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.

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.

Gabapentin (Neurontin) is synthetic analog of GABA that functions as a voltage‐gated calcium channel (VDCC) blocker and is FDA approved for the management of neuropathic pain and seizure disorders. While not a controlled substance, gabapentin misuse is associated with illicit opioid use, suggesting, along with anecdotal reports, that gabapentin may elicit positive subjective effects. The present study was conducted to examine the subjective effects of gabapentin using rats (N=10) trained to discriminate a 30.0 mg/kg dose of gabapentin (60 min pretreatment time) versus saline in a two‐choice drug discrimination task. The discrimination was acquired in all 10 animals (M = 67.4 sessions, +/− 7.2 SEM). A time course assessment using the gabapentin training dose revealed full substitution (> 80% Gabapentin‐appropriate responding) at 30 and 60 minutes post‐injection. In addition to the training dose, full substitution also occurred for a 60 and 120 mg/kg dose of Gabapentin. Full substitution was shown for the barbiturate and GABAA receptor positive modulator pentobarbital and for the gabapentin analog and VDCC blocker pregabalin. Partial substitution was shown with the psychostimulant d‐amphetamine and the anxiolytic drug and 5‐HT1A partial agonist buspirone. The present findings demonstrate gabapentin's discriminative stimulus effects appear to be primarily mediated by GABAA receptors and VDCC blockade and partially mediated by dopamine and 5‐HT receptors. Full substitution by pentobarbital and partial substitution by amphetamine suggests the potential for positive subjective effects produced by gabapentin.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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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.