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Anxiety disorders represent a prevalent group of mental health conditions characterized by patients experiencing excessive worry, fear, and distress. The neurobiological underpinnings of anxiety disorders are complex and involve multiple neurotransmitter systems. One such system is the glutamatergic system, which plays a critical role in anxiety regulation. Over the past few decades, much evidence has been gathered, substantiating the involvement of metabotropic glutamate receptors (mGluRs) in anxiety. Consequently, mGluRs have emerged as promising targets for treating anxiety disorders. This book chapter will provide an overview of the role of mGluRs in anxiety, focusing on their involvement in anxiety-related behaviors and their potential as therapeutic targets.
Departments of Ophthalmology and Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Yongling Zhu
Departments of Ophthalmology and Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
*Address all correspondence to: jian-xu@northwestner.edu
1. Introduction
Anxiety disorders are among the most prevalent mental health conditions worldwide, affecting people of all ages. According to the World Health Organization (WHO), approximately 275 million people suffer from anxiety disorders globally. This staggering number reflects these conditions’ profound impact on individuals, families, and communities.
Although the causes of anxiety disorders are not yet fully understood, the condition is believed to arise from a complex interaction of genetic, biological, environmental, and psychological factors [1]. Converging lines of evidence from various branches of neuroscience indicate that anxiety disorders are frequently associated with imbalances in the brain’s neurotransmitter systems, including the glutamatergic system [2, 3, 4, 5, 6, 7]. Thus, understanding the involvement of the glutamatergic system in anxiety regulation can provide insights into potential therapeutic targets for treatment.
Glutamate is the most abundant excitatory neurotransmitter in the brain. It acts on two primary classes of glutamate receptors, ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The iGluRs include three subfamilies: N-methyl-D-aspartate receptor (NMDA-Rs), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs), and kainite receptors (KA-Rs). The mGluRs can be classified into group I, group II, and group III [8, 9, 10].
Among all glutamate receptors, mGluRs hold particular interest from a pharmacological standpoint for several reasons: (1) Diverse functions: Unlike iGluRs that primarily mediate fast synaptic transmission, mGluRs are involved in a wide range of cellular processes beyond simple neurotransmission. They can influence gene expression, intracellular signaling pathways, and various physiological responses, making them attractive targets for therapeutic intervention. (2) Broader therapeutic scope: Due to their involvement in numerous signaling pathways, targeting mGluRs presents promising opportunities for the development of drugs to address a wide range of conditions and neurological disorders. (3) Modulatory effects: mGluRs modulate synaptic transmission and neural circuitry in more nuanced and complex ways than iGluRs. This modulation allows for fine-tuning of neural activity, which could be beneficial in treating conditions where neural imbalances are involved. (4) Reduced risk of excitotoxicity: iGluRs can mediate excitotoxicity, a process that leads to neuronal damage and death due to excessive glutamate signaling. In contrast, mGluRs do not directly trigger such responses, reducing the risk of harmful side effects. (5) Drug specificity: Targeting mGluRs provides an opportunity to design drugs with better specificity, minimizing off-target effects and increasing therapeutic efficacy. Together, these reasons make mGluRs promising candidates for drug development, offering the potential to treat a wide range of neurological disorders, including anxiety and depression.
The objective of this chapter is to comprehensively examine the roles of mGluRs in anxiety disorders by reviewing the existing evidence. Additionally, we will summarize the findings from preclinical studies investigating the effects of targeting mGluRs for anxiety. Furthermore, this review will also assess results from clinical trials involving mGluR drugs for treating anxiety disorders.
In 1985, a groundbreaking discovery occurred when Sladeczek and coworkers demonstrated that glutamate possesses the capability to initiate the formation of molecules associated with a major second messenger system [11]. This finding unveiled the ability of glutamate to stimulate the production of inositol phosphates. Soon after, further evidence for the existence of mGluRs was discovered [12]. Built on these findings, Masu et al. successfully cloned the first mGluR, the mGluR1, in 1991 [13]. Subsequently, seven other mGluR subtypes were cloned by researchers. Together, a total of eight subtypes of mGluRs have been identified in the mammalian system [9]. Over the past three decades, tremendous strides have been made in comprehending the functions of these mGluRs.
2.2 Structure and function of mGluRs
mGluRs are a class of G-protein coupled receptors that bind glutamate. In contrast to iGluRs, mGluRs do not function as ion channels. Instead, their mode of operation involves initiating complex biochemical cascades. The eight subtypes of mGluRs exhibit distinct characteristics based on their sequence homology, signal transduction mechanisms, and pharmacological properties, leading to the categorization of mGluR subtypes into groups of groups I, II, and III mGluRs [14].
Structurally, all eight mGluRs contain an agonist-binding Venus fly trap (VFT) domain, which uses the cysteine-rich domain (CRDs) to connect to the highly conserved seven-pass trans-membrane domain (7TM) [15]. On cell membranes, mGluRs form obligate dimers. A recent structural study has revealed that when an agonist binds to these receptors’ VFT domain, it induces a compaction of the inter-subunit dimer interface. As a result, the CRDs come into close interactions, leading to the repositioning of the 7TM. This conformational change initiates the signaling process [16].
2.3 Insights from mGluR’s brain localization
Research on the localization of brain function highlights the association of specific brain regions with distinct functions. For example, anxiety has been linked to specific brain areas, including the hippocampus, prefrontal cortex, amygdala, bed nuclei of the stria terminalis, and hypothalamus [17, 18, 19]. Thus, when investigating the involvement of mGluRs in anxiety regulation and development, it becomes essential to examine mGluR’s precise expression patterns and localization within these brain regions. In this context, we have compiled mouse brain in situ hybridization data from the Allen Brain Institute and present these data in two figures, Figures 1 and 2. Please note that immunohistochemistry and in situ, mRNA hybridization have been extensively used to study the expression of mGluRs in the brain, and a wealth of literature is available [9] in addition to Allen Brain Atlas resources. Overall, analysis of mRNA in situ hybridization for different subtypes has led to several crucial observations:
Diverse expression patterns: The eight mGluRs exhibit distinct expression patterns in the brain, reflecting their varied functions.
Expression levels: The abundance of mGluRs varies significantly, with mGluR5 and mGluR4 being the most prevalent.
Anxiety-related brain regions: In line with their role in anxiety regulation, mGluR expression has been identified in various regions, including the hippocampus, prefrontal cortex, amygdala, bed nuclei of the stria terminalis, and hypothalamus. These brain areas are known to be associated with anxiety-related processes.
Figure 1.
In situ hybridization of mGluR1–8 in mouse brain sagittal slices. Images were exported from Allen brain institute (https://mouse.brain-map.org/). At the bottom is the brain atlas with arrows pointing to hippocampus and amygdala. The sagittal plane is about 3.0 mm from the midline. Scale Bar, 1200 μm.
Figure 2.
In situ hybridization of mGluR1–8 in mouse brain sagittal slices. Images were exported from Allen brain institute (https://mouse.brain-map.org/). At the bottom is the brain atlas with arrows pointing to hippocampus, hypothalamus, bed nucleus of the stria terminalis (BNST) and medial prefrontal cortex, and amygdala. The sagittal plane is about 0.5 mm from the midline. Scale Bar, 1200 μm.
While the understanding of brain localization of mGluRs in rodents is rather extensive, the localization of mGluRs in humans remains much less explored. However, novel imaging techniques are under active development to investigate the mGluRs in humans. These advancements in imaging studies offer promising avenues to examine the location and abundance of mGluRs in living individuals as well as in postmortem tissue [20, 21, 22]. Undoubtedly, future human studies will provide valuable insights into the brain localization of mGluRs, deepening our understanding of their potential roles in anxiety.
2.4 Subtypes of mGluRs
2.4.1 Group I mGluRs
Group I mGluRs consist of two subtypes: mGluR1 and mGluR5. Both mGluR5 and mGluR1 receptors are primarily located postsynaptically in the central nervous system (CNS). They play important roles in regulating synaptic transmission, neuronal excitability, and plasticity [9, 23, 24, 25, 26].
mGluR1 and mGluR5 display structural similarities and share common signaling mechanisms. Upon binding with glutamate, they both initiate the activation of the Gq/11 protein, subsequently leading to the activation of phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 then promotes the release of calcium ions from intracellular stores, while DAG activates protein kinase C (PKC). These intracellular signaling pathways mediate the effects of group I mGluRs.
In the brain group I mGluRs are predominantly expressed in the hippocampus, cortex, and striatum, where they modulate synaptic transmission and synaptic plasticity. These receptors involve in many physiological processes, including motor activities, learning and memory, neuronal development, addiction, and emotion regulations [26, 27, 28, 29, 30, 31, 32]. Clinically, group I mGluRs have been associated with various neurological conditions, encompassing anxiety, depression, epilepsy, Parkinson’s disease, and fragile X syndrome. Consequently, these receptors have become potential targets for therapeutic interventions [33, 34, 35, 36].
2.4.2 Group II mGluRs
Group II mGluRs have two subtypes: mGluR2 and mGluR3 [37]. They are primarily located presynaptically in CNS where they act as autoreceptors [38]. Activation of mGluR2 or mGluR3 predominantly elicits an inhibitory response through a G-protein-coupled mechanism. When glutamate binds to group II mGluRs, it triggers the activation of G i/o proteins. The activated G i/o proteins inhibit adenylate cyclase (AC), leading to a decrease in cyclic AMP (cAMP) levels. The reduction in cAMP ultimately results in the inhibition of neurotransmitter release. Additionally, the dissociated beta-gamma subunits of the G-protein may modulate the activity of ion channels, leading to changes in membrane potential and ion flow across the cell membrane [39].
mGluR3 exhibits broad expression in CNS, whereas mGluR2 displays limited and overall low expression. It shows modest expression in the dentate gyrus and olfactory regions and weak expression in the thalamus, striatum, and cortex.
The functions of group II mGluRs have been associated with various physiological functions such as motor activities, learning and memory, emotion regulation, addiction, and neuroprotection [40, 41, 42, 43, 44, 45]. Group II mGluRs are also implicated in pathological conditions such as anxiety, depression, schizophrenia, pain, and neurodegenerative disorders [33, 46, 47].
2.4.3 Group III mGluRs
Group III mGluRs include four subtypes: mGluR4, mGluR6, mGluR7, and mGluR8. They are coupled to heteromeric Gi/Go protein. Activation of group III mGluRs also leads to the inhibition of adenylate cyclase [9].
Among the four group III mGluRs, mGluR6 is primarily located in the ON-bipolar cells of the retina [48]. In contrast, mGluR4, mGluR6, and mGluR7 are expressed in CNS with relatively widespread distributions. Specifically, mGluR4 is found in most brain regions, displaying the highest intensity in the cerebellum and moderate levels in the cortex, striatum, amygdala, and hippocampus. On the other hand, mGluR7 exhibits high expression in the hippocampus, and it also demonstrates a relatively strong presence in the amygdala and striatum. Although mGluR8 was initially identified in the retina [49], it is also expressed in the CNS, particularly in regions like the cerebellum, olfactory bulb, cortex, and hippocampus. However, the expression levels of mGluR8 in these CNS regions are lower than that of mGluR4.
Like group II mGluRs, group III mGluRs are also primarily located in the presynaptic terminals of neurons in the CNS [50], where they act as autoreceptors, responding to the release of glutamate from the same neuron to regulate neurotransmitter release. Group III mGluRs can also be found on postsynaptic neurons, which modulate postsynaptic responses to neurotransmitter signaling [51].
mGluR4 and mGluR8 have a much higher affinity to glutamate than mGluR7, which shows a low affinity for glutamate and is activated only by high glutamate concentrations [52, 53]. Overall, these versatile receptors play crucial roles in a wide range of physiological processes, including motor functions, learning and memory, fear extinction, anxiety, social behaviors, and epilepsy [54, 55, 56, 57, 58, 59, 60]. Furthermore, their implications extend to human neurological conditions, including epilepsy, anxiety disorders, depression, pain modulation, and addiction [33, 61, 62].
3. Preclinical studies for the roles of mGluRs in anxiety
3.1 History
Shortly after discovering mGluR genes in the 1990s, researchers began exploring the functions of mGluR subtypes at glutamatergic synapses and the possible roles of mGluRs in neurological disorders, including anxiety. Numerous preclinical studies have been conducted to examine the effects of different mGluR compounds in animal models of anxiety. Encouragingly, a considerable body of evidence has quickly emerged and confirmed that some mGluR compounds demonstrate anxiolytic and antidepressant-like properties in animal models. Particularly, studies in rodents have shown that antagonists of group I mGluRs, and agonists of group II mGluRs can act as anxiolytics and antidepressants [63, 64, 65, 66, 67, 68, 69]. These findings have laid a solid foundation for further research in this promising field.
Besides the pharmacological approach, mGluR mutant animal models have also been developed and tested extensively to explore mGluRs’ role in anxiety. Furthermore, through electrophysiological, cellular, and biochemical studies, optogenetics and chemogenetics, valuable insights have been gained into the specific modulation of synaptic transmission, intrinsic excitability, and synaptic plasticity of mGluRs in brain regions that govern emotions and anxiety, such as the amygdala, hippocampus, and prefrontal cortex [19, 70, 71].
Together, these collective data from preclinical research have significantly deepened our understanding of anxiety disorders’ molecular and neural foundations. Furthermore, these studies offer promising therapeutic avenues by targeting mGluRs for potential anxiety treatments.
3.2 Roles of group I mGluRs in anxiety
Group I mGluRs have long been implicated in regulating anxiety and anxiety disorders. These receptors are primarily expressed in brain regions associated with emotional processing, including the amygdala, prefrontal cortex, and hippocampus.
Numerous animal studies investigating drugs targeting group I mGluRs and their effects on anxiety-like behaviors have been conducted, yielding consistent findings. Overall, antagonistic treatment has shown significant anxiolytic responses in experimental animals, indicating their potential as therapeutic agents for anxiety-related disorders. These compounds have demonstrated a notable capacity to lower anxiety levels in preclinical models. This is supported by their ability to reduce fear-conditioned freezing, increase the time spent in the center of the open field, and decrease marble-burying behavior, among other positive indicators. However, it is important to point out that the anxiolytic effects of group I mGluR compounds may vary based on their specific brain region activation. Activation of mGluR1 or mGluR5 in particular brain regions, such as the hippocampus, amygdala, and the prefrontal cortex, may be particularly relevant to anxiety regulation. Also, the effects of group I mGluR compounds on anxiety may exhibit dose-dependent responses, with different outcomes observed at varying concentrations.
Owing to their significance and relevance, a plethora of exclusive reviews are available on animal studies focusing on drugs targeting group I mGluRs. Consequently, readers can refer to these articles to delve into comprehensive details regarding drug studies. Here are a few illustrative examples. Swanson et al. reviewed in 2005 animal studies on drugs targeting mGluRs on anxiety-like behaviors [72]. Krystal et al. reviewed in 2010 the preclinical animal studies that examined mGluR agonists and antagonists in rodent models of anxiety [73]. Of the studies examined in this 2010 review, about 90% of them reported an anxiolytic effect with mGluR5 antagonists. Riaza Bermudo-Soriano et al. provided another review [3]. In this comprehensive review conducted in 2012, the authors examined the effects of mGluR5 antagonists on anxiety through 43 animal studies. Remarkably, all but two of these studies revealed anxiolytic effects, indicating a strong potential for mGluR5 antagonists in anxiety treatment. Additionally, the authors assessed 20 animal studies involving mGluR1 antagonists and their impact on anxiety. Among these studies, an encouraging 13 of them demonstrated anxiolytic effects, further highlighting the promising therapeutic role of mGluR1 antagonists in addressing anxiety-related conditions.
3.3 Roles of group II mGluRs in anxiety
mGluR3 exhibits broad expression in many brain regions, including those known to be involved in emotional processing, such as the amygdala, prefrontal cortex, hippocampus, and bed nucleus of the stria terminalis. In contrast, mGluR2 shows a more limited expression pattern, with moderately strong presence in the dentate gyrus and olfactory regions and weaker expression in the thalamus, striatum, and cortex.
Group II mGluRs inhibit the release of glutamate, and by reducing excessive glutamate release, these receptors can help regulate neuronal activity and maintain a balance in the brain’s excitatory signaling, which may contribute to anxiety reduction. Indeed, many animal studies on drugs targeting the group II mGluRs on anxiety-like behaviors have been conducted, and rather consistent findings have been reported.
Overall, agonists and positive allosteric modulators of mGluR2 and/or mGluR3 receptors have been found to elicit anxiolytic responses in experimental animals. For example, mGluR2/3 agonists have been shown to reduce fear-potentiated startle, decrease stress-induced hyperthermia, and increase open-arm entries in the elevated plus maze [43, 74, 75]. Other studies showed that pharmacological activation of mGlu2/3 receptors shortens the time that was required for the conventional antidepressants to be effective as antidepressants in these rats, proposing the combination of mGluR2/3 agonists with other antianxiety agents as a potential treatment for anxiety [76, 77]. In line with the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist, Nasca et al. showed that L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors [78].
While it was somewhat expected that mGluR2/3 agonists might act as antianxiety agents, as mentioned earlier, some later studies brought about surprising findings. These studies revealed that negative allosteric modulators targeting mGluR2/3 also exhibited antidepressant and anxiolytic activity in rodents. The anxiolytic effect was demonstrated in various behavioral paradigms, including the learned helplessness (LH) paradigm [79], marble-burying, and forced swim test (FST) [80]. Therefore, these results suggest that the blockade mGluR2/3 may also hold promise as a treatment for depressive and anxiety disorders. In the 2012 review by Riaza Bermudo-Soriano et al., nine studies with mGluR2/3 antagonists were listed, with six demonstrated anxiolytic effects. Meanwhile, 28 studies with mGluR2/3 agonists were recorded, all but three demonstrated anxiolytic effects [3].
As such, the anxiolytic effects observed with the blockade or activation of mGluR2/3 have led to some conflicting findings. While the exact reasons for these discrepancies remain not fully understood, various factors, such as differences in behavioral assays, routes of drug administration, and dosages, may play a significant role in the observed outcomes. Therefore, it is imperative to conduct further research and engage in in-depth discussions to fully elucidate the potential of mGluR2/3 agonists or antagonists in anxiety treatment.
3.4 Roles of group III mGluRs in anxiety
The expression patterns of group III mGluRs indicate that they might also play significant roles in anxiety regulation. Notably, mGluR4, mGluR7, and mGluR8 are all present in the hippocampus, and there is a possibility of mGluR6 having low expression in this region as well. Additionally, these receptors, mGluR4, mGluR7, and mGluR8, are found in other crucial areas such as the hypothalamus, prefrontal cortex, and amygdala. Given their presence in these regions, the activation of these receptors could potentially influence synaptic transmission and impact anxiety-related processes.
While the specific roles of each subtype of group III mGluRs in anxiety are still an active area of research, evidence also suggests their involvement in anxiety regulation. Group III mGluR ligands have been comparatively less studied for their efficacy in anxiety disorders when compared to group I and II ligands; nevertheless, a substantial number of studies have been conducted thus far. Notably, the administration of group III mGluR agonists has demonstrated anxiolytic-like and antidepressant-like effects in experimental animal models. For example, Systemic administration of mGluR8 receptor agonist (S)-3,4-DCPG induces c-fos in stress-related brain regions in wild-type but not mGluR8 receptor knockout mice, suggesting that mGluR8 receptors are involved in anxiety regulation [81]. Several studies have demonstrated that the administration of group III mGluR agonists results in anxiolytic-like and antidepressant-like effects in behavioral tests [82, 83, 84]. In a separate study, mGluR4 PAM exhibited an anxiolytic effect but did not produce an antidepressant-like effect [85]. Recently, mGluR7 specific agonist was also found to be able to produce anxiolytic effects [86]. Compared to mGluR4, mGluR7, and mGluR8, the role of mGluR6 in anxiety remains uncertain. This uncertainty arises from its predominantly expressed location in the retina, with very low expression in the CNS. However, when tested in rats, pharmacological activation of mGluR6 in vivo using a selective agonist produced some anxiolytic-like effects, suggesting mGluR6 might also play a role in anxiety-related processes [82].
In summary, research indicates that among the four group III mGluRs, mGluR4, mGluR7, and mGluR8 are all associated with anxiety behaviors. Additionally, mGluR6 might also play a role in anxiety, though its involvement requires further investigation. Despite the progress over the years, the specific roles of the group III mGluR subtypes in anxiety remain largely unknown, emphasizing the need for further research to elucidate their exact functions and significance in anxiety behaviors.
3.5 mGluR animal models in anxiety
Alongside the pharmacological approach, researchers have extensively developed and tested mGluR mutant animal models to explore the roles of these receptors in anxiety. Constitutive knockouts for all mGluR genes have been generated [26, 42, 45, 56, 59, 87, 88, 89], and conditional knockout mice for specific mGluR genes have also been created [28, 34, 90]. Using mutant animals provides a significant advantage in terms of subtype precision, allowing researchers to target specific mGluR subtypes, which can be challenging to achieve with pharmacological compounds. However, it is crucial to acknowledge the limitations of knockout studies using mutant animals, such as potential gene compensation issues. Despite these challenges, using mutant animal models remains a valuable tool in advancing our understanding of mGluRs’ involvement in anxiety and related processes. Table 1 presents the findings from studies involving mGluR mutant mice.
Gene
Model
Test
Behavior phenotypes
Anxiety
Ref
Grm5
ko
OFT
Grm5 ko mice spent more time in the middle of the arena compared to the control.
Grm1 ko mice exhibited a significant PPI deficit despite their smaller body size and abnormal gait. Note: Evidence exists for the coupling of reduced PPI and certain anxiety disorders.
Grm2 ko and Grm3 ko mice were grossly normal. However, the anxiolytic-like activity of LY354740 (20 mg/kg, s.c.) was not evident in either Grm2 or Grm3 ko mice.
Grm7 ko mice displayed anxiolytic activity in four different behavioral tests, i.e., the light-dark box, the elevated plus maze, the staircase test, and the stress-induced hyperthermia test,
Grm8 ko mice showed increased measures of anxiety in the open field and the elevated plus maze, and an increased acoustic startle response were seen in 6- and 12-month-old Grm8 ko male mice.
Abbreviations: OFT: open field test, EZM: Elevated zero maze, DLB: Dark–Light Box test, FPS: Fear-potentiated startle, VC: Vogel conflict test, BWA: The Black & White Alley, SIH: stress-induced hyperthermia test.
Note: in mice, mGluR1–8 are encoded by Grm1–8 genes respectively.
As summarized above, Grm1 ko mice exhibit significant impairments in movement and gait [87], which pose challenges in interpreting behavioral measurements. Despite that, the Grm1 ko mice displayed a significant prepulse inhibition (PPI) deficit [32]. It is noteworthy that reduced PPI has been observed in patients with certain anxiety disorders [97, 98]. On the other hand, there is some disagreement in the effects of Grm5 ko mice when compared to the impact of mGluR5 agonists. Considering the consistent and robust anxiolytic effects of mGluR5 antagonists, it was expected for the Grm5 ko mice to display reduced anxiety. Indeed, in the open field test (OFT) and Marble-Burying Test (MBT), the Grm5 ko mice showed less anxiety. However, Grm5 ko mice also exhibited severe impairments in fear extinction [28], widely considered a key mechanism in posttraumatic stress disorder (PTSD). This finding suggests that an agonist of mGluR5, instead of an antagonist, may be helpful as a treatment option to treat severe anxiety in people who have experienced traumatic events [99, 100].
Despite the clear anxiolytic effects observed in mGlu2/3 ligands, the lack of an anxiety phenotype in Grm2 ko and Grm3 ko mice, as well as the double ko mice, was unexpected. But the anxiolytic-like activity of LY354740 in wild-type mice was not evident in either Grm2 or Grm3 ko mice, suggesting that anxiolytic-like activity was indeed meditated by mGluR2 and mGluR3 [43]. The exact reason for the unaltered anxiety in these knockout mice remains unknown. One possible explanation could be the presence of redundancy and compensation mechanisms. However, even in the Grm2/Grm3 double ko mice, the anxiety-like behaviors were not significantly affected, which suggests that redundancy and compensation alone may not fully account for the observation. Another plausible explanation could be that Grm2 and Grm3 ko mice may experience developmental changes, which could influence the outcome. Future testing with conditional knockout mice may prove helpful to further investigate and resolve this discrepancy.
The behavioral effects of knocking out genes for group III mGluRs, Grm4, Grm6, Grm7, and Grm8, were also quite intricate. In the case of Grm4 ko mice, the consequences of gene deletion were discovered to be dependent on age and gender [95]. Interestingly, Grm7 ko mice exhibited reduced anxiety [60, 96], while Grm8 ko mice displayed increased anxiety [58]. These outcomes do not entirely align with the pharmacological results, where the administration of group III mGluR agonists generally produces anxiolytic effects. As a result, further studies are necessary to address and clarify these discrepancies.
4. Human studies linking mGluRs in anxiety disorders
4.1 History
In 1982, a clinical study was published demonstrating the potential efficacy of fenobam in treating anxiety [101]. At that time, the specific target of fenobam was not yet known, and it was not until 20 years later that Porter et al. [102] discovered that fenobam actually acted as a selective and potent mGluR5 receptor antagonist. As a result, the 1982 study [101] provided the initial evidence for the involvement of mGluRs in anxiety, marking an essential milestone in comprehending the roles of these receptors in anxiety disorders. Since the 1982 report, numerous additional studies have been conducted, encompassing both animal studies and preclinical and clinical investigations. Collectively, these studies have overwhelmingly supported the roles of mGluRs in anxiety. The expanding body of evidence reinforce the initial findings and solidify our understanding of mGluR’s importance in anxiety disorders [33, 35, 73, 103, 104].
It is worth noting that mGluRs have been implicated in obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD), both of which were previously classified as anxiety disorders before the introduction of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Additionally, while this chapter focuses on mGluR in anxiety disorder, it is important to highlight that mGluRs are also implicated in depression disorders. Although anxiety and depression are distinct disorders with unique characteristics, they often co-occur and share some similarities in symptoms and treatment approaches. Many individuals experience symptoms of both conditions simultaneously, leading to what is known as comorbid anxiety and depression. Therefore, this section also includes specific clinical evidence that implicates mGluRs in depression.
4.2 Findings from human genetic studies
Genetic linkage and association studies have been extensively conducted to identify chromosomal risk loci and susceptibility genes for anxiety and depression [105]. Among the findings, there is a multiple of evidence supporting the roles of GRM genes in anxiety (see Table 2 for details). Particularly, at least four studies have implicated either GRM7 or GRM8 in depression disorder [106, 107, 108, 109], giving strong support for the involvement of group III mGluRs in depression. Furthermore, genetic studies have strongly indicated the involvement of GRM5 in autism spectrum disorder (ASD) [110, 111, 112, 113]. Although ASD and anxiety are distinct conditions, it is worth noting that many ASD patients also experience anxiety disorder. As a result, these human genetic studies may offer insights into potential shared neural mechanisms underlying depression, anxiety, and even ASD, despite their different diagnostic classification.
Studies
Findings
Reference
GRM7
Linkage studies
There is a genome-wide significant linkage to chromosome 3p26-3p25, with a peak signal near the gene GRM7 in depression.
The glutamatergic synaptic transmission gene set (GO:0035249) includes 16 genes, of which six genes, SLC1A4, CACNA1A, GRM8, PARK2, UNC13A, and SHC3, showed nominal association with MDD.
High throughput sequencing has identified de novo GRM5 mutations and enrichment of rare variants of genes encoding components of mGluR signaling pathways. Increase in the prevalence GRM5 copy number variants in ASD was reported.
Evidence from genetic studies implicating GRM genes in anxiety.
Abbreviations: GSAA: gene-set-based association analysis, GWAS: genome-wide association scans, WES: whole-exome sequencing, ASD: autism spectrum disorder, MDD: major depression disorder, SNPs: single nucleotide polymorphisms.
4.3 Findings from emission tomography (PET)
PET has emerged as a valuable tool in diverse neurologic and psychiatric applications. Particularly, over the last two decades, significant advancements have been made in developing mGluR PET ligands, leading to an increasing number of PET radioligands that target mGluRs. These innovative ligands provide a noninvasive in vivo imaging technique, enabling the quantification of mGluR receptors in normal and disease-state conditions [7, 114].
For group I mGluRs, the pioneer tracer for both preclinical and clinical applications, [11C]ABP688, was developed in 2006 [115]. Since then, several more radioligands have been introduced, including [18F]FIMX for mGluR1 [116], [18F]FPEB [117], and [18F]SP203 [118] for mGluR5. These radioligands have been employed in clinical trials and have played a pivotal role in investigating the involvement of mGluRs in anxiety disorders. Among these ligands, mGluR5 has been the most extensively studied. The critical findings for these studies are summarized in Table 3. Interestingly, it appears that mGluR5 expression can vary significantly, showing either upregulation or downregulation depending on the specific disorder. For instance, individuals with MDD may exhibit lower levels of mGluR5, while those with PTSD may experience upregulation of this receptor (Table 3). As a result, when contemplating pharmacological interventions targeting mGluRs, it becomes crucial to meticulously justify their usage based on how the receptors are altered in different medical conditions.
Receptors
Ligands
Disorders
Findings
mGluR5
Ref
mGluR5
[18F]FPEB
MDD
No significant between-group differences were observed. Individuals with MDD had higher ACC glutamate, Importantly, the ACC mGluR5 DVR negatively correlated with glutamate.
There is higher availability of mGluR5 in individuals with PTSD than healthy control and MDD groups. Furthermore, higher mGluR5 availability was associated with scan-day suicidal ideation among individuals with PTSD, but not MDD.
Abbreviations: MDD: major depressive disorder, PTSD: posttraumatic stress disorder, OCD: obsessive-compulsive disorder, ACC: anterior cingulate, DVR: distribution volume ratio.
As of now, some PET ligands have also been developed for group II mGluRs, specifically targeting mGluR2 and mGluR3, with [11C]JNJ42491293 [123] being a notable ligand that has been used in clinical studies to probe mGluR2 in the human brain. On the other hand, the availability of group III PET ligands remains limited [124]. Although several ligands have been developed for PET imaging purposes, there is currently a lack of reports on their usage in human patients.
The utilization of pharmacological modulation of glutamate transmission has long been regarded as a highly valuable therapeutic approach [3, 125, 126]. The mGluRs have emerged as potential targets for safely altering glutamate-driven excitation. Preclinical data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders [3, 72, 73, 127]. Numerous clinical trials have been conducted to explore the potential of targeting mGluRs for treating various neurological diseases. A recent review comprehensively summarized the findings from these clinical studies involving compounds that specifically interact with mGluRs [104].
Anxiety disorders are the most common mental disorders, affecting about 30% of the population at some point in life. Given the involvement of mGluRs in anxiety regulation, there has been tremendous interest in developing mGluR drugs for therapeutic use in anxiety disorders. Indeed, a number of mGluR antagonists or agonists have been used in clinical studies of anxiety disorder. These data are summarized in Table 4.
Clinical studies on the effects of mGluR compounds on anxiety disorders and related conditions.
Abbreviations: HA and CGI: Hamilton Anxiety and Clinical Global Impression, MDD: major depressive disorder, OCD: obsessive-compulsive disorder, GAD: generalized anxiety disorder, HDR: Hamilton Depression Rating, MADRS: Montgomery-Asberg Depression Rating Scale, SSRI: selective serotonin reuptake inhibitors, SNRIs: serotonin and norepinephrine reuptake Inhibitors.
Currently, the only FDA-approved medication targeting mGluRs is fenobam, which initially received approval as an anxiolytic [101] before its characterization as a mGluR5 receptor antagonist [102]. Despite numerous clinical trials exploring mGluR-targeting compounds for treating anxiety, OCD, depression, and panic disorder, the results have not been as promising as anticipated. Notably, three studies targeting group II mGluRs [130, 131, 132] and two studies targeting mGluR5 [128, 129] did not yield the robust outcomes desired. The development of group III mGluRs as potential therapeutic targets has been relatively limited compared to other mGluR receptors. As of now, there have been no reports of human clinical trials involving group III compounds.
Rest assured, laboratories’ dedication to developing novel mGluR drugs will persist, and preclinical research will continue to advance our understanding of mGluR functions. Despite encountering various challenges, clinical inquiry into mGluRs will not cease. There remains a hopeful outlook that effective treatments can be developed based on the functions of mGluRs. With ongoing efforts and scientific exploration, we can aspire to find new therapeutic approaches for anxiety disorders.
This book chapter offers a comprehensive investigation into the roles of mGluRs in anxiety disorders. Through an exploration of their classification, neurobiological mechanisms, and potential therapeutic implications, the aim is to enhance our understanding of these receptors as potential targets for developing innovative treatments for anxiety disorders. The chapter begins with an exploration of the biology of mGluRs. It then transitions to an investigation of how mGluRs influence anxiety-related behaviors in animals, utilizing animal models as a foundation to understand the neurobiological mechanisms underlying the actions of mGluRs. In the subsequent section, the chapter delves into the clinical implications and therapeutic potential of mGluRs in anxiety disorders.
Preclinical data strongly supports the potential of mGluRs as promising therapeutic targets for anxiety disorders. A wealth of evidence demonstrates that certain mGluR compounds exhibit high efficacy as anxiolytic agents in animal models. However, from a mechanistic standpoint, many important questions remain unanswered, such as the specific roles of individual receptors and the underlying cellular mechanisms and neural circuits through which these receptors ultimately influence anxiety. Further research is needed to address these aspects and fully harness the therapeutic benefits of targeting mGluRs for anxiety disorders.
Unfortunately, despite initial expectations, the clinical studies on mGluR receptor ligands as anxiolytics have yielded somewhat disappointing results. However, we should approach this situation with cautious optimism. It is crucial to recognize that these ligands have been tested only in a limited range of anxiety disorders, and their full therapeutic potential remains yet to be defined. There is hope that through further exploration and broader clinical trials, more promising outcomes for these ligands may be revealed. Furthermore, ongoing advancements in developing new compounds with improved pharmacokinetic and safety profiles offer great potential for enhanced efficacy and better tolerability. This progress may ultimately pave the way for more effective mGluR-based treatments, providing renewed possibilities for individuals seeking relief from anxiety disorders.
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Written By
Jian Xu and Yongling Zhu
Submitted: 04 August 2023Reviewed: 07 August 2023Published: 09 October 2023
Open access peer-reviewed chapter
