Synaptogyrin-3 Prevents Cocaine Addiction and Dopamine Deficits.

Synaptogyrin-3, a functionally obscure synaptic vesicle protein, interacts with vesicular monoamine and dopamine transporters, bringing together dopamine release and reuptake sites. Synaptogyrin-3 was reduced by chronic cocaine exposure in both humans and rats, and synaptogyrin-3 levels inversely correlated with motivation to take cocaine in rats. Synaptogyrin-3 overexpression in dopamine neurons reduced cocaine self-administration, decreased anxiety-like behavior, and enhanced cognitive flexibility. Overexpression also enhanced nucleus accumbens dopamine signaling and prevented cocaine-induced deficits, suggesting a putative therapeutic role for synaptogyrin-3 in cocaine use disorder.

Use of Quantitative Electroencephalography to Inform Age- and Sex-Related Differences in NMDA Receptor Function Following MK-801 Administration.

Sex- and age-related differences in symptom prevalence and severity have been widely reported in patients with schizophrenia, yet the underlying mechanisms contributing to these differences are not well understood. N-methyl-D-aspartate (NMDA) receptor hypofunction contributes to schizophrenia pathology, and preclinical models often use NMDA receptor antagonists, including MK-801, to model all symptom clusters. Quantitative electroencephalography (qEEG) represents a translational approach to measure neuronal activity, identify targetable biomarkers in neuropsychiatric disorders and evaluate possible treatments. Abnormalities in gamma power have been reported in patients with schizophrenia and correspond to psychosis and cognitive impairment. Further, as gamma power reflects cortical glutamate and GABA signaling, it is highly sensitive to changes in NMDA receptor function, and NMDA receptor antagonists aberrantly increase gamma power in rodents and humans. To evaluate the role of sex and age on NMDA receptor function, MK-801 (0.03-0.3 mg/kg, SC) was administered to 3- and 9-month-old male and female Sprague-Dawley rats that were implanted with wireless EEG transmitters to measure cortical brain function. MK-801-induced elevations in gamma power were observed in 3-month-old male and female and 9-month-old male rats. In contrast, 9-month-old female rats demonstrated blunted maximal elevations across a wide dose range. Importantly, MK-801-induced hyperlocomotor effects, a common behavioral screen used to examine antipsychotic-like activity, were similar across all groups. Overall, sex-by-age-related differences in gamma power support using qEEG as a translational tool to evaluate pathological progression and predict treatment response across a heterogeneous population.

Metabotropic glutamate receptor function and regulation of sleep-wake cycles.

Metabotropic glutamate (mGlu) receptors are the most abundant family of G-protein coupled receptors and are widely expressed throughout the central nervous system (CNS). Alterations in glutamate homeostasis, including dysregulations in mGlu receptor function, have been indicated as key contributors to multiple CNS disorders. Fluctuations in mGlu receptor expression and function also occur across diurnal sleep-wake cycles. Sleep disturbances including insomnia are frequently comorbid with neuropsychiatric, neurodevelopmental, and neurodegenerative conditions. These often precede behavioral symptoms and/or correlate with symptom severity and relapse. Chronic sleep disturbances may also be a consequence of primary symptom progression and can exacerbate neurodegeneration in disorders including Alzheimer's disease (AD). Thus, there is a bidirectional relationship between sleep disturbances and CNS disorders; disrupted sleep may serve as both a cause and a consequence of the disorder. Importantly, comorbid sleep disturbances are rarely a direct target of primary pharmacological treatments for neuropsychiatric disorders even though improving sleep can positively impact other symptom clusters. This chapter details known roles of mGlu receptor subtypes in both sleep-wake regulation and CNS disorders focusing on schizophrenia, major depressive disorder, post-traumatic stress disorder, AD, and substance use disorder (cocaine and opioid). In this chapter, preclinical electrophysiological, genetic, and pharmacological studies are described, and, when possible, human genetic, imaging, and post-mortem studies are also discussed. In addition to reviewing the important relationships between sleep, mGlu receptors, and CNS disorders, this chapter highlights the development of selective mGlu receptor ligands that hold promise for improving both primary symptoms and sleep disturbances.

Partial mGlu5 Negative Allosteric Modulator M-5MPEP Demonstrates Antidepressant-Like Effects on Sleep Without Affecting Cognition or Quantitative EEG.

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.