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.
"Several ion channels have been proposed as potential therapeutic targets for the treatment of depression and anxiety. These include voltage-gated calcium (Ntype ), potassium (Kv7), serotonin 5-HT 3 , purinergic P2X7 channels, and glutamate receptors, such as AMPA and NMDA (for a review see: (Amiel and Mathew, 2007; Lodge and Li, 2008; Mico and Prieto, 2012). With the exception of pain signaling, current information regarding the role of TRPA1 in the brain is limited. "
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Transient 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 such as anxiety and depression has been reported, little is known regarding the role of TRPA1 in these conditions.
We investigated the role of TRPA1 in mice models of depression [forced swimming test (FST)] and anxiety [elevated plus maze (EPM) test].
Administration of the TRPA1 antagonist (HC030031, 30 nmol in 2 μL, i.c.v.) reduced immobility time in the FST. Similar results were obtained after oral administration of HC030031 (30-300 mg·kg(-1) ). The reduction in immobility time in FST induced by HC030031 (100 mg·kg(-1) ) was completely prevented by pretreatment with TRPA1 agonist, cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se was inactive. In the EPM test, pretreatment with cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se did not affect behaviour response, prevented the anxiolytic-like effect (increased open arm exploration) evoked by TRPA1 blockade (HC030031, 100 mg·kg(-1) , p.o.). Treatment with either cinnamaldehyde or HC030031 did not affect spontaneous ambulation. Furthermore, TRPA1-deficient mice showed anxiolytic- and antidepressant-like phenotypes in the FST and EPM test respectively.
Conclusion and implications:
The present findings indicate that genetic deletion or pharmacological blockade of TRPA1 produces inhibitory activity in mouse models of anxiety and depression. These results imply that TRPA1 exerts tonic control, promoting anxiety and depression, and that TRPA1 antagonism has potential 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 · 4.84 Impact Factor
Jeffrey S Bedwell, Pamela D Butler, Chi C Chan, Benjamin J Trachik
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