Targeting mGlu5 for Methamphetamine Use Disorder

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Abstract

Methamphetamine abuse leads to devastating consequences, including addiction, crime, and death. Despite decades of research, no medication has been approved by the U.S. Food and Drug Administration for the treatment of Methamphetamine Use Disorder. Thus, there is a need for new therapeutic approaches. Animal studies demonstrate that methamphetamine exposure dysregulates forebrain function involving the Group-I metabotropic glutamate receptor subtype 5 (mGlu5), which is predominantly localized to postsynaptic sites. Allosteric modulators of mGlu5 offer a unique opportunity to modulate glutamatergic neurotransmission selectively, thereby potentially ameliorating methamphetamine-induced disruptions. Negative allosteric modulators of mGlu5 attenuate the effects of methamphetamine, including rewarding/reinforcing properties of the drug across animal models, and have shown promising effects in clinical trials for Anxiety Disorder and Major Depressive Disorder. Preclinical studies have also sparked great interest in mGlu5 positive allosteric modulators, which exhibit antipsychotic and anxiolytic properties, and facilitate extinction learning when access to methamphetamine is removed, possibly via the amelioration of methamphetamine-induced cognitive deficits. Clinical research is now needed to elucidate the mechanisms underlying the mGlu5 receptor-related effects of methamphetamine and the contributions of these effects to addictive behaviors. The growing array of mGlu5 allosteric modulators provides excellent tools for this purpose and may offer the prospect of developing tailored and effective medications for Methamphetamine Use Disorder.

Introduction

Psychostimulant abuse places an enormous burden on society, leading to addiction and other devastating consequences. In the United States, overdose deaths linked to psychostimulants with abuse potential, such as methamphetamine, have risen five-fold from 2012 to 2018 (Centers for Disease Control and Prevention, 2020; Kariisa, Scholl, Wilson, Seth, & Hoots, 2019), and further increases are predicted for 2020 (Katz, Goodnough, & Sanger-Katz, 2020). Methamphetamine Use Disorder is characterized by mood disturbances (London et al., 2004), psychosis (Lecomte, Dumais, Dugré, & Potvin, 2018), and impairments in executive function that have been linked to corticostriatal deficits and can interfere with engagement in behavioral therapies (Dean, Groman, Morales, & London, 2013; London, Kohno, Morales, & Ballard, 2015). Yet, decades of research have not yielded an effective medication for the treatment of this disorder. Clinical trials have evaluated pharmacologically diverse medications, such as direct and indirect dopaminergic agonists, antidepressants, cognitive enhancers, and immune modulators (Chan et al., 2019; Paulus & Stewart, 2020; Siefried, Acheson, Lintzeris, & Ezard, 2020). Failures of these trials may be partly attributed to small sample sizes in the face of high dropout rates (Chan et al., 2019; Lee, Jenner, Harney, & Cameron, 2018; Siefried et al., 2020), heterogeneities associated with drug use disorders (Regier, Kampman, & Childress, 2020; Soares & Pereira, 2019), medication nonadherence (Lee et al., 2018; Siefried et al., 2020), and the unrealistic requirement by the U.S. Food and Drug Administration for sustained abstinence as the only valid endpoint in clinical trials for pharmacotherapies for drug use disorders (Kiluk et al., 2016). In addition, it may be helpful to investigate compounds that interact with novel targets. The goal of this review is to encourage research on a class of such compounds, specifically allosteric modulators of the Group-I metabotropic glutamate receptor subtype 5 (mGlu5) in the quest for an effective pharmacotherapy to treat Methamphetamine Use Disorder.

The potential efficacy of mGlu5 allosteric modulators as medications for addiction was highlighted over a decade ago (Markou, 2009; Olive, 2010), and considerable research has promoted interest in the mGlu5 receptor as a target for Cocaine (Mihov & Hasler, 2016), Alcohol (Kumar et al., 2018) and Tobacco Use disorders (Barnes, Sheffler, Semenova, Cosford, & Bespalov, 2018; Chiamulera, Marzo, & Balfour, 2017). As described below, animal studies document a major involvement of mGlu5 in vulnerability to methamphetamine self-administration and its consequences. They indicate substantial potential for mGlu5 allosteric modulators to reduce methamphetamine reward/reinforcement, drug craving and relapse. Here, we review this literature with the goal of expediting its translation into clinical research to develop a medication for Methamphetamine Use Disorder. PubMed and Web of Science were used to search multiple databases for relevant articles, which were then screened for additional literature. Due to space limitations, we do not cover evidence that negative allosteric modulators (NAMs) of mGlu5 protect against methamphetamine-induced neurotoxicity (Battaglia et al., 2002; Cao, Fu, Kumar, & Kumar, 2016; Golembiowska, Konieczny, Wolfarth, & Ossowska, 2003; Miyatake, Narita, Shibasaki, Nakamura, & Suzuki, 2005; Shah, Silverstein, Singh, & Kumar, 2012; Tokunaga et al., 2009).

Section snippets

Group-I metabotropic glutamate receptor subtype 5 (mGlu5)

The mGlu5 receptor belongs to the family of Group-I metabotropic glutamate receptors, which are class C G protein-coupled receptors and part of the seven transmembrane-spanning receptor superfamily (Koehl et al., 2019). These receptors form full-length dimers with their large extracellular N-terminal domains connected by a disulfide bridge and containing the binding sites for glutamate and other orthosteric ligands (Koehl et al., 2019). They also possess a cysteine-rich domain, which propagates

Methamphetamine action and mGlu5 receptor influence on dopamine dynamics

Methamphetamine exerts its psychomotor stimulant effects primarily via acting at plasma membrane monoamine transporters (including the dopamine transporter) and vesicular monoamine transporters, and also by inhibiting monoamine oxidase activity (Sulzer, Sonders, Poulsen, & Galli, 2005). Through these mechanisms, methamphetamine profoundly increases extracellular dopamine in the forebrain (Sulzer et al., 2005). Studies of methamphetamine-induced psychomotor sensitization implicate metabotropic

Psychomotor sensitization to methamphetamine in rodents and mGlu5

Methamphetamine is a psychostimulant that induces motor hyperactivity and repetitive motor patterns, termed stereotypies, in humans (Rusyniak, 2013) and laboratory animals. In rats, the effect is dose-dependent – lower doses increase horizontal movement and higher doses induce stereotypies (Hadamitzky, McCunney, Markou, & Kuczenski, 2012). Repeated methamphetamine exposure sensitizes rats to its psychomotor-activating effects, augmenting drug-elicited motor excitability or inducing stereotypies

Addiction vulnerability and mGlu5: methamphetamine intake and preference in rodents (Table 1)

Inasmuch as high methamphetamine intake or preference in rodents models vulnerability to methamphetamine addiction (Phillips, Mootz, & Reed, 2016; Phillips & Shabani, 2015), a hyperglutamatergic state, involving mGlu5 receptors in the nucleus accumbens, apparently confers such vulnerability (Szumlinski et al., 2017). Mice selectively bred for high methamphetamine intake by drinking (“high-drinking”, MAHDR) exhibit higher methamphetamine-evoked increases in extracellular glutamate and levels of

Animal models of methamphetamine addiction: pharmacological studies targeting mGlu5

Further evidence that mGlu5 receptor signaling is a crucial determinant of methamphetamine preference is provided by place-conditioning studies with the NAMs, MPEP and MTEP. MPEP suppressed the development of methamphetamine-conditioned place preference in mice (Miyatake et al., 2005), and MPEP as well as MTEP inhibited methamphetamine-conditioned place preference in rats (Herrold, Voigt, & Napier, 2013). The observation that an mGlu1 NAM did not alter place preference in rats implicated an mGlu

Methamphetamine-related cognitive deficits and recovery involving mGlu5

Impairments in pivotal cognitive functions (including attention, learning, and memory) are associated with Methamphetamine Use Disorder (Dean et al., 2013; Potvin et al., 2018; Sabrini, Wang, Lin, Ian, & Curley, 2019) and predict poor treatment retention and outcome across substance use disorders (Brorson, Ajo Arnevik, Rand-Hendriksen, & Duckert, 2013). Although there is overlap in performance of individuals with and those without Methamphetamine Use Disorder, the preponderance of evidence

Translational research on glutamate and mGlu5 in substance use disorders

There are no reports on the expression levels or functional status of mGlu5 receptors in the brains of humans who have used methamphetamine chronically, but the question is currently under investigation (https://grantome.com/grant/NIH/R33-DA031441-06). However, lower levels of glutamatergic neurometabolites (glutamate, glutamate + glutamine, N-acetylaspartate + N-acetylaspartylglutamate) have been measured using magnetic resonance spectroscopy in multiple cortical regions of abstinent

Allosteric modulators of mGlu5 as potential medications for Methamphetamine Use Disorder

As reviewed here, mGlu5 NAMs reduce the rewarding/reinforcing properties of methamphetamine across animal models (Table 2). Yet various forms of learning and memory are also altered by mGlu5 NAMs (Perry, Olive, & Lawrence, 2017). These effects include impairment of extinction learning, leading to relapse-like behavior in methamphetamine-preferring mice (Huang et al., 2016). In addition, lack of efficacy and adverse effects, including disturbance in attention and derealization, have been

Conclusions

Animal models demonstrate that mGlu5 receptor signaling is critically involved in vulnerability to and maintenance of methamphetamine-related behaviors and their detrimental sequelae (Table 1, Table 2). Moreover, they show that mGlu5 allosteric modulators block methamphetamine reward/reinforcement, prevent relapse-like behavior and recover methamphetamine-induced cognitive deficits (Table 2). Allosteric modulators of mGlu5 have also produced promising findings in clinical trials for depression

Author ORCID IDs

JP: https://orcid.org/0000-0003-4163-9014. KKS: https://orcid.org/0000-0003-1078-1077. EDL: https://orcid.org/0000-0003-3577-7808

Funding

This work was supported in part by a postdoctoral research grant from the Max Kade Foundation (JP). Other support was provided by the Thomas P. and Katherine K. Chair in Addiction Studies (EDL) and the Marjorie Greene Family Trust (EDL). The funders had no role in the conception of this review, the selection and interpretation of research reports, the preparation of the manuscript, or the decision to submit it for publication.

Conflict of Interest Statement

The authors declare no conflicts of interest.

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