Advances in the treatment of anxiety: Targeting glutamate

Simon, Asher B.; Gorman, Jack M.

doi:10.1016/j.nurx.2005.12.005

Cited by 49 publications

(21 citation statements)

References 178 publications

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“…This is presumed to increase their firing rate in a way that may resemble the hyperactive limbic cortical areas seen in functional imaging of OCD patients; indeed, these transgenic mice are described as engaging in perseverative behaviors that mimic some aspects of OCD and Tourette's syndrome. 78,79 MK-801, a noncompetitive use-dependent antagonist of the NMDA glutamate receptor that may indirectly increase presynaptic glutamate release, 80 has been shown to worsen these perseverative behaviors, and to induce an additional category of "limbic seizure-like" stereotypies. 81 Interestingly, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of AMPA-type glutamate receptors, does not affect baseline OCD-like behaviors in these mice or their exacerbation by MK-801, but does reduce the "seizure-like" stereotypies.…”

Section: Preclinical Evidence Suggesting Increased Glutamate Activitymentioning

confidence: 99%

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Pittenger

Krystal

Coric

2006

NeuroRX

195

128

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Summary:Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD.These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.

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Section: Preclinical Evidence Suggesting Increased Glutamate Activitymentioning

confidence: 99%

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Pittenger

Krystal

Coric

2006

NeuroRX

195

128

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“…Studies on the pathophysiology of anxiety have proven an intensification of glutamatergic transmission [6,7]. Nuclear imaging studies have shown in patients suffering from anxiety disorders, that brain regions with high glutamate concentration (hippocampus, amigdalla, etc) had structural changes or hyperactivity [8,9].…”

Section: Introductionmentioning

confidence: 99%

Experimental research on the interactions between some anxiolytics and dietary sodium monoglutamate

Buzescu

Cristea

Chiriac

et al. 2014

Acta Medica Marisiensis

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Objectives: Monosodium glutamate, the salt of glutamic acid, is largely used as a flavour enhancer (E621). In this study, we determine if monosodium glutamate, after repeated oral administration, can induce any degree of anxiety. Taking into account the interdependence between glutamate and GABA neurotransmissions, we studied the possible interactions of monosodium glutamate with some representatives belonging to benzodiazepines therapeutical class, diazepam and alprazolam, used as first line therapy for the treatment of anxiety. Methods: For determining the degree of anxiety, the specific cross-labyrinth test was used. The medium time spent in the closed-arms of the crosslabyrinth is correlated with increased anxiety and the medium time spent in the opened arms is correlated with a low degree anxiety. NMRI adult mice received 300 mg/kg monosodium glutamate for 21 days, dose representing 1/50 from mice LD50 (15000mg/kg) and twice the maximum admitted dose/ day for human. Results: When compared to control group, the group receiving monosodium glutamate, showed a not statistically significant slight increase in the degree of anxiety. The groups receiving benzodiazepines presented a significant reduction of the degree of anxiety, proving their anxiolytic effect. The groups receiving glutamate and diazepam or alprazolam, showed a lower reduction of the degree of anxiety, than group receiving only benzodiazepines, phenomenon which proves an antagonism between glutamate and the anxiolytics used in this study. Conclusions: The oral administration of monosodium glutamate increases slightly, not statistically significant, the degree of anxiety in mice and significantly alters the response to the benzodiazepines therapy, reducing the effect for both alprazolam and diazepam.

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“…Several studies with rodents suggest that blockage of mGluR1 could ameliorate CNS disorders, including pain, neurodegeneration, and psychiatric diseases (Varney and Gereau, 2002;Millan, 2003;Spooren et al, 2003;Palucha and Plic, 2005;Simon and Gorman, 2006;Belozertseva et al, 2007). On the other hand, to date the involvement of mGluR1 in human CNS disorders has not been shown.…”

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confidence: 99%

Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)

Suzuki

Kimura²,

Satow³

et al. 2007

J Pharmacol Exp Ther

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A highly potent and selective metabotropic glutamate receptor (mGluR) 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2, 3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC), is described. FTIDC inhibits, with equal potency, L-glutamate-induced intracellular Ca 2ϩ mobilization in Chinese hamster ovary cells expressing human, rat, or mouse mGluR1a. The IC 50 value of FTIDC is 5.8 nM for human mGluR1a and 6200 nM for human mGluR5. The maximal response in agonist concentration-response curves was reduced in the presence of higher concentrations of FTIDC, suggesting the inhibition in a noncompetitive manner. FTIDC at 10 M showed no agonistic, antagonistic, or positive allosteric modulatory activity toward mGluR2, mGluR4, mGluR6, mGluR7, or mGluR8. FTIDC did not displace [ 3 H]L-quisqualate binding to human mGluR1a, indicating FTIDC is an allosteric antagonist. Studies using chimeric and mutant receptors of mGluR1 showed that transmembrane (TM) domains 4 to 7, especially Phe801 in TM6 and Thr815 in TM7, play pivotal roles in the antagonism of FTIDC. FTIDC inhibited the constitutive activity of mGluR1a, suggesting that FTIDC acts as an inverse agonist of mGluR1a. Intraperitoneally administered FTIDC inhibited face-washing behavior elicited by a group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine in mice at doses that did not produce motor impairment. Oral administration of FTIDC also inhibited the face-washing behavior. FTIDC is a highly potent and selective allosteric mGluR1 antagonist and a compound having oral activity without species differences in its antagonistic activity on recombinant human, mouse, and rat mGluR1. FTIDC could therefore be a valuable tool for elucidating the functions of mGluR1 not only in rodents but also in humans.Metabotropic glutamate receptors (mGluRs) are G proteincoupled receptors, and they are thought to contribute to the fine-tuning of fast synaptic response, neuronal excitability, and neurotransmitter release. To date, eight mGluR subArticle, publication date, and citation information can be found at

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Advances in the treatment of anxiety: Targeting glutamate

Cited by 49 publications

References 178 publications

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Experimental research on the interactions between some anxiolytics and dietary sodium monoglutamate

Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)

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