mGlu Receptors Research Articles

Effects of positive mGlu5 modulation on D2 signaling and nicotine-conditioned place preference: Mechanisms of epigenetic inheritance in a transgenerational model of drug abuse vulnerability in psychosis.

The metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential target for the treatment of psychosis that is suggested to have greater efficacy than antipsychotic medications that are currently utilized. This study sought to elucidate mechanisms of therapeutic action associated with the modulation of the mGlu5 receptor in a disordered system marked by dopamine dysfunction. We further explored epigenetic mechanisms contributing to heritable transmission of a psychosis-like phenotype in a novel heritable model of drug abuse vulnerability in psychosis. F1 generation male and female Sprague-Dawley rats that were the offspring of two neonatal quinpirole-treated (QQ) or two saline-treated (SS) animals were tested on nicotine-conditioned place preference (CPP). Regulators of G protein signaling 9 (RGS9) and β-arrestin 2 (βA2), which mediate dopamine (DA) D2 signaling, were measured in the nucleus accumbens shell, prelimbic and infralimbic cortices. Reduced Representation Bisulfite Sequencing (RRBS) was used to analyze the cytosine methylation in these brain regions. Pretreatment with the mGlu5-positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) 20 min prior to conditioning trials blocked enhanced nicotine CPP and mitigated aberrant G protein-dependent and -independent signaling in QQ animals. RRBS analysis revealed region-specific changes in several pathways, including nicotine addiction, dopamine synapses, and neural connectivity. These results reveal an important region-specific mechanism of action for CDPPB in a system marked by enhanced DAD2 receptor signaling. Results additionally reveal DNA methylation as an epigenetic mechanism of heritability, further validating the current model as a useful tool for the study of psychosis and comorbid nicotine use.

Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer

Metabotropic glutamate (mGlu) receptor protomers can heterodimerize, leading to different pharmacology compared to their homodimeric counterparts. Here, we use complemented donor-acceptor resonance energy transfer (CODA-RET) technology that distinguishes signaling from defined mGlu heterodimers or homodimers, together with targeted mutagenesis of receptor protomers and computational docking, to elucidate the mechanism of activation and differential pharmacology in mGlu2/4 heteromers. We demonstrate that positive allosteric modulators (PAMs) that bind an upper allosteric pocket in the mGlu4 transmembrane domain are active at both mGlu4/4 homomers and mGlu2/4 heteromers, while those that bind a lower allosteric pocket within the same domain are efficacious in homomers but not heteromers. We further demonstrate that both protomers of mGlu2/4 heteromers are cis-activated by their orthosteric agonists, signaling independently with no trans-activation detected. Intriguingly, however, upper pocket mGlu4 PAMs enable trans-activation in mGlu2/4 heteromers from mGlu4 to the mGlu2 protomer and also enhance cis-activation of the mGlu2 protomer. While mGlu2 PAMs enhanced mGlu2 cis-activation in the heterodimer, we were unable to detect trans-activation in the opposite direction from mGlu2 to the mGlu4 protomer, suggesting an asymmetry of signaling. These insights into the molecular logic of this receptor heteromer are critical to building toward precision targeted therapies for multiple neuropsychiatric disorders.

Replication and extension of the subregion selectivity of glutamate-related changes within the nucleus accumbens associated with the incubation of cocaine-craving

Cue-elicited drug-seeking behavior intensifies with the passage of time during withdrawal from drug taking and this “incubation of cocaine-craving” involves alterations in nucleus accumbens (NA) glutamate transmission. Here, we employed a combination of in vivo microdialysis and immunoblotting approaches to further examine changes in biochemical indices of glutamate transmission within NA subregions that accompany the incubation of cocaine-craving exhibited by male rats with a 10-day history of 6-h access to intravenous cocaine (0.25 mg/infusion). Immunoblotting on whole cell lysates from the core subregion (NAc core) revealed interactions between cocaine self-administration history, withdrawal and drug cue re-exposure for Homer2a/b, mGlu1, and GluN2b expression, as well as indices of Akt and ERK activity. With the exception of PKCε phosphorylation, most protein changes within the shell subregion (NAc shell) depended on drug cue re-exposure and cocaine history rather than varying in a consistent time-dependent manner. Reduced basal extracellular glutamate content was apparent only in the NAc core of cocaine-experienced rats during protracted (30 days) withdrawal and this was accompanied by a markedly blunted capacity of the mGlu1/5 agonist DHPG to elevate glutamate levels within this subregion. Finally, over-expressing neither Homer1c nor Homer2b within the NAc core during protracted cocaine withdrawal altered the magnitude of cue-elicited responding, its extinction or cocaine-primed reinstatement of drug-seeking behavior. The present findings are consistent with the extant literature implicating changes in Group 1 mGlu receptor function within the NAc core subregion as central to incubated cocaine-craving and provide further evidence against a major role for Homer proteins in gating incubated cocaine-craving. Further, our results provide novel correlational evidence implicating elevated Akt and blunted ERK activity within the NAc core as potential contributors to the expression of incubated cocaine-craving, worthy of future investigation.

MGlu4R, mGlu7R, and mGlu8R allosteric modulation for treating acute and chronic neurodegenerative disorders.

Neuroprotection, defined as safeguarding neurons from damage and death by inhibiting diverse pathological mechanisms, continues to be a promising approach for managing a range of central nervous system (CNS) disorders, including acute conditions such as ischemic stroke and traumatic brain injury (TBI) and chronic neurodegenerative diseases like Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). These pathophysiological conditions involve excessive glutamatergic (Glu) transmission activity, which can lead to excitotoxicity. Inhibiting this excessive Glu transmission has been proposed as a potential therapeutic strategy for treating the CNS disorders mentioned. In particular, ligands of G protein-coupled receptors (GPCRs), including metabotropic glutamatergic receptors (mGluRs), have been recognized as promising options for inhibiting excessive Glu transmission. This review discusses the complex interactions of mGlu receptors with their subtypes, including the formation of homo- and heterodimers, which may vary in function and pharmacology depending on their protomer composition. Understanding these intricate details of mGlu receptor structure and function enhances researchers' ability to develop targeted pharmacological interventions, potentially offering new therapeutic avenues for neurological and psychiatric disorders. This review also summarizes the current knowledge of the neuroprotective potential of ligands targeting group III mGluRs in preclinical cellular (in vitro) and animal (in vivo) models of ischemic stroke, TBI, PD, AD, and MS. In recent years, experiments have shown that compounds, especially those activating mGlu4 or mGlu7 receptors, exhibit protective effects in experimental ischemia models. The discovery of allosteric ligands for specific mGluR subtypes has led to reports suggesting that group III mGluRs may be promising targets for neuroprotective therapy in PD (mGlu4R), TBI (mGlu7R), and MS (mGlu8R).

Metabotropic Glutamate Receptors Type 3 and 5 Feature the "NeuroTransmitter-type" of Glioblastoma: A Bioinformatic Approach.

Glioblastoma (GBM) represents an aggressive and common tumor of the central nervous system. The prognosis of GBM is poor, and despite a refined genetic and molecular characterization, pharmacological treatment is largely suboptimal. Contribute to defining a therapeutic line in GBM targeting the mGlu3 receptor in line with the principles of precision medicine. Here, we performed a computational analysis focused on the expression of type 3 and 5 metabotropic glutamate receptor subtypes (mGlu3 and mGlu5, respectively) in high- and low-grade gliomas. The analysis allowed the identification of a particular high-grade glioma type, characterized by a high expression level of both receptor subtypes and by other markers of excitatory and inhibitory neurotransmission. This so-called neurotransmitter-GBM (NT-GBM) also shows a distinct immunological, metabolic, and vascularization gene signature. Our findings might lay the groundwork for a targeted therapy to be specifically applied to this putative novel type of GBM.

A 'double-edged' role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs.

We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic, and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when the light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of presumed BLA input, and decreased BLA-driven feedforward inhibition of amygdala output neurons. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.

Adaptive Changes in Group 2 Metabotropic Glutamate Receptors Underlie the Deficit in Recognition Memory Induced by Methamphetamine in Mice.

Cognitive dysfunction is associated with methamphetamine use disorder (MUD). Here, we used genetic and pharmacological approaches to examine the involvement of either Group 2 metabotropic glutamate (mGlu2) or mGlu3 receptors in memory deficit induced by methamphetamine in mice. Methamphetamine treatment (1 mg/kg, i.p., once a day for 5 d followed by 7 d of withdrawal) caused an impaired performance in the novel object recognition test in wild-type mice, but not in mGlu2-/- or mGlu3-/- mice. Memory deficit in wild-type mice challenged with methamphetamine was corrected by systemic treatment with selectively negative allosteric modulators of mGlu2 or mGlu3 receptors (compounds VU6001966 and VU0650786, respectively). Methamphetamine treatment in wild-type mice caused large increases in levels of mGlu2/3 receptors, the Type 3 activator of G-protein signaling (AGS3), Rab3A, and the vesicular glutamate transporter, vGlut1, in the prefrontal cortex (PFC). Methamphetamine did not alter mGlu2/3-mediated inhibition of cAMP formation but abolished the ability of postsynaptic mGlu3 receptors to boost mGlu5 receptor-mediated inositol phospholipid hydrolysis in PFC slices. Remarkably, activation of presynaptic mGlu2/3 receptors did not inhibit but rather amplified depolarization-induced [3H]-D-aspartate release in synaptosomes prepared from the PFC of methamphetamine-treated mice. These findings demonstrate that exposure to methamphetamine causes changes in the expression and function of mGlu2 and mGlu3 receptors, which might alter excitatory synaptic transmission in the PFC and raise the attractive possibility that selective inhibitors of mGlu2 or mGlu3 receptors (or both) may be used to improve cognitive dysfunction in individuals affected by MUD.

Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity.

Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PV grm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.

The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats

RationaleCocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders.ObjectiveIn the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history.MethodsWe used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion [0.1 ml]) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle.ResultsBoth intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions.ConclusionsThese findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder

BackgroundElucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD. MethodsPositron emission tomography (PET) with [18F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25). ResultsConsistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028). LimitationsThe modest sample size is the primary limitation. ConclusionsDeficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights.

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model

The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.

Parvalbumin interneuron mGlu5 receptors govern sex differences in prefrontal cortex physiology and binge drinking.

Despite established sex differences in the prevalence and presentation of psychiatric disorders, little is known about the cellular and synaptic mechanisms that guide these differences under basal conditions. The proper function of the prefrontal cortex (PFC) is essential for the top-down regulation of motivated behaviors. The activity of the PFC is tightly controlled by parvalbumin-expressing interneurons (PV-INs), a key subpopulation of fast-spiking GABAergic cells that regulate cortical excitability through direct innervations onto the perisomatic regions of nearby pyramidal cells. Recent rodent studies have identified notable sex differences in PV-IN activity and adaptations to experiences such as binge drinking. Here, we investigated the cellular and molecular mechanisms that underlie sex-specific regulation of PFC PV-IN function. Using whole-cell patch-clamp electrophysiology and selective pharmacology, we report that PV-INs from female mice are more excitable than those from males. Moreover, we find that mGlu1 and mGlu5 metabotropic glutamate receptors regulate cell excitability, excitatory drive, and endocannabinoid signaling at PFC PV-INs in a sex-dependent manner. Genetic deletion of mGlu5 receptors from PV-expressing cells abrogates all sex differences observed in PV-IN membrane and synaptic physiology. Lastly, we report that female, but not male, PV-mGlu5-/- mice exhibit decreased voluntary drinking on an intermittent access schedule, which could be related to changes in ethanol's stimulant properties. Importantly, these studies identify mGlu1 and mGlu5 receptors as candidate signaling molecules involved in sex differences in PV-IN activity and behaviors relevant to alcohol use.

Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain.

Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.

S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

The limbic system, particularly the NAc, shows a high concentration of metabotropic glutamate receptors (mGluRs). Recent evidence suggests the significant involvement of mGluRs in mental disorders, including substance abuse and addiction. The objective of this study was to examine the involvement of mGlu8 receptors in the NAc in the mechanisms underlying the extinction and reinstatement of conditioned place preference (CPP) induced by morphine. Male Wistar rats underwent surgical implantation of bilateral cannulas in the NAc and were assessed in a CPP protocol. In study 1 at the same time as the extinction phase, the rats were given varying doses of S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl). In study 2, rats that had undergone CPP extinction were given S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl) five minutes prior to receiving a subthreshold dose of morphine (1 mg/kg) in order to reactivate the previously extinguished morphine response. The findings demonstrated that administering S-3,4-DCPG directly into the accumbens nucleus resulted in a decrease in the duration of the CPP extinction phase. Moreover, dose-dependent administration of S-3,4-DCPG into the NAc inhibited CPP reinstatement. The observations imply that microinjection of S-3,4-DCPG as a potent orthosteric agonist with high selectivity for the mGlu8 receptor into the NAc promotes the process of extinction while concurrently exerting inhibitory effects on the reinstatement of morphine-induced CPP. This effect may be associated with the modulation of glutamate engagement within the NAc and the plasticity of reward pathways at the synaptic level.

Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice.

Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu5) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. Partial mGlu5 receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced (R)-ketamine action in mice, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.

MGlu2 and mGlu3 receptor negative allosteric modulators attenuate the interoceptive effects of alcohol in male and female rats

RationaleThe subjective effects of alcohol are associated with alcohol use disorder (AUD) vulnerability and treatment outcomes. The interoceptive effects of alcohol are part of these subjective effects and can be measured in animal models using drug discrimination procedures. The newly developed mGlu2 and mGlu3 negative allosteric modulators (NAMs) are potential therapeutics for AUD and may alter interoceptive sensitivity to alcohol. ObjectivesTo determine the effects of mGlu2 and mGlu3 NAMs on the interoceptive effects of alcohol in rats. MethodsLong-Evans rats were trained to discriminate the interoceptive stimulus effects of alcohol (2.0 g/kg, i.g.) from water using both operant (males only) and Pavlovian (male and female) drug discrimination techniques. Following acquisition training, an alcohol dose-response (0, 0.5, 1.0, 2.0 g/kg) experiment was conducted to confirm stimulus control over behavior. Next, to test the involvement of mGlu2 and mGlu3, rats were pretreated with the mGlu2-NAM (VU6001966; 0, 3, 6, 12 mg/kg, i.p.) or the mGlu3-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol administration (2.0 g/kg, i.g.). ResultsIn Pavlovian discrimination, male rats showed greater interoceptive sensitivity to 1.0 and 2.0 g/kg alcohol compared to female rats. Both mGlu2-NAM and mGlu3-NAM attenuated the interoceptive effects of alcohol in male and female rats using Pavlovian and operant discrimination. There may be a potential sex difference in response to the mGlu2-NAM at the highest dose tested. ConclusionsMale rats may be more sensitive to the interoceptive effects of the 2.0 g/kg alcohol training dose compared to female rats. Both mGlu2-and mGlu3-NAM attenuate the interoceptive effects of alcohol in male and female rats. These drugs may have potential for treatment of AUD in part by blunting the subjective effects of alcohol.

Testing PET-[11C]ABP688 as a tool to quantify glutamate release in vivo

Abstract The excitatory neurotransmitter glutamate plays a critical role in experience-dependent neuroplasticity, including addiction-related processes. To date, however, it is not possible to measure glutamate release in the living human brain. Positron emission tomography (PET) with [11C]ABP688, a selective allosteric antagonist of metabotropic type 5 glutamate (mGlu5) receptors, could offer an effective strategy. To test this proposition, we conducted a series of studies in rats using microdialysis and [11C]ABP688 microPET imaging, and in humans using PET and magnetic resonance spectroscopy (MRS). Significant calcium-dependent glutamate release was identified in the ventral striatum of awake rats (190.5 ± 34.7%, p < 0.05; n = 7) following administration of a low dose of ethanol (EtOH; 20%, 0.5 g/kg), a pharmacological challenge readily translatable to human research. Simultaneous microdialysis and microPET studies in anesthetized rats yielded concurrent increases in glutamate release (126.9 ± 5.3%, p < 0.001; n = 11) and decreases in striatal [11C]ABP688 binding (6.8 ± 9.6%, p < 0.05). These latter two effects, however, were not significantly correlated (r = 0.25, p = 0.46). In humans, a laboratory stressor yielded significant changes in self-reported mood (ps < 0.041), sympathetic system activations (ps < 0.042), and the MRS index of striatal glutamate reuptake following excitatory neurotransmission, Glx/Cr levels (p = 0.048). These effects, however, were not accompanied by significant changes in [11C]ABP688 BPND (ps > 0.21, n = 9) or correlated with each other (ps > 0.074). Together, these studies document EtOH-induced glutamate release from neurons, EtOH-induced decreases in [11C]ABP688 binding, and stress-induced changes in glutamate turnover, yet fail to provide evidence that the PET [11C]ABP688 method can be exploited to quantify moderate changes in glutamate release. The results underscore the need for highly controlled testing conditions during PET measures of mGlu5 receptors.

Loss of mGlu5 receptors in somatostatin-expressing neurons alters negative emotional states.

Subtype 5 metabotropic glutamate receptors (mGlu5) are known to play an important role in regulating cognitive, social and valence systems. However, it remains largely unknown at which circuits and neuronal types mGlu5 act to influence these behavioral domains. Altered tissue- or cell-specific expression or function of mGlu5 has been proposed to contribute to the exacerbation of neuropsychiatric disorders. Here, we examined how these receptors regulate the activity of somatostatin-expressing (SST+) neurons, as well as their influence on behavior and brain rhythmic activity. Loss of mGlu5 in SST+ neurons elicited excitatory synaptic dysfunction in a region and sex-specific manner together with a range of emotional imbalances including diminished social novelty preference, reduced anxiety-like behavior and decreased freezing during retrieval of fear memories. In addition, the absence of mGlu5 in SST+ neurons during fear processing impaired theta frequency oscillatory activity in the medial prefrontal cortex and ventral hippocampus. These findings reveal a critical role of mGlu5 in controlling SST+ neurons excitability necessary for regulating negative emotional states.

Modulation of mGlu5 reduces rewarding associative properties of nicotine via changes in mesolimbic plasticity: Relevance to comorbid cigarette smoking in psychosis

RationaleAntipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D2 heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia. ObjectiveThe current study sought to explore the use of the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) as a treatment to reduce symptoms related to psychosis and comorbid nicotine use. MethodsNeonatal treatment of animals with the dopamine D2-like receptor agonist quinpirole (NQ) from postnatal day (P)1–21 produces a lifelong increase in D2 receptor sensitivity, showing relevance to psychosis and comorbid tobacco use disorder. Following an 8-day conditioning paradigm, brain tissue in the mesolimbic pathway was analyzed for several plasticity markers, including brain derived neurotrophic factor (BDNF), phosphorylated p70 ribosomal S6 kinase (phospho-p70S6K), and cadherin-13 (Cdh13). ResultsPretreatment with CDPPB was effective to block enhanced nicotine conditioned place preference observed in NQ-treated animals. Pretreatment was additionally effective to block the nicotine-induced increase in BDNF and sex-dependent increases in cadherin-13 in the ventral tegmental area (VTA), as well as increased phospho-p70S6K in the nucleus accumbens (NAcc) shell found in NQ-treated animals. ConclusionIn conjunction with prior work, the current study suggests positive allosteric modulation of the mGlu5 receptor, an emerging target for schizophrenia therapeutics, may be effective for the treatment of comorbid nicotine abuse in psychosis.