Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene

Abstract

The tachykinin neuropeptide substance P and its receptor neurokinin 1 have been implicated in the regulation of many physiological and pathological processes, including the control of emotional behaviors. The present study examines mice with a targeted deletion of the Tac1 gene, which encodes the neuropeptides substance P and neurokinin A, in animal models relevant to depressive illness and anxiety. In depression-related paradigms, Tac1-deficient mice were more active in the Porsolt's forced-swimming test and the tail-suspension test, and they did not become hyperactive after bulbectomy. Tac1 mutant mice were also less fearful in several animal models of anxiety. They were more active and less affected by the light conditions in the central area of the open-field arena; they showed more social interactions in an aversive environment, they were more active in the open areas of an elevated zero-maze, and they had a reduced latency to feed in the Thatcher-Britton conflict paradigm. These results demonstrate that tachykinins are powerful mediators of depression-like or anxiety-related behaviors in mice. The tachykinin system therefore may play an important role in the regulation of emotional states and the development of anxiety disorders and depression.

Fig. 1.

Behavior ofTac1^+/+ andTac1^−/−male mice in behavioral despair models of depression. A, Forced-swimming test. **p < 0.01; ***p < 0.001 (one-way ANOVA followed by Dunnett's test). B, Tail-suspension test. **p< 0.01 (Student's unpaired t test). Each error bar represents the mean time spent in immobility (±SEM) of 10 animals.

Fig. 2.

Horizontal (distance traveled) and vertical (number of rearings) motor activity of sham-operated and bulbectomizedTac1^+/+ andTac1^−/− mice in the open-field apparatus. Each value represents the distance traveled or number of rearings (mean ± SEM; n = 10–11). **p < 0.01; ***p < 0.001 according to two-way ANOVA (surgery × genotype) followed by SNK test.

Fig. 3.

Locomotor activity ofTac1^+/+ andTac1^−/− mice in the open-field apparatus.A, Total horizontal activity. B, Activity in the central part. Each value represents the mean distance traveled (±SEM) of 10 animals. **p < 0.01; ***p < 0.001 according to two-way ANOVA (genotype × illumination) followed by SNK test.

Fig. 4.

Activity of Tac1^+/+control, reference compound-treated, andTac1^−/− knock-out mice in zero-maze test. Error bars represent mean distance traveled in the open part (A) and number of stretching postures (B) (± SEM) of 10 animals. **p < 0.01; ***p < 0.001 (one-way ANOVA followed by Dunnett's test).

Fig. 5.

A, Thatcher-Britton novelty conflict paradigm. Error bars represent mean latency time until eating in the center of the lit open arena (±SEM) of 10 animals.B, Social interaction test. Each columnrepresents time spent with social activity in unfamiliar and aversive (high light) environment (±SEM) of 10 animals. *p≤ 0.05; **p ≤ 0.01 (Student's unpairedt test).