The blockade of transient receptor potential ankirin 1 (TRPA1) signalling mediates antidepressant- and anxiolytic-like actions in mice

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.

Experimental approach: We investigated the role of TRPA1 in mice models of depression [forced swimming test (FST)] and anxiety [elevated plus maze (EPM) test].

Key results: 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.

Figure 1

Effects of nortriptyline (3–30 mg·kg⁻¹, i.p.) (A), TRPA1 antagonist HC030031 (30 nmol in 2 μL, i.c.v.) (B), HC030031 (30, 100 and 300 mg·kg⁻¹, p.o.) (C), pretreatment with cinnamaldehyde (50 mg·kg⁻¹, p.o.) on reduction of immobility time induced by TRPA1 antagonist (HC030031, 100 mg·kg⁻¹, p.o.) (D) and genetic deletion of TRPA1 (E) on the immobility time in the FST in mice. Each column is presented as mean ± SEM of at least 7 animals per group or 5 animals per group with genetic deletion of TRPA1.*P < 0.05 versus vehicle values and #P < 0.05 versus HC030031 values (one- or two-way anova followed by Student–Newman–Keuls test or Student's t-test).

Figure 2

Effects of the standard anxiolytic diazepam (1 mg·kg⁻¹, i.p.) (A), HC030031 (100 ·mg kg⁻¹, p.o.) (C), cinnamaldehyde (50 mg·kg⁻¹, p.o.) (E), cinnamaldehyde (50 mg·kg⁻¹, p.o.) on mice treated with HC030031 (100 mg·kg⁻¹, p.o.) (G) on the time spent in open arms and on the frequency of entries into closed arms (B, D, F and H, respectively) in the EPM test in mice. Each column is presented as mean ± SEM of at least 9 animals per group.*P < 0.05 versus vehicle values (Student's t-test or one-way anova followed by Bonferroni's test) and #P < 0.05 versus HC030031 values.

Figure 3

Behavioural phenotype of wild-type and knockout mice for the TRPA1 receptor in the EPM test. The behavioural parameters evaluated were the time spent in open arms (A), and the frequency of entries into closed arms (B) of the apparatus *P < 0.05 versus wild-type group (Student's t-test). Each column is presented as mean ±SEM of at least 5 animals per group.

Figure 4

Effects of the treatment with HC030031 (100 mg·kg⁻¹, p.o.), cinnamaldehyde (30 and 50 mg·kg⁻¹, p.o.) and genetic deletion of TRPA1 receptor on the ambulation of mice in the open field test, shown as an average distance travelled in 5 min observation time (A, C, E). The locomotor activity during 30 min of observation in the open field is presented in panels B, D and F. Each column or point represents the mean of 5–8 animals per group and the vertical lines indicate the SEM.