New perspectives in glutamate and anxiety
Abstract
Anxiety and stress-related disorders, namely posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (ODC), social and specific phobias, and panic disorder, are a major public health issue. A growing body of evidence suggests that glutamatergic neurotransmission may be involved in the biological mechanisms underlying stress response and anxiety-related disorders. The glutamatergic system mediates the acquisition and extinction of fear-conditioning. Thus, new drugs targeting glutamatergic neurotransmission may be promising candidates for new pharmacological treatments. In particular, N-methyl-d-aspartate receptors (NMDAR) antagonists (AP5, AP7, CGP37849, CGP39551, LY235959, NPC17742, and MK-801), NMDAR partial agonists (DCS, ACPC), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) antagonists (topiramate), and several allosteric modulators targeting metabotropic glutamate receptors (mGluRs) mGluR1, mGluR2/3, and mGluR5, have shown anxiolytic-like effects in several animal and human studies. Several studies have suggested that polyamines (agmatine, putrescine, spermidine, and spermine) may be involved in the neurobiological mechanisms underlying stress-response and anxiety-related disorders. This could mainly be attributed to their ability to modulate ionotropic glutamate receptors, especially NR2B subunits. The aim of this review is to establish that glutamate neurotransmission and polyaminergic system play a fundamental role in the onset of anxiety-related disorders. This may open the way for new drugs that may help to treat these conditions.
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Inhibition of NMDA receptors at synapses blocks fear acquisition, and acute stress appears to increase glutamate release as well as glutamate receptor expression, particularly the NMDA receptors that modulate secretion of CRF/CRH in the central amygdala.
“It has been previously demonstrated that the inhibition of NMDA receptors at synapses blocks fear acquisition, and that acute stress appears to increase glutamate release as well as glutamate receptor expression, particularly the NMDA receptors that modulate the secretion of corticotropin-releasing factor (CRF)/corticotropin-releasing hormone (CRH), discussed later, in the CeA (Levenson and Sweatt”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Riaza Bermudo-Soriano et al., 2012
Glutamate is capable of binding to two types of receptors, NMDA and AMPA, which are gated Ca2+ and Na+/K+ channels, respectively.
“It is capable of binding to two types of receptors, NMDA and AMPA, which are gated Ca2+ and Na+/K+ channels, respectively (Riaza Bermudo-Soriano et al., 2012).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Riaza Bermudo-Soriano et al., 2012
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- Authors
- Riaza Bermudo-Soriano, C., Perez-Rodriguez, M. M., Vaquero-Lorenzo, C., & Baca-Garcia, E.
- Venue
- Pharmacology Biochemistry and Behavior
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 100
- Issue
- 4
- Pages
- 752-774
- ISSN
- 0091-3057 (ISSN-L)
- OpenAlex
- W1970956725
- Cited by
- 207
- References
- 33
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 8 · 2023: 13 · 2022: 14 · 2021: 12 · 2020: 10 · 2019: 14 · 2018: 16 · 2017: 7 · 2016: 13 · 2015: 22 · 2014: 21 · 2013: 23 · 2012: 13
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology Biochemistry and Behavior (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- glutamatergic neurotransmission, anxiety disorders, stress response, post-traumatic stress disorder, generalized anxiety disorder, obsessive-compulsive disorder, phobia, panic disorder, fear conditioning, NMDA receptor antagonists, AMPA receptor antagonists, topiramate, metabotropic glutamate receptors, polyamines, agmatine, putrescine, spermidine, spermine, NR2B subunit, anxiolytics
- MeSH terms
- Animals, Anxiety, Humans, Polyamines, Stress, Psychological, Glutamic Acid
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