ReviewMetabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: Focus on pharmacology and preclinical translational models
Highlights
► Targeting glutamate holds great promise for improved treatment of anxiety disorders. ► Anxiolytic activity of mGluR2/3 agonists have achieved the greatest success to date. ► Positive and negative allosteric modulators offer an improved benefit/risk profile. ► Translational models of anxiety and stress disorders respond to glutamate modulation. ► Activity in standard anxiety tests must be replicated in translational animal models.
Section snippets
General introduction
Anxiety disorders have a 12 month prevalance of 17% and a life-time prevalance of 24.9%, and as a group are amongst the most disabling of psychiatric illnesses (Kessler et al., 1994). Despite the availability of psycho- and pharmacotherapies, underdiagnosis and undertreatment of these conditions contribute to their enormous personal and economic costs (Dupont et al., 1996). The major DSM-IV anxiety disorders, including general anxiety disorder (GAD), posttraumatic stress disorder (PTSD), social
Glutamate signaling in the central nervous system
Maintenance of a physiological balance between inhibitory and excitatory neurotransmission in the central nervous system (CNS) is critical in determining normal brain function and behavior. This relies on a functional, perhaps yin–yang type, interaction between γ-amino butyric acid (GABA) and glutamate, the major neurotransmitters involved in mediating inhibitory and excitatory synaptic activity, respectively (Harvey, 1996). Glutamate plays an important and diverse role in the CNS. However,
Extinction and its role in anxiety disorders
It is increasingly evident that some psychiatric illnesses, and especially those that comprise an element of fear and/or aversive behavior, involve a learned component. Memory or associations with the aversive event/experience trigger a conditioned response that invariably involves a maladaptive response leading to an exagerrated stress response together with fearful and anxious behavior (Myers et al., 2011). Recent work has described the important contribution of glutamate in the extinction of
Role of glutamate receptors in anxiety and stress-related disorders
The excitatory action of glutamate in the mammalian brain and spinal cord have been known for more than fifty years (e.g. Curtis and Watkins, 1960). Glutamate exerts a diverse array of biological responses that are responsible for its central role in neurodevelopment, synaptic plasticity and memory, as well as neurotoxicity and neurodegeneration (Meldrum, 2000). At both the metabolic and physiological level, the fate of glutamate as well as its functional activity is closely tied to that of
NMDA receptor modulation
There are various approaches whereby NMDA receptor active drugs may block activation of the NMDA-ionophore complex. These include competitive inhibition of the NMDA site itself e.g. with AP5 (2-amino-5-phosphonopentanoic acid), ifenprodil, dizocilpine (MK-801), non-competitive inhibition by blocking the ion channel e.g. with memantine, modulation of the NMDA/glycine-sensitive site e.g. with d-cycloserine or spermine, blockade of the polyamine binding site (see Bermudo-Soriano and colleagues in
Metabotropic glutamate receptors in anxiety: a preclinical perspective
Based on the hypothesis that stress or fear induced glutamate release in cortical and limbic structures may be of relevance to the pathology of anxiety disorders, the presynaptic mGluR2/3 autoreceptors have received the most attention from a drug discovery perspective (Table 5). Indeed considerable progress has been made in the identification of PAMs and agonists of these receptors, some of which have been tested clinically in proof of concept studies. LY354740 is the most advanced molecule
Animal models of anxiety and stress-related disorders
Although the different anxiety and stress related disorders present with anxiety as a common overall symptom, each illness nevertheless presents with its own unique range of biological and behavioral manifestations that underlie its differential diagnosis. Differences in underlying neurobiology may imply a differential response to glutamate modulating agents. Moreover, these illnesses all differ with respect to the type and duration of stress that can be associated with an earlier precipitating
Future perspective and summary
Current frontline pharmacological treatments and key approaches in drug discovery and development in anxiety disorders is summarized in Fig. 5. Monoamine reuptake inhibitors (e.g. SSRIs, SNRIs), GABA-A receptor potentiators (benzodiazepines) and a 5HT1A partial agonist, buspirone, form the main therapeutic options for patients suffering from an anxiety disorder. These generally work with varying success across different anxiety disorders except OCD which responds selectively to SSRIs. However,
Concluding remarks
Encouraging evidence has emerged from both preclinical and clinical research to support the glutamate system as a promising pathway for discovering improved mechanistically novel therapies for the treatment of anxiety disorders, especially given the central role of glutamate as a regulator of neuroplasticity. Scientific rationale exists for modulators of both ionotropic and metabotropic receptors, although based on currently available evidence, the latter approach seems to be more attractive.
Conflict of interest
Dr Mohammed Shahid was an employee of MSD, a part of Merck, at the time of writing this manuscript.
Dr Brian Harvey has participated as an invited speaker, has received sponsorship, pharmaceutical compound or honoraria, or is a member of an advisory board, for Bristol-Myers Squibb, Organon, Pfizer and Servier, and has received research funding from Lundbeck. Apart from receiving Org 26576 from Organon for research purposes, there are no conflicts of interest to declare of relevance for this work.
Acknowledgements
The authors would like to thank Rachel van Schalkwyk for assistance during the preparation of the manuscript. Dr Harvey is funded by the National Research Foundation and the South African Medical Research Council. None of the funding sources have a vested interest in the author's work cited in this review.
References (387)
- et al.
NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin
Neuropharmacol
(2005) - et al.
tc-99 m HMPAO brain perfusion SPECT in drug-free obsessive–compulsive patients without depression
Psychiatry Res
(2001) - et al.
Pharmacological characterization of glutamatergic agonists and antagonists at recombinant human homomeric and heteromeric kainate receptors in vitro
Neuropharmacology
(2004) - et al.
A role for AMPA receptors in mood disorders
Biochem Pharmacol
(2006) - et al.
A novel class of antagonists for metabotropic glutamate receptors, 7-(hydroxyimino)cyclopropa[b]chromen1a-carboxylates
Bioorg Med Chem Lett
(1996) - et al.
Anxiolytic-like effects of N-methyl-d-aspartate-associated glycine receptor ligands in the rat potentiated startle test
Eur J Pharmacol
(1993) - et al.
Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam
Neurosci
(1997) Current treatments of the anxiety disorders in adults
Biol Psychiatry
(1999)- et al.
Pharmacologic characterization of MDL 105,519, an NMDA receptor glycine site antagonist
Eur J Pharmacol
(1997) - et al.
Glutamate and anxiety
Eur Neuropsychopharmacol
(2004)
Behavioral characteraization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression
Eur J Pharmacol
The entorhinal cortex plays a role in extinction
Neurobiol Learn Mem
Metabotropic glutamate receptor 5 modulates the nitric oxide-cGMP pathway in cerebellum in vivo through activation of AMPA receptors
Neurochem Int
d-cycloserine facilitates context-specific fear extinction learning
Neurobiol Learn Mem
Stress and re-stress increases conditioned taste aversion learning in rats: possible frontal cortical and hippocampal muscarinic receptor involvement
Eur J Pharmacol
Anxiolytic-like activity of the mGluR5 antagonist MPEP a comparison with diazepam and buspirone
Pharmacol Biochem Behav
Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex
Neuron
Relationship between short- and long-term memory and short- and longterm extinction
Neurobiol Learn Mem
Induction of LTD by activation of group I mGluR in the dentate gyrusin vitro
Neuropharmacol
MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity
Neuropharmacol
Correlation between lipid peroxidation-induced TBARS level and disease severity in obsessive–compulsive disorder
Prog Neuropsychopharmacol Biol Psychiatry
Effects of 5,7 dichlorokynurenic acid on conflict, social interaction and plus maze behaviour
Neuropharmacol
Effects of 5,7 dichlorokynurenic acid on conflict, social interaction and plus maze behaviors
Neuropharmacol
Riluzole augmentation in treatment-resistant obsessive–compulsive disorder: an open-label trial
Biol Psychiatry
Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats
Behav Brain Res
Prefrontal cortex-nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex
Pharmacol Biochem Behav
Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze
Eur J Pharmacol
Stereoselective R-(+) enantiomer of HA-966 displays anxiolytic effects in rodents
Eur J Pharmacol
Role of metabotropic glutamate receptors in the control of neuroendocrine function
Neuropharmacol
Effects of glutamate-related drugs on marble-burying behavior in mice: implications for obsessive–compulsive disorder
Eur J Pharmacol
Expression and conditioned inhibition of fear-potentiated startle after stimulation and blockade of AMPA/Kainate and GABA(A) receptors in the dorsal periaqueductal gray
Brain Res
NMDA receptors in the pontine brainstem are necessary for fear potentiation of the startle response
Eur J Pharmacol
Pharmacogenetics and schizophrenia
Clin Lab Med
Interactions between ifenprodil and dizocilpine on mouse behaviour in models of anxiety and working memory
Eur Neuropsychopharmacol
Neuroimaging in social anxiety disorder: a systematic review of the literature
Prog Neuropsychopharmacol Biol Psychiatry
Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory
Biol Psychiatry
Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS
Neuron
Deficits in acquisition and extinction of conditioned responses in mGluR7 knockout mice
Neurobiol Learn Mem
Polyaminergic agents modulate contextual fear extinction in rats
Neurobiol Learn Mem
Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope
Am J Pharmacogenomics
The role of NMDA receptors in the signal attenuation rat model of obsessive–compulsive disorder
Psychopharmacol (Berl)
Antipsychotic drugs reverse the AMPA receptor-stimulated release of 5-HT in the medial prefrontal cortex
J Neurochem
Diagnostic and statistical manual of mental disorders
Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior
Curr Drug Targets
Plasma nitrate values in patients with obsessive–compulsive disorder
Psychiatry Clin Neurosci
d-Cycloserine and performance under different states of anxiety in healthy volunteers
Psychopharmacol (Berl)
The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning
Behav Neurosci
Role of pregabalin in the treatment of generalized anxiety disorder
Neuropsychiatr Dis Treat
The effect of the MGlu5 receptor antagonist MPEP in rodent test of anxiety and cognition: a comparison
Psychopharmacol (Berl)
Remission rates in patients with anxiety disorders treated with paroxetine
J Clin Psychiatry
Cited by (72)
The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment
2021, Biomedicine and PharmacotherapyKetamine effects on anxiety and fear-related behaviors: Current literature evidence and new findings
2020, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :However, these drugs present several limitations that limit their use (Bandelow et al., 2017; Blier and Abbott, 2001; Nash and Nutt, 2005) and drive the search for other molecular targets and new drugs. A plenty body of evidence from clinical and preclinical studies suggests the involvement of glutamatergic neurotransmission in anxiety disorders (Averill et al., 2017; Griebel and Holmes, 2013; Harvey and Shahid, 2012; Riaza Bermudo-Soriano et al., 2012). For instance, adolescent patients diagnosed with GAD showed a positive correlation between glutamatergic tone and severity of anxiety symptoms (Strawn et al., 2013) whereas patients with social anxiety showed an increase in glutamate/creatine ratio in the anterior cingulate cortex (Phan et al., 2005).
Early sexual trauma is related with the tapetum in patients with panic disorder
2020, Journal of Affective DisordersBisphenol-A exposure induced neurotoxicity in glutamatergic neurons derived from human embryonic stem cells
2019, Environment InternationalPsychological co-morbidities in COPD: Targeting systemic inflammation, a benefit for both?
2019, European Journal of Pharmacology
- 1
Current address: Orion Corporation ORION PHARMA, Research and Development, Turku, Finland.