subthreshold dose of the NMDAR antagonist, MK-801, using a paired-associates learning (PAL) cognition task and electroencephalography (EEG) in rats. M-5MPEP and VU0424238 decreased rapid eye movement (REM) sleep and increased REM sleep latency, both putative biomarkers of antidepressant-like activity. Neither compound alone affected accuracy, but 30 mg/kg VU0424238 combined with MK-801 decreased accuracy on the PAL task. Using quantitative EEG, VU0424238, but not M-5MPEP, prolonged arousal-related elevations in high gamma power, and, in combination, VU0424238 potentiated effects of MK-801 on high gamma power. Together, these studies further support a functional interaction between mGlu5 and NMDARs that may correspond with cognitive impairments. Present data support further development of partial mGlu5 NAMs given their potentially broader therapeutic index than full mGlu5 NAMs and use of EEG as a translational biomarker to titrate doses aligning with therapeutic versus adverse effects.
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.
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.
Many symptoms associated with opioid withdrawal contribute to continued used and relapse. Long‐lasting sleep disturbances are common symptoms of opioid use and withdrawal, contributing to high rates of relapse. Thus, reducing sleep impairments during abstinence may be a novel and effective treatment approach for opioid use disorder. Understanding the acute and long‐term effects of opioid exposure on sleep is critical, yet understudied in animal models of opioid use disorder (OUD). Although oxycodone is widely used medically and recreationally, no study to date has assessed progressive changes in sleep/wake architecture following oxycodone self‐administration in animals. In the present studies, male (n=12) and female (n=6) Sprague Dawley rats were implanted with both electroencephalography (EEG) recording devices and intravenous jugular catheters to monitor sleep duration and quality prior to and following oxycodone self‐administration. Rats were first trained to self‐administer sucrose pellets on a fixed ratio 3 (FR3) schedule of reinforcement during the first 2 hours of the dark cycle. Next, half of the rats continued to self‐administer sucrose pellets, while the other half self‐administered oxycodone (0.1 mg/kg/inf) for 30 days. Rats then underwent 20 days of extinction where the reinforcer and light cues were absent and responding had no scheduled consequences. EEG recordings were collected on the last day of sucrose pellet self‐administration and every 5th day of oxycodone self‐administration or abstinence. EEGs were recorded from each rats’ homecage, following completion of each self‐administration session and lasted for 21 hours. EEG data were analyzed using Neuroscore software, each 10s epoch was manually scored as wake, rapid eye movement (REM) sleep, non‐REM (NREM) sleep. Sleep and quantitative EEG were examined using within‐subject changes from a drug‐free baseline as well as between‐subject changes (oxycodone vs sucrose pellet self‐administration) using custom Matlab scripts and GraphPad prism. On average, rats self‐administered 2.6 mg/kg oxycodone per 2‐hr session, with considerable variability in overall intake (0.8‐5mg/kg per day). Preliminary analysis suggests subtle alterations in sleep duration across the self‐administration period. Specifically, acute increases in time awake were present within the first 3 hours following self‐administration, yet dissipated across the 30 day self‐administration period. Group effects on sleep duration during abstinence were not found. State‐dependent spectral analysis is still ongoing, but preliminary data suggest sleep quality (e.g. delta power during non‐REM sleep) is reduced during the initial week of self‐administration and rebounds during abstinence. Correlative analyses between intake and sleep measures are still ongoing. Understanding the direct and long‐lasting pharmacological effects of oxycodone self‐administration on sleep will be beneficial to examine novel pharmacotherapies to ameliorate sleep disturbances associated with OUD.
Opioid use disorder (OUD) is an ongoing global public health concern. Opioid analgesics such as oxycodone are major contributors to this epidemic because of their abuse potential. Thus, understanding acute and long‐term effects of opioid exposure is critical. Sleep disturbances are commonly reported yet understudied symptoms of OUD commonly associated with relapse. Normalizing the sleep disturbances associated with OUD could be a novel therapeutic approach for relapse prevention. No study to date has assessed progressive changes in sleep/wake architecture following contingent or non‐contingent oxycodone exposure in animals. In the present studies, effects of oxycodone on sleep/wake architecture and quantitative electroencephalography (EEG) were examined in freely moving, Sprague‐Dawley rats implanted with EEG surface electrodes and wireless transmitters. 24 hr EEG home cage recordings were scored manually as wake, rapid eye movement (REM) and non‐REM (NREM) sleep. In one cohort, effects of acute, noncontingent oxycodone (1‐3 mg/kg; sc) were examined when administered 2 hr into the light cycle. Oxycodone dose‐dependently increased time awake and reduced NREM and REM sleep duration. Spectral power analysis showed that oxycodone dose‐dependently increased high frequency gamma power (50‐100Hz). In a second cohort, rats were implanted with both EEG implants and intravenous jugular catheters to examine effects of oxycodone self‐administration (SA) on sleep. Rats were trained to self‐administer sucrose pellets on a fixed ratio 3 (FR3) schedule of reinforcement during the first 2 hours of the dark cycle. Next, rats were divided into two groups; half continued to self‐administer sucrose pellets, while the other self‐administered oxycodone (0.056 mg/kg/inf for 7 days; then 0.1 mg/kg/inf for 10 days). On average, rats self‐administered 1.04 mg/kg oxycodone per 2‐hr session. Rats then underwent response extinction for 5 days where the reinforcer and light cues were absent followed by a single light‐cue elicited reinstatement session. EEG was recorded from the home cages for the remaining 22 hours per day. Preliminary data suggest that, compared to the last day of sucrose pellet SA, oxycodone SA increased time awake and decreased NREM and REM sleep. These changes were not seen in rats self‐administering sucrose pellets. The increase in wake duration persisted throughout oxycodone SA sessions, but the reduction in REM sleep dissipated over time. Ongoing analyses are examining sleep during abstinence to determine whether abstinence‐related changes in sleep occur in a similar manner to other illicit drug classes. The effects of noncontingent oxycodone are more prominent than self‐administered despite similar total daily intake. Self‐administration paradigms yielding higher daily intake may be necessary to engender greater sleep disturbances. Although preliminary, understanding the direct pharmacological effects of oxycodone self‐administration on sleep will be beneficial to examine potential novel pharmacotherapies to normalize ...
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