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. Author manuscript; available in PMC: 2025 Sep 13.
Published in final edited form as: Neuroscience. 2024 Jul 15;555:83–91. doi: 10.1016/j.neuroscience.2024.06.016

mGluR5 Positive Allosteric Modulation Prevents MK-801 Induced Increases in Extracellular Glutamate in the Rat Medial Prefrontal Cortex

Amber L LaCrosse 1,3,*, Christina E May 2,4, William C Griffin 2, M Foster Olive 1
PMCID: PMC11344657  NIHMSID: NIHMS2010374  PMID: 39019391

Abstract

Potentiation of metabotropic glutamate receptor subtype 5 (mGluR5) function produces antipsychotic-like and pro-cognitive effects in animal models of schizophrenia and can reverse cognitive deficits induced by N-methyl-D-aspartate type glutamate receptor (NMDAR) antagonists. However, it is currently unknown if mGluR5 positive allosteric modulators (PAMs) can modulate NMDAR antagonist-induced alterations in extracellular glutamate levels in regions underlying these cognitive and behavioral effects, such as the medial prefrontal cortex. We therefore assessed the ability of the mGluR5 PAM, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), to reduce elevated extracellular glutamate levels induced by the NMDAR antagonist, dizocilpine (MK-801), in the medial prefrontal cortex. Male Sprague-Dawley rats were implanted with a guide cannula aimed at the medial prefrontal cortex and treated for ten consecutive days with MK-801 and CDPPB or their corresponding vehicles. CDPPB or vehicle was administered thirty minutes before MK-801 or vehicle each day. On the final day of treatment, in vivo microdialysis was performed, and samples were collected every thirty minutes to analyze extracellular glutamate levels. Compared to animals receiving only vehicle, administration of MK-801 alone significantly increased extracellular levels of glutamate in the mPFC. This effect was not observed in animals administered CDPPB before MK-801, nor in those administered CDPPB alone, indicating that CDPPB decreased extracellular glutamate release stimulated by MK-801. Results indicate that CDPPB attenuates MK-801 induced elevations in extracellular glutamate in the medial prefrontal cortex. This effect of CDPPB may underlie neurochemical adaptations associated with the pro-cognitive effects of mGluR5 PAMs in rodent models of schizophrenia.

Keywords: CDPPB, Glutamate, Cognition, NMDAR, MK-801, mGluR5

Graphical Abstract

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Introduction

Schizophrenia is a neurodevelopmental disorder characterized by complex symptoms that present on a spectrum (Owen and O’Donovan, 2017). Symptoms fall into two categories, positive and negative. Positive symptoms include perception disorders, such as delusions of grandeur and paranoia. Negative symptoms include anhedonia, social withdrawal, and cognitive impairments (Basso et al., 1998). Cognitive impairments in schizophrenia may affect working memory, reference memory, attention, and executive functioning. Individuals with schizophrenia presenting with cognitive impairments report a lower quality of life due to difficulty maintaining employment, independence, and relationships (Silver et al., 2003; Green et al., 2004; Aquila and Citrome, 2015; Rekhi et al., 2023). Current antipsychotic treatments remain inadequate for reducing the cognitive impairments associated with schizophrenia (Aquila and Citrome, 2015; Rekhi et al., 2023).

N-methyl-D-aspartate type glutamate receptors (NMDAR) may play a role in the development and onset of schizophrenia symptoms (Coyle et al., 2012; Gilmour et al., 2012; Zhou and Sheng, 2013). The dissociative anesthetics phencyclidine (PCP), ketamine, and dizocilpine (MK-801) are noncompetitive NMDAR antagonists that produce effects consistent with the positive and negative symptoms of schizophrenia and produce cognitive impairments closely resembling those observed in patients with schizophrenia (Allen and Young, 1978; Javitt and Zukin, 1991; Vollenweider, 2001; Krus and Bustillo, 2022). Analysis of postmortem brain tissue from individuals with schizophrenia was found to have decreased dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) (Glantz and Lewis, 2000). An additional study found increased NMDAR expression with abnormal subunit composition in the DLPFC that may indicate frontal lobe hypofunction (Dracheva et al., 2001). Further research reported abnormal NMDAR subunit composition but no difference in protein expression in the PFC (Deakin et al., 1989). Cumulatively, these findings indicate that NMDAR dysregulation is linked to schizophrenia, leading to the development of the glutamate hypothesis of schizophrenia (Allen and Young, 1978; Javitt and Zukin, 1991; Krystal et al., 2003). This hypothesis has evolved into two competing theories; for the scope of this paper, we will detail those regarding cognitive function. The first hypothesis suggests that hypofunctional NMDAR located on glutamatergic neurons fail to sufficiently activate dopamine (DA) neurons in the ventral tegmental area, leading to reduced DA in the PFC and impaired cognitive function (Olney et al., 1999; Paz et al., 2008; Marek et al., 2010). The second hypothesis suggests a hyperglutamatergic state, causing excitotoxicity or cell atrophy in frontal cortical regions, impairing cognitive function (Javitt and Zukin, 1991; Paz et al., 2008; Marek et al., 2010). This may be driven by hypofunctional NMDAR on cortical GABAergic interneurons, which disinhibit subcortical glutamatergic projection neurons, producing excessive glutamate in the PFC and subsequent excitotoxicity and cognitive impairment (Javitt and Zukin, 1991; Paz et al., 2008; Marek et al., 2010). It has been suggested that the hypofunctional DA state compensates for the previously continuous hyperglutamatergic state (Javitt and Zukin, 1991; Paz et al., 2008).

Group I metabotropic glutamate receptors, particularly type 5 metabotropic glutamate receptor (mGluR5), are physically linked to NMDAR by various scaffolding proteins (such as Homer, Shank, and GKAP) and positively modulate NMDAR function. On a biochemical level, by activating protein kinase C, mGluR5 signaling increases the phosphorylation of various NMDAR subunits, increasing the probability of NMDAR channel opening (Niswender and Conn, 2010). Consequently, mGluR5 potentiation may reverse hypofunctioning NMDAR and normalize DA levels in the PFC, thus attenuating cognitive impairment. Interestingly, mGluR5 potentiation may also compensate for NMDAR hypofunction on GABAergic inhibitory neurons, reversing the hyperglutamatergic state, regulating glutamate levels in the PFC, and subsequently attenuating cognitive impairment. Rodent studies have demonstrated that mGluR5 positive allosteric modulators (PAMs), such as 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), reverses cognitive impairments induced by NMDA antagonists. Our own prior findings demonstrated that pre-treatment with CDPPB prevented MK-801 induced impaired performance in an operant-based cognitive flexibility task (LaCrosse et al., 2015). Aligning with our results, several studies report similar findings while evaluating the effect of mGluR5 PAMs and MK-801 in various behavior assays, including operant tasks, spatial alteration tasks, reversal learning digging paradigm, social novelty discrimination, and novel object recognition (Darrah et al., 2008; Uslaner et al., 2009; Stefani and Moghaddam, 2010; Reichel et al., 2011; Gastambide et al., 2012; Clifton et al., 2013; Fowler et al., 2013; Gilmore et al., 2013; Horio et al., 2013). As a follow-up to our behavior study, the present experiment incorporated the previous treatment regimen from LaCrosse et al. (2015) to determine whether CDPPB and MK-801 induce neurochemical changes that relate to cognitive function.

Studies utilizing in vivo microdialysis have demonstrated that administration of MK-801 or other NMDA antagonists increases extracellular levels of glutamate in the medial prefrontal cortex (mPFC), and traditional antipsychotics can reverse these effects (Moghaddam et al., 1997; Adams and Moghaddam, 2001; Zuo et al., 2006; López-Gil et al., 2007; López-Gil et al., 2009; Pietraszek et al., 2009; Roenker et al., 2011; Roenker et al., 2012). However, studies examining the effects of mGluR5 PAMs on extracellular neurotransmitter levels are few and have focused primarily on changes in extracellular levels of DA (Lecourtier et al., 2007; Liu et al., 2008). Currently, only one other study has analyzed glutamate levels following pre-treatment with mGluR5 PAMs in MK-801 treated rodents (Isherwood et al., 2018). This study administered the mGluR5 PAM [S-(4-Fluoro-phenyl)-{3-[3-(4-fluorophenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone] (ADX47273), which produces allosteric effects that differ mechanistically from those of CDPPB (Bradley et al., 2011). To the best of our knowledge, this is the first study to examine the effects of the mGluR5 PAM, CDPPB, when administered alone and as a pre-treatment to MK-801, on extracellular glutamate levels in the mPFC of male rodents.

Materials and Methods

Subjects

Subjects were male Sprague-Dawley rats (Harlan Laboratories, Livermore, CA) weighing 250-300 g upon arrival. Rats were pair-housed until surgical procedures, after which they were single-housed for the duration of the study. The colony room was held at a temperature of 22±1°C, and a 12-hour reversed light/dark cycle (lights off at 7:00 am) was used. Food and water were available to the animals ad libitum throughout the experiment. Animals were maintained following the guidelines described in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Academy Press, 1996), and all procedures and facilities were approved by the Institutional Animal Care and Use Committee at Arizona State University.

Surgery

For stereotaxic guide cannula implantation, rats were anesthetized with isoflurane (2%) at a flow rate of 2 L/min. Following induction of anesthesia, rats were mounted in a stereotaxic frame (Stoelting, Wood Dale, IL). A stainless guide cannula (21-gauge, Synaptech, Marquette, MI) equipped with a dummy probe was unilaterally aimed at the medial PFC (Figure 2; coordinates were anterior +3.2, lateral +0.6, and vertical – 2.2 mm, relative to bregma and the skull surface (Paxinos and Watson, 2006). Cannulae were secured to the skull with stainless steel skull screws and cranioplastic dental cement and were allowed to recover for at least two days before beginning drug treatment.

Figure 2. mPFC microdialysis probe placement.

Figure 2

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Schematic indicating the area required for consideration of probe placement to be accurately implanted into the mPFC (Paxinos and Watson, 2007).

Drugs

CDPPB was synthesized by Chemir Analytical Services (Maryland Heights, MO). CDPPB was suspended in 10% v/v Tween 80 (Sigma-Aldrich, St. Louis, MO) and administered subcutaneously at a dose of 20 mg/kg. MK-801 (Sigma-Aldrich, St. Louis, MO) was dissolved in sterile saline and administered at a dose of 0.06 mg/kg. Rats were divided into four treatment groups (N=10 per group), receiving daily subcutaneous injections in a volume of 0.5 ml for ten consecutive days. Rats were randomly assigned to one of the following drug combinations: vehicle/vehicle, vehicle/CDPPB, CDPPB/MK-801, and vehicle/MK-801. The initial injection (CDPPB or vehicle) was administered immediately after the fourth sample collection. The second injection (MK-801 or saline) was administered 30 minutes later, directly following the fifth sample collection. Doses of CDPPB and MK-801 were selected based on previous studies conducted in our laboratory and by other researchers. In a prior study, we demonstrated that chronic administration of 0.06 mg/kg of MK-801 significantly impaired cognition in an operant-based set-shifting task, while chronic pre-treatment with 20 mg/kg of CDPPB prevented these impairments (LaCrosse et al., 2015). Other studies have reported that 0.06 mg/kg of MK-801 induces observable cognitive deficits, and the pro-cognitive effects of CDPPB have been well established within the dosage range of 10 to 30 mg/kg (Chadman et al., 2006; Uslaner et al., 2009; Stefani and Moghaddam, 2010; Isherwood et al., 2018).

Microdialysis

On the 9th day of drug treatment, rats were lightly anesthetized with isoflurane, dummy probes were removed, and microdialysis probes equipped with 2 mm cuprophane membranes (20 kDa cut-off weight, outer diameter 0.36 mm, Synaptech, Marquette, MI) were implanted into the mPFC. Rats were housed overnight in cylindrical cages with dual-channel liquid swivels mounted onto counterbalanced lever arms (Instech Laboratories, Plymouth Meeting, PA). Rats were provided with food and a water bottle. Probes were perfused overnight with artificial cerebrospinal fluid (aCSF) containing (125 mM NaCl, 2.5 mM KCL, 0.5 mM NaH2PO4·H2O, 5 mM Na2HPO4, 1 mM MgCl2·6H2O, 5 mM D-glucose, 1.2 mM CaCl2·2H2O, pH-7.3-7.5) at a flow rate of 0.05 μl/min. The following morning, the flow rate was increased to 1.5 μl/min, and samples were collected every 30 minutes. After collecting four baseline samples, a pretreatment injection of CDPPB or vehicle was given, followed 30 minutes later by MK-801 or vehicle. A total of 5 post-injection samples were collected. Samples were stored at −80°C for subsequent analyses. At the end of the sample collection, rats were deeply anesthetized with isoflurane and euthanized by decapitation. Brains were extracted, sectioned on a cryostat, and stained with cresyl violet for histological verification of correct microdialysis probe placement (Figure 2; Paxinos and Watson, 2006). Rats were removed from groups due to probe misplacement or microdialysis probe patency issues during sample collection.

Glutamate was quantified in microdialysis samples using isocratic high-performance liquid chromatography with fluorescence detection, as previously published (Griffin et al., 2014; Griffin et al., 2015). Briefly, samples were stored in a cooling tray (8°C) in a Shimadzu SIL-10AF autosampler and derivatized in a 3 min reaction with 30 μL of a solution containing o-phthalaldehyde (OPA, 10 mg/mL in methanol diluted 1:30 with OPA Diluent (Pickering Laboratories, Mountain View, CA) and mixed with β-mercaptoethanol at a 1:2000 ratio. Sample separation was accomplished using an ESA HR-80 × 3.2 column with a 3 μm particle size (ESA, Chelmsford, MA). The mobile phase consisted of 0.1 M dibasic sodium phosphate (pH 6.75) and 28% v/v methanol and was continuously pumped at 0.5 mL/min using a Shimadzu LC-20AD Prominence pump. A Shimadzu RF-10XL Fluorescence Detector was set with an excitation wavelength of 348 nm and an emission wavelength of 450 nm. Glutamate concentrations were determined against external standards using peak heights specified by LabSolutions Software (Shimadzu, LC solution Version 1.22 SP1). The lower detection limit for this assay was ~25 nM, and the limit of quantification was ~135 nM.

Data Analysis

To analyze dialysate glutamate content, the average glutamate levels (in μM) in the four baseline samples from each animal were averaged to create a baseline level, which was compared across treatment groups. To examine the effect of treatments, we converted all dialysate glutamate values to a percentage of the baseline level for each animal. A one-way ANOVA was used to compare treatment effects (CDPPB, MK-801, or vehicle) on glutamate levels compared across baseline samples. Subsequently, a two-way repeated measures ANOVA (RM ANOVA) was used to detect differences between treatment groups and time points. Last, a mixed model analysis compared averaged baseline and post-treatment samples between treatment groups. This analysis was used to accommodate the unequal data points between the baseline (1-4) and post-treatment samples (5-10). Tukey’s post-hoc multiple comparisons test identified significant group differences. Statistical analyses were performed using Prism Software, version 10.0.0 (GraphPad, Boston, MA). P-values < 0.05 were considered statistically significant for all data analyzed.

Results

Each experimental group had an initial sample size of n=10 rats per group. However, due to incorrect probe placement or microdialysis probe patency issues during sample collection, the final group sample sizes were as follows: vehicle/vehicle (n=7), CDPPB/vehicle (n=9), CDPPB/MK-801 (n=6), and vehicle/MK-801 (n=6).

The raw average glutamate values for the four baseline samples, expressed as mean +/− SEM (in μM), are as follows: vehicle/vehicle = 0.92 +/− 0.24, CDPPB/vehicle = 0.80 +/− 0.22, CDPPB/MK-801 = 1.39 +/− 0.29, and vehicle/MK-801 = 1.64 +/− 0.26. A one-way ANOVA did not detect significant group differences in baseline glutamate levels (F3,24=2.336, p=0.0991). Figures 3A and 3B demonstrate experimental results. Figure 3A displays the time course of drug effects between all four treatment groups, expressed as a percentage of the glutamate baseline level. A two-way RM ANOVA observed a significant effect of time x treatment (F27,216=1.755, p=0.0153). Post-hoc comparison tests compared the treatment group with each sample time. Significantly elevated glutamate levels were detected in samples 6-8 of the vehicle/MK-801 group compared to the other groups. Vehicle/MK-801 significantly differed from CDPPB/vehicle in sample 6 (p=0.0063). Vehicle/MK-801 was significantly different compared to all other treatment groups in sample 7; vehicle/MK-801 compared to vehicle/vehicle (p=0.0011), vehicle/MK-801 compared to CDPPB/vehicle (p=0.0010), and vehicle/MK-801 compared to CDPPB/MK-801 (p=0.0073). Vehicle/MK-801 significantly differed compared to vehicle/vehicle in sample 8 (p=0.0276). All other sample time points by treatment group were insignificant (all p-values > 0.05). Significant within-group differences were only detected in the vehicle/MK-801 group. Significant differences among samples in this group were detected between sample 1 and sample 7 (p=0.0045), between sample 2 and sample 7 (p=0.004), between sample 3 and both sample 6 (p=0.0363) and sample 7 (p=0.0025), and between sample 7 and sample 10 (p=0.0072). All samples (1-10) within the vehicle/vehicle group, the CDPPB/vehicle group, and the CDPPB/MK-801 group did not significantly differ in the level of glutamate from one another (all p-values >0.05). Figure 3B presents the data grouped by treatment and by the averaged baseline or post-treatment samples, the latter factor representing the time and the former factor as treatment. A mixed model analysis detected a significant effect of time (F1,12=8.52, p=0.0129), treatment group (F3,20=3.85, p=0.0252), and time by treatment interaction (F3,12=4.94, p=0.0184). When post-hoc comparisons were made between baseline and post-treatment glutamate levels, significant increases were observed only in the vehicle/MK-801 group (p=0.0006). Comparisons among all other groups showed no significant differences between baseline and post-treatment glutamate levels (all p-values > 0.05). In addition, dialysate glutamate levels in samples 5-10 were significantly increased in the vehicle/MK-801 group versus those in samples 5-10 in the vehicle/vehicle group (p=0.0001). Also, within the post-treatment samples, vehicle/MK-801 glutamate levels were significantly elevated compared to the CDPPB/vehicle group (p=0.0002). However, no such differences were observed in post-treatment glutamate levels between the vehicle/vehicle and CDPPB/MK-801 groups (p=0.3310), suggesting that CDPPB attenuated MK-801 induced increases in extracellular glutamate levels. This was confirmed by a significant reduction in glutamate levels in post-treatment samples of the CDPPB/MK-801 group compared to the vehicle/MK-801 group (p=0.0124).

Figure 3A. Time course displaying the effect of treatment on extracellular glutamate levels.

Figure 3A

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Effects of repeated administration of vehicle/vehicle, CDPPB/vehicle, CDPPB/MK-801, and vehicle/MK-801 on extracellular glutamate levels in the mPFC of rats. Data points represent mean values within each treatment group over the course of ten samples that were collected every 30 minutes. The data are expressed as percent change from mean glutamate concentrations obtained from each rat while collecting four baseline samples and five post-treatment samples. The first treatment injection (vehicle or CDPPB) was given at the first arrow (sample 4), followed 30 minutes later by the second treatment injection (vehicle or MK-801), as indicated by the second arrow (sample 5). Data are presented as mean±SEM. * indicates p<0.05 between the specified treatment groups. n.s. = not significant. Group sizes were as follows: vehicle/vehicle (n=7), CDPPB/vehicle (n=9), CDPPB/MK-801 (n=6), and vehicle/MK-801 (n=6). Animals were removed from groups due to probe misplacement during surgery or microdialysis probe patency issues during sample collection.

Figure 3B. Impact of treatment on extracellular glutamate levels between averaged baseline and post-treatment samples.

Figure 3B

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Effects of repeated administration of vehicle/vehicle, CDPPB/vehicle, CDPPB/MK-801, and vehicle/MK-801 on extracellular glutamate levels in the mPFC of rats. Data points represent the baseline and post-treatment sample means within each treatment group. The data are expressed as percent change from mean glutamate concentrations obtained from each rat while collecting four baseline and five post-treatment samples. Data are presented as mean±SEM. * indicates p<0.05 between the specified treatment groups. n.s. = not significant. Group sizes were as follows: vehicle/vehicle (n=7), CDPPB/vehicle (n=9), CDPPB/MK-801 (n=6), and vehicle/MK-801 (n=6). Animals were removed from groups due to probe misplacement during surgery or microdialysis probe patency issues during sample collection.

Discussion

The primary findings from this study are 1) CDPPB treatment significantly prevents MK-801 induced increases in extracellular glutamate in the mPFC, and 2) CDPPB alone did not affect extracellular glutamate levels. Given that CDPPB and other mGluR5 PAMs have been reported to reverse performance deficits in PFC-mediated cognitive tasks induced by NMDAR blockade (Stefani and Moghaddam, 2010; Horio et al., 2013; LaCrosse et al., 2015), our findings may provide a potential neurochemical correlate of the pro-cognitive effects of mGluR5 PAMs. Our results are consistent with those from previous electrophysiological studies, which demonstrated that CDPPB prevents MK-801 induced increases in spontaneous activity of pyramidal neurons in the mPFC and normalizes MK-801 induced disruption in burst activity of these neurons (Lecourtier et al., 2007). The results of this study, combined with previous research, indicate that PAM of mGluR5 function contributes to cellular mechanisms that facilitate the regulation of disrupted excitatory neurotransmission in cortical-mediated circuitry. The subsequent normalization of excitatory signaling through mGluR5 modulation, particularly in the mPFC, may reduce cognitive impairments linked to neuropsychiatric disorders such as schizophrenia. From a broader framework, mGluR5 PAMs also potentiate extinction learning following alcohol self-administration via actions in the mPFC (Gass et al., 2014), and reverse methamphetamine induced disruptions in novel object recognition (Reichel et al., 2011). Thus, mGluR5 PAMs may also restore cognitive function in the context of drug addiction and potentially assist in preventing drug relapse (Olive, 2009).

Our study utilized a chronic (10-day) treatment regimen to model daily dosing patterns used in treatment (Figure 1). We found no significant differences in the basal extracellular glutamate levels across the four treatment groups. Prior studies demonstrated that acute treatment with MK-801 or other NMDA antagonists increases extracellular glutamate levels in the mPFC (Adams and Moghaddam, 2001; Zuo et al., 2006; López-Gil et al., 2009; Pietraszek et al., 2009; Roenker et al., 2012). We expected to observe higher baseline levels of extracellular glutamate in the vehicle/MK-801 group compared to the vehicle/vehicle group. One explanation for this is that the chronic treatment schedule used in this experiment may have allowed enough time for compensatory or adaptive neural mechanisms to develop, preventing increased baseline levels of extracellular glutamate. In support of this explanation, an additional study reported that seven consecutive daily treatments of MK-801 reduced levels of extracellular glutamate in the mPFC, while acute MK-801 administration increased extracellular glutamate levels. It should be noted that the study mentioned above used a much higher dose of MK-801 (0.6 mg/kg); It is also possible that repeated administration of the lower dose used in the present study (0.06 mg/kg) did not lead to the same neuronal adaptations that alter the directionality of MK-801 induced changes in extracellular glutamate levels in the mPFC (Zuo et al., 2006). An additional explanation is that the baseline microdialysis samples in our study were collected on the morning following the 9th injection and before the final injection. Studies that administered high doses of MK-801 (ranging between 1 and 5 mg/kg) to rodents observed a range of behavioral effects, including stereotypy, hyperlocomotion, and ataxia, all of which subside within 24 hours (Janus et al., 2023). Therefore, any increases in glutamate levels resulting from the direct pharmacological actions of MK-801 administered the previous day were likely resolved before baseline sample collection. Regardless, the observed MK-801 induced increase in extracellular glutamate levels following MK-801 treatment on the sampling day is consistent with the numerous reports mentioned above, showing similar increases following acute administration.

Figure 1. Procedure timeline.

Figure 1

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Timeline of the current experimental design

We also found no significant differences in baseline or post-injection levels of glutamate between animals treated with CDPPB alone and those treated with vehicle. Contrary to our findings, Isherwood and colleagues found that mGluR5 PAMs increased glutamate efflux in the mPFC in a dose-dependent manner, whereas mGluR5 NAMs decreased glutamate efflux (Isherwood et al., 2018). A number of factors could have contributed to these discrepancies. Isherwood and colleagues administered ADX47273 to Wistar rats via a perioral route at a dose of 100 mg/kg, and mPFC glutamate levels were detected through a wireless glutamate biosensor system. Consequently, a direct comparison of results between our studies is challenging, as differences may be due to rodent strain, route of administration, dose, the molecular profile of mGluR5 PAM administered, and the method of glutamate detection. We posit that the slower modulatory effects of mGluR5 PAMs and their allosteric mode of action may contribute to the observed lack of effects of CDPPB alone on extracellular glutamate levels in the mPFC. Since the effects of CDPPB or other mGluR5 PAMs on extracellular glutamate levels have been largely unexamined, future studies employing additional doses of mGluR5 PAMs, as well as longer and shorter treatment regimens, are necessary to understand better how each parameter affects extracellular glutamate levels in the mPFC. This future direction of study is essential in light of the research presented above and findings reporting that activation of mGluR5 with orthosteric agonists can increase basal or evoked glutamate release from the forebrain and other brain regions (Pinter et al., 2000; Thomas et al., 2000; de Novellis et al., 2003; Fazal et al., 2003).

The precise neurochemical circuits and signaling mechanisms underlying both the ability of MK-801 to increase extracellular glutamate in the mPFC and its reversal by CDPPB are currently unknown and require further research. Both NMDAR and mGluR5 are predominantly localized to postsynaptic membranes on dendritic spines (Niswender and Conn, 2010; Mitsushima et al., 2013), hence the effects of ligands on these receptors are not likely to be mediated by actions on presynaptically localized mGluR5 or NMDAR, though some investigators have reported evidence of small populations of cortical neurons expressing these receptors on presynaptic terminals (Romano et al., 1995; Corlew et al., 2008; Duguid et al., 2013). A more likely mechanism is that both CDPPB and MK-801 act on multi-synaptic feedback mechanisms that regulate local glutamate levels in the mPFC (Figure 4). For instance, it has been demonstrated that local perfusion of NMDA antagonists into the mPFC does not evoke increases in extracellular glutamate (Lorrain et al., 2003), suggesting that NMDA antagonists act elsewhere in the brain to produce their effects on extracellular glutamate levels in this region. It has been suggested that NMDA antagonists such as MK-801 inhibit GABAergic inputs onto mPFC glutamatergic neurons, thus disinhibiting local glutamate transmission (Olney et al., 1995; Moghaddam et al., 1997; Yonezawa et al., 1998; Krystal et al., 2003). In support of this suggestion, GABAergic interneurons in subcortical regions, such as the limbic cortex and hippocampus, appear to be more responsive to NMDA antagonists than cortical pyramidal neurons, indicating that low to moderate doses of MK-801 (Grunze et al., 1996; Li et al., 2002), similar to the dose used in the present study, may act in extra-mPFC regions to influence local GABAergic regulation of glutamatergic transmission in the mPFC. While mGluR5 are widely spread throughout the neocortex, dense populations are localized to various types of GABAergic interneurons (Kerner et al., 1997). Finally, repeated administration of CDPPB has also been reported to increase the total levels of NR1 subunits of NMDAR as well as levels of phosphorylated NR1 and NR2B in the frontal cortex (Uslaner et al., 2009), providing another potential mechanism for the ability of mGluR5 PAMs to restore disrupted NMDAR functionality. Notably, novel mGluR5 PAMs with unique biased ligand profiles can exert anti-psychotic and pro-cognitive effects independent of indirect potentiation of NMDAR function (Rook et al., 2015). However, in that study, the lack of observed effects of such ligands on NMDAR function was only investigated in the hippocampus. Therefore, it remains to be determined if mGluR5 PAMs such as CDPPB can exert NMDAR-independent pro-cognitive effects in the mPFC. Despite a lack of full understanding of underlying mechanisms, mGluR5 PAMs may restore impaired NMDAR functionality across various psychiatric disorders, including addiction, post-traumatic stress disorder, and emotion regulation disorders (Reichel et al., 2011; Gass et al., 2014; Chong et al., 2019; Shallcross et al., 2021).

Figure 4. Proposed schematic of glutamate circuitry involving mGluR5 and NMDAR.

Figure 4

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Schematic of the proposed circuitry for mGluR5 and NMDA regulation of extracellular glutamate levels in relation to neuropsychiatric disorders such as schizophrenia.

Previously we demonstrated that MK-801 produced deficits in a delayed matching/non-matching-to-sample operant set-shifting task, and these effects were reversed by pre-treatment with CDPPB 30 minutes prior to, but not simultaneously, with MK-801 (LaCrosse et al., 2015). As mentioned in the introduction, numerous additional rodent studies found similar pro-cognitive effects from CDPPB treatment and have established that treatment can prevent or reverse MK-801 induced deficits. Linking existing data with results from this study provides a potential neurochemical basis for the effect(s) of treatment on male rodent behavior.

A significant limitation of the current study is the exclusion of female rats. Hormones such as estrogen and testosterone can influence mGluR5 expression and function. Estradiol rapidly activated mGluR5 signaling in specific brain regions, including the hippocampus and striatum. The activation of mGluR5 by estradiol led to the modulation of intracellular signaling pathways that regulate synaptic plasticity and cognitive functions (Boulware et al., 2005). Along these lines, structural and functional variations between male and female rat brains also impact mGluR5 expression and signaling pathways. Female rats exhibit higher mGluR5 expression in the hippocampus and cortex compared to male rats (Giacometti et al., 2020). Sex differences may also impact the use of MK-801 as a model for psychiatric disorders. MK-801 administration induces different behavioral responses from male and female rats, with the predominant suggestion that females generally exhibit greater sensitivity to the drug's effects on locomotor activity and anxiety-like behavior (Andiné et al., 1999). A noteworthy study from 2013, which used novel behavior measures, various paradigms, and robustly controlled for confounding variables, also detected sex differences, but interestingly, their research yielded results contradictory to the existing literature (Feinstein et al., 2013). This study highlights how traditional behavior measures and interpretations may be problematic when generalized to both rodent sexes, as male and female rodents very likely present different behaviors under similar contexts. In future research, including female rodents will be essential in uncovering the complex interactions between sex, disease models, and treatment targets like mGluR5 modulation.

In summary, we have demonstrated that CDPPB pre-treatment prevents MK-801's ability to increase extracellular glutamate levels in the mPFC while showing no evidence of an effect on glutamatergic transmission when administered alone. The ability of CDPPB to reverse disruptions in excitatory transmission in the mPFC is consistent with the ability of this class of compounds to reverse pharmacologically induced disturbances in cognitive function. Our findings further support the notion that mGluR5 PAMs may be a novel therapeutic target to restore cognitive function in neuropsychiatric disorders such as schizophrenia and drug addiction.

Highlights.

  • mGluR5 PAM pre-treatment prevents MK-801 induced increased extracellular glutamate

  • mGluR5 PAM does not affect mPFC extracellular glutamate when given alone

  • mGluR5 PAM may restore cognitive function by regulating mPFC glutamate

  • Targeting mGluR5 with PAMs may treat neuropsychiatric disorder impairments

Acknowledgments:

The authors wish to acknowledge BioRender.com for creating the Graphical Abstract, and Ethan MacNeil for creating graphic design (Figure 4).

Funding:

This research was supported by Public Health Service grant DA024355 from the National Institute on Drug Abuse.

Footnotes

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Declarations of Interest: The authors have none to declare.

Data Availability Statement:

Data will be made available immediately upon request.

References

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