Invited reviewMetabotropic glutamate 7 (mGlu7) receptor: A target for medication development for the treatment of cocaine dependence
Highlights
► mGlu7 receptors inhibited the reinforcing and motivational effects of cocaine. ► mGlu7 receptors inhibited the reward-enhancing effects induced by cocaine. ► mGlu7 receptors inhibited cocaine-induced reinstatement of drug-seeking behavior. ► mGlu7 receptors are important target for the treatment of drug dependence.
Introduction
Drug abuse is a serious social and health problem, for which no effective treatments are currently available. A better understanding of the neurophysiological mechanisms involved in drug dependence is important for the development of effective medications for treatment of drug addiction. The majority of previous studies investigating the neuromechanisms of drug dependence have been largely focused on the mesocorticolimbic dopamine system that originates from the midbrain ventral tegmental area (VTA) and projects to the forebrain nucleus accumbens (NAc) and the prefrontal cortex (PFC) (Kalivas and Volkow, 2005, Koob, 1992, Wise, 1996b). Studies suggest that the excitatory glutamate transmission in the NAc also plays an important role in the development and maintenance of drug dependence, particularly in reinstatement to drug-seeking behavior (Kalivas et al., 2009, Kalivas et al., 2005, Tzschentke and Schmidt, 2003, Wise and Morales, 2010). One mechanism via which the glutamatergic system affects drug dependence is direct or indirect modulation of dopaminergic system activity (Tzschentke and Schmidt, 2003, Wise and Morales, 2010). For instance, both the VTA and the NAc receive rich glutamatergic afferent projections from various brain areas such as the PFC, amygdala and hippocampus (Christoph et al., 1986, Floresco et al., 2001, Floresco et al., 1998, Geisler et al., 2007). Direct interaction of glutamate and dopamine has been found in the VTA, NAc, PFC and the amygdala (Omelchenko and Sesack, 2007, Sesack et al., 2003). Glutamate efflux in the VTA increases the bursting activity of dopaminergic neurons and increases dopamine release in projection areas, such as the NAc, the PFC and the amygdala (Tzschentke and Schmidt, 2003, Wise, 1996b, Wise and Morales, 2010). Thus, administration of most drugs of abuse increases both dopamine and glutamate transmission (Kalivas et al., 2005, Wise and Morales, 2010). These actions are hypothesized to be critically involved in different aspects of drug dependence, such as reinforcement, withdrawal and reinstatement to drug use (Kalivas and Volkow, 2005, Wise and Morales, 2010). Therefore, efforts have been undertaken to block the reinforcing effects of drugs of abuse, as well as reinstatement of drug-seeking, by pharmacological manipulation of glutamate transmission (Gass and Olive, 2008, Kalivas et al., 2009). A large body of literature has indicated that decreases of glutamatergic transmission by modulation of glutamate receptors are effective in attenuating the reinforcing effects of drugs of abuse and in prevention of reinstatement to drug-seeking behavior (Gass and Olive, 2008, Olive, 2009). Table 1 provides descriptions of the main behavioral procedures used to study the reinforcing effects of drugs of abuse and drug seeking.
Section snippets
Metabotropic glutamate receptors and drug addiction
The actions of glutamate are mediated by activation of ionotropic and metabotropic glutamate (mGlu) receptors (Kew and Kemp, 2005). Numerous studies indicated that blockade of ionotropic receptors, such as N-methyl-d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxale propionate (AMPA) receptors, inhibited drug reinforcement and reinstatement of drug-seeking behavior of most drugs of abuse (Bisaga et al., 2000, Gass and Olive, 2008). However, compounds acting at ionotropic glutamate
AMN082, the first widely available and selective mGlu7 receptor allosteric agonist
The prototypical Group III ligands developed previously, such as the receptor agonist l-AP4 and antagonist (RS)-alpha-methylserine-O-phosphate (MSOP), are orthosteric compounds that bind at the highly conserved glutamate-binding site in the N terminal of the receptor (Niswender and Conn, 2010, Thomas et al., 1996). Although these compounds have significant Group selectivity, they do not distinguish between members of a receptor Group. Moreover, both l-AP4 and MSOP cannot penetrate the
Activation of mGlu7 receptors inhibits the reinforcing and motivational effects of drugs of abuse
The rewarding effects of drugs of abuse play a key role in driving acquisition and initiation of drug use, as well as in the maintenance of substance use and dependence (Koob, 1992, Wise and Bozarth, 1987). Thus, treatments that block these effects of drugs of abuse could help people maintain abstinence. The fact that addictive drugs serve as reinforcers in maintaining operant drug-taking behavior has led to the development of the intravenous drug self-administration procedure as an animal
Effects of AMN082 on the reward-enhancing effects of drugs of abuse
One of the pharmacological effects of drugs of abuse that is common to drugs from various pharmacological classes and which is hypothesized to contribute to the perpetuation of drug dependence is the enhancement of brain reward. This action may partly account for the intrinsic reinforcing properties of drugs of abuse and also reflect how drugs of abuse potentiate or summate with the reinforcing actions of non-drug rewarding stimuli (Bauco and Wise, 1997, Markou and Koob, 1992, O’Brien and
A nucleus accumbens – ventral pallidum GABAergic mechanism may underlie the actions of AMN082 on cocaine reward
In vivo microdialysis studies indicated that systemic or local administration of AMN082 into the NAc, VP or dorsal striatum did not alter basal or cocaine-induced increases in extracellular dopamine in either drug naïve rats or in cocaine self-administering rats 24 h after cocaine self-administration, suggesting that a non-dopaminergic mechanism mediates the antagonism of cocaine reward by this compound (Fig. 5A) (Li et al., 2009). This neurochemical finding is consistent with previous
Activation of mGlu7 receptors inhibits reinstatement of drug-seeking behavior
A major challenge in the treatment of drug addiction in humans is the high rate of relapse to drug-taking and drug-seeking behavior even after prolonged periods of abstinence. In both humans and experimental animals, drug craving and reinstatement (a putative animal model of relapse; Shaham et al., 2003; however, see Katz and Higgins, 2003) to drug-seeking can be precipitated by re-exposure to drugs of abuse, presentation of environmental stimuli (cues) previously associated with drug taking,
A glutamate mGlu2/3 receptor mechanism underlies the antagonism of cocaine seeking by AMN082
To determine whether a dopamine-dependent mechanism underlies the antagonism of cocaine seeking, we first measured cocaine- and AMN082-induced changes in extracellular dopamine in the NAc, VP and dorsal striatum (Li et al., 2010). AMN082 did not alter cocaine-induced increases in extracellular dopamine in these brain regions in rats during reinstatement testing (Fig. 8A), suggesting again that a non-dopaminergic mechanism underlies the actions of AMN082 on reinstatement of drug-seeking.
Emerging
mGlu7 receptor involvement in other psychiatric disorders
Glutamate is the major excitatory neurotransmitter in the central nervous system and is critically involved in many processes in the brain functions, including fast and slow excitatory neurotransmission, synaptic plasticity and control of basal neuronal activity. Abnormal glutamate transmission is associated with a range of psychiatric and neurological disorders. Because of the inherently modulatory role of mGlu7 receptors in glutamate neurotransmission, AMN082 has been shown to have
Potential “off-target” profile of AMN082
Although most of the studies cited above indicate that AMN082 is a highly selective mGlu7 receptor allosteric agonist, there are findings suggesting that some effects of AMN082 may not be mediated by the mGlu7 receptors. AMN082 neither altered mGlu7 receptor-induced intracellular Ca++ mobilization in mGlu7 receptor-expressing cell lines (Suzuki et al., 2007), nor induced mGlu7 receptor-mediated activation of GIRK potassium channels in HEK cells (Ayala et al., 2008). It also failed to activate
Summary
Activation of mGlu7 receptors by AMN082 significantly inhibits the rewarding and motivational effects of drugs of abuse, such as cocaine, heroin and ethanol as evaluated by the intravenous self-administration procedure under both FR and PR schedules of reinforcement. AMN082 also inhibits the reward-enhancing effects induced by cocaine and heroin as evaluated by the ICSS procedure, and blocks cocaine- and heroin-induced reinstatement of drug-seeking behavior. These findings suggest an important
Financial disclosures
AM has received contract research support from Lundbeck, Bristol-Myers Squibb Co., F. Hoffman-La Roche, Pfizer, and Astra-Zeneca, and honoraria/consulting fees from Abbott GmbH and Company, Astra-Zeneca, and Pfizer during the past 3 years. AM has a patent application on the use of metabotropic glutamate compounds for the treatment of nicotine dependence. The remaining authors report no financial conflicts of interests.
Acknowledgments
XL was supported by a new investigator award 20KT-0064 by the Tobacco-Related Disease Research Program from the State of California. AM was supported by NIH grant DA011946. Z-XX was supported by Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health.
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2021, Biomedicine and PharmacotherapyCitation Excerpt :Curiously, the GRM7 gene expresses the protein mGlu7 receptor, which is the target of AMN 082. AMN 082 fully activates mGlu7 by binding to the transmembrane domain of the mGlu7 receptor [91]. Although AMN 082 inhibited tumor sphere formation, overexpression of GRM7 had no effect on tumor sphere formation (Fig. 4H,I), and GRM7 was not related to stemness or survival in the clinical data (Fig. S4).
AMN082, a metabotropic glutamate receptor 7 allosteric agonist, attenuates locomotor sensitization and cross-sensitization induced by cocaine and morphine in mice
2015, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Thus, increased glutamate availability in the NAc appears to be effective after exposure to these drugs, in spite of the fact that the basal levels of extracellular glutamate were not significantly altered after heroin withdrawal (LaLumiere and Kalivas, 2008), in contrast to the withdrawal from cocaine (Baker et al., 2003; Pierce et al., 1996). Because an increase in NAc glutamate, after AMN082 administration, leads to an increased binding to presynaptic mGluR2/3 autoreceptors, it is hypothesized that such mGluR2/3-mediated inhibition of glutamate release underlie the antagonism of cocaine-triggered reinstatement by AMN082 of drug-seeking behavior (Li et al., 2010, 2013). This finding is supported by the evidence demonstrating that the mGluR2/3 agonist and MMPIP, a selective mGluR7 antagonist, blocked the inhibitory effect of AMN082 on cocaine priming-induced increases in extracellular glutamate in the NAc and reinstatement of cocaine seeking.
Metabotropic glutamatergic receptors and their ligands in drug addiction
2014, Pharmacology and TherapeuticsCitation Excerpt :The inhibitory actions of AMN082 were mediated by mGlu7 receptors localized to the NAc and linked to the direct inhibition of Glu release and to indirect decrease in GABA transmission (Li et al., 2013). Since the responses of AMN082 were independent of pharmacokinetic factors, fluid intake, taste preference or locomotor activity of animals (Li et al., 2013), these data (although limited) seem to implicate mGlu7 receptor as a potential new target for drug addiction treatments. The gene encoding human mGlu8 receptor has been localized on human chromosome 7 (7q31.33), and on 4q22 in rats and 6 A3 in mice [ncbi].
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