Glutamate and anxiety disorders.
ABSTRACT Anxiety disorders are among the most prevalent psychiatric disorders, but they represent a particular challenge for treatment. The standard first-line treatments, including antidepressants, benzodiazepines, and buspirone, result in significant response rates for a majority of patients; however, unfavorable side effect profiles or risk for dependency for particular agents might limit their use by anxious patients, who often have low thresholds for medication discontinuation. Novel pharmacologic agents that modulate particular receptors, ion channels, or transporters relevant to glutamatergic neurotransmission may represent a new approach to the treatment of anxiety disorders, with generally more favorable side effect profiles. Although the role of glutamate in the pathophysiology of anxiety disorders is still being elucidated, the use of these agents in treatment of anxiety disorders and commonly comorbid conditions such as substance abuse and mood disorders will continue to increase.
SourceAvailable from: Jin-Hui Wang[Show abstract] [Hide abstract]
ABSTRACT: AimAnxiety is one of common mood disorders, in which the deficit of serotonergic and GABAergic synaptic functions in the amygdala and prefrontal cortex is believed to be involved. The pathological changes at the glutamatergic synapses and neurons in these brain regions as well as their underlying mechanisms remain elusive, which we aim to investigate.Methods An agonist of kainate-type glutamate receptors, kainic acid, was applied to induce anxiety-related behaviors. The morphology and functions of glutamatergic synapses in the prelimbic region of mouse prefrontal cortex were analyzed using cellular imaging and electrophysiology.ResultsAfter kainate-induced anxiety is onset, the signal transmission at the glutamatergic synapses is upregulated, and the dendritic spine heads are enlarged. In terms of the molecular mechanisms, the upregulated synaptic plasticity is associated with the expression of more protein kinase C (PKC) in the dendritic spines. Chelerythrine, a PKC inhibitor, reverses kainate-induced anxiety and anxiety-related glutamatergic synapse upregulation.Conclusion The activation of glutamatergic kainate-type receptors leads to anxiety-related behaviors and glutamatergic synapse upregulation through protein kinase C in the prelimbic region of the mouse prefrontal cortex.CNS Neuroscience & Therapeutics 09/2014; DOI:10.1111/cns.12313 · 4.46 Impact Factor
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ABSTRACT: Severe adverse life events during pregnancy may increase the risk of anxiety disorders in the offspring. Glutamate receptors are neurobiological targets in anxiety disorders. In this study, we investigated the effects of prenatal chronic mild stress (PCMS) on anxiety-like behavior by using elevated plus maze (EPM), and evaluated the effects of PCMS and/or anxiogenic challenge on glutamate receptors in different brain regions. Our results showed that PCMS increased anxiety-like behavior in both male and female offspring. Moreover, compared with the male naïve rats, male EPM rats showed a significant reduction of mGluR2/3 in the prefrontal cortex, mGluR1 and mGluR2/3 in the hippocampus, and increments of mGluR5, NR1, NR2B and PSD95 in the amygdala. In contrast, compared with female naïve rats, female EPM rats showed decreased levels of mGluR5 in the hippocampus, and mGluR2/3 and mGluR5 in the prefrontal cortex, and increased levels of NR2B and PSD95 in the amygdala. Furthermore, PCMS seemed not to affect the baseline expression of glutamate receptors in adult offspring, but induced significant alterations of them triggered by anxiogenic challenge with a sex difference. These data strengthen the pathophysiological hypothesis that prenatal stress as a risk factor involves in the development of anxiety disorder in the offspring. Copyright © 2015. Published by Elsevier Ltd.International Journal of Developmental Neuroscience 01/2015; 41. DOI:10.1016/j.ijdevneu.2015.01.003 · 2.92 Impact Factor
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ABSTRACT: Background and purposeTransient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) are involved in many biological processes, including nociception and hyperalgesia. Whereas the involvement of TRPV1 in psychiatric disorders as anxiety and depression has been reported, little is known regarding the role of TRPA1 in these conditions.Experimental approachWe investigated the role of TRPA1 in mice models of depression (forced swimming test, FST) and anxiety (elevated plus maze test, EPM).Key resultsIntracerebroventricular (i.c.v.) administration of the TRPA1 antagonist (HC030031, 30 nmol/2 μl) reduced immobility time in the FST test. Similar results were obtained by oral administration of HC030031 (p.o., 30-300 mg/kg). Reduction in the immobility time in the FST induced by HC030031 (100 mg/kg) was completely prevented by pretreatment with TRPA1 agonist, cinnamaldehyde (50 mg/kg, p.o.), which per se was inactive. In the EPM test, pretreatment with cinnamaldehyde (50 mg/kg, p.o.), which per se did not affect behavior response, prevented the anxiolytic-like effect (increased open arms exploration) evoked by TRPA1 blockade (HC030031, 100 mg/kg, p.o.). Treatment with either cinnamaldehyde or HC030031 did not affect spontaneous ambulation. Finally, TRPA1-deficient mice showed anxiolytic- and antidepressant-like phenotypes in the FST test and EPM test, respectively.Conclusion and implicationsPresent findings indicate that genetic deletion or pharmacological blockade of the TRPA1 produce inhibitory activity in mouse models of anxiety and depression. Results imply that TRPA1 exerts a tonic control promoting anxiety and depression and suggests TRPA1 antagonism as an innovative strategy for the treatment of anxiety and mood disorders.British Journal of Pharmacology 05/2014; 171(18). DOI:10.1111/bph.12786 · 5.07 Impact Factor