Key Points
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Anxiety disorders represent a range of conditions that include generalized anxiety, panic attacks, post-traumatic stress disorder, obsessive–compulsive syndrome and social phobias.
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Some forms of anxiety are relatively resistant to treatment with current drugs, and furthermore, these drugs are often associated with serious side effects, such as sedation, memory impairment, ataxia, abuse potential and physical dependence. It has therefore become increasingly apparent that alternative treatment strategies are needed.
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In general, anxiety- and stress-related illnesses are thought of as a collection of disorders that have in common excessive or inappropriate brain excitability within crucial brain circuits. As glutamate is the major excitatory neurotransmitter in the mammalian brain, it is logical that new approaches for anxiety could include drugs that modulate glutamatergic functions.
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The metabotropic glutamate (mGlu) receptors are a novel family of class C GPCRs that comprise at least eight known subtypes. A growing body of evidence indicates that these receptors might serve as potential therapeutic targets for a variety of pathological states, including anxiety disorders.
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In particular, as discussed in this article, group II mGlu receptors and group I mGlu receptors seem to be important in the physiological and behavioural sequelae associated with stressful stimuli.
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Moreover, compounds selective for mGlu receptors, particularly mGlu2/3 and/or mG1u5, have proven as effective as classical anxiolytics in various animal models of anxiety without producing many of the unwanted side effects that are typical of current therapies.
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The precise anxiolytic actions of selective mGlu receptor compounds have yet to be fully elucidated. However, a number of studies suggest that both group II mGlu receptor agonists and group I mGlu receptor antagonists might generally act to regulate neuronal hyperexcitability by direct or indirect suppression of excitatory transmission.
Abstract
Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu1 and mGlu5), group II (mGlu2 and mGlu3), and group III (mGlu4, mGlu7 and mGlu8) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu2/3) receptors and antagonists for group I (in particular mGlu5) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.
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The authors are employees of Eli Lilly & Co., which is developing drugs that target metabotropic glutamate receptors.
Glossary
- IONOTROPIC RECEPTOR
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A ligand-gated ion channel receptor that modulates cell excitability.
- GLYCINE SITE
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The NMDA receptor is unique in that glycine (possibly D-serine) acts as a co-agonist with glutamate at a different site on the receptor complex.
- ELEVATED PLUS MAZE
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A commonly used anxiety test for rodents in which the animal can choose to explore an 'open' unprotected arm or a 'closed' protected arm of a cross-shaped elevated platform. Animals which are less fearful spend more time in the open arm and enter it more often.
- MORRIS WATER MAZE
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A learning task in which an animal is placed in a pool filled with opaque water and has to use spatial cues to find a hidden platform that is placed at a constant position.
- DELAYED MATCHING TO POSITION TEST
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Rats are trained to press a lever for food rewards, then trained to make either a matching or non-matching response in a task. The task consists of an illuminated lever being presented and retracted (sample stage) followed by a nose poke into the food tray, delivering two levers. For a correct matching response the animal presses the previous (sample stage) lever for a food reward; for a correct non-matching response the animal presses the other (non-sample stage) lever for a food reward.
- VOGEL TEST
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Also known as the conflict drinking test, this test uses water-deprived rats that are punished with an electric shock when drinking. Anxiolytic drugs increase drinking behaviour that has been suppressed under threat of shock in this test.
- FOUR-PLATE TEST
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A test in which the test animal is placed on a plate and allowed to explore, after which each time the animal passes from one plate to another a shock is delivered. Anxiolytic drugs reduce the fear of shock and increase the number of punished crossings.
- GELLER–SEIFTER TEST
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An anxiety test in which animals learn to press a lever for food, after which food is only delivered under threat of shock. Anxiolytic drugs increase lever pressing that is normally suppressed by the threat of shock punishment.
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Swanson, C., Bures, M., Johnson, M. et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4, 131–144 (2005). https://doi.org/10.1038/nrd1630
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DOI: https://doi.org/10.1038/nrd1630
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