Behavior of Tac1 and NK1R Knockout Mice in Models of Depression

The stress-related behavior of tac1~'~ mice derived from these homozygous animals on a congenic C57BL/6J genetic background was analyzed in models of depression and anxiety (Bilkei-Gorzo et al. 2002). Based on the clinical association of depressive episodes and stressful life events, many of the animal models for the evaluation of antidepressant drug activity assess stress-precipitated be haviors. The two most widely employed animal models for antidepressant drug screening are the behavioral despair models of depression, such as the forced-swim (Porsolt 1997; Porsolt et al. 1977b) and tail-suspension tests (Steru et al. 1985). These models are based on the observation that rodents, when forced into an aversive situation from which they cannot escape, will rapidly cease attempts to escape and become immobile. Although the relationship between immobility and depression remains controversial (Gardier and Bourin 2001), drugs with antidepressant activity generally reduce the time in which the animals remain immobile (Borsini and Meli 1988; Porsolt et al. 1977a). Both the forced-swimming test and the tail-suspension test are conceptually similar, but they seem to be controlled by different sets of genes. A recent quantitative trait loci (QTL) study has identified several genetic links to the propensity of behavioral despair using the same assays (Yoshikawa et al. 2002). Unexpectedly, only a small number of QTLs was shared, and one common QTL on chromosome 8 displayed opposite effects in the two tests. Thus, although the test paradigms appear to be similar, distinct genetic pathways may underlie the despair-like behaviors in these tests. This idea is supported by the common observation that the efficacies of antidepressant drugs are different in the forced-swimming and the tail-suspension tests.

In the forced-swimming test, active escape periods alternated with periods in which the animals were completely inactive, or made only the movements necessary to keep their head above water. Tac1-/- mice were more active in this test than tac1+l+ animals; they spent less time in immobility. These animals behaved like wildtype animals treated with antidepressant drugs, including the tricyclic uptake inhibitors imipramine and amitriptyline, or the selective serotonin reuptake inhibitor fluoxetine. In the tail suspension test, the immobility time in tac1~'~ mice was also significantly reduced. A significantly decreased immobility time in the forced-swimming test was also observed in mouse strains with genetic deletion of monoamine oxidase A (MAO A) (Cases et al. 1995) or MAO B (Grimsby et al. 1997). Both MAO A and MAO B are key enzymes of the degradation of catecholamines. Pharmacological blockade of these enzymes is used clinically for the treatment of depression. Tac1-/- mice were also tested in another model of depression-related behavior, in the bulbectomy-induced hyperactivity test. The bulbectomy test is fundamentally different from the forced-swim or tail-suspension tests. It does not involve the concept of behavioral despair, but is rather based on the observation that bulbectomy will induce behavioral and neuroendocrinal changes similar to those observed in depressive patients, which can be reversed with antidepressant treatment (Jesberger and Richardson 1988). In rodents bulbectomy induces a hypermotility, which can be reversed by chronic antidepressant treatment (Otmakhova et al. 1992). Tac1-/- animals did not show any bulbectomy-induced hyperactivity, and they also behaved like animals treated with antidepressant in this test.

NK1R~'~ mice also exhibited a reduced proneness to depression in the forced-swimming and tail suspension tests (Rupniak et al. 2001). Also, the selective NK1 receptor antagonist GR205171, as well as the serotonin reuptake inhibitor fluoxetine, was active in the forced-swimming test, proving that either acute pharmacological or life-long genetic blockade of NK1 receptor function has a similar effect as antidepressant treatment. On the other hand, pharmacological blockage of NK1 receptors with GR205171 failed to influence the activity of animals in the tail-suspension test. The authors concluded that in this model the increased activity of NK1R~'~ mice is not related directly to the null mutation (Rupniak et al. 2001). Rather, desensitization of the presynaptic 5-HT1A receptors, which was observed in this strain (Santarelli et al. 2001), might be responsible for the altered behavior of NK1R knockouts in this model.

The results with tad~'~ and NK1R~'~ mice in these models of depression strongly support the idea that the tachykinin system is involved in the patho-physiology of depression.

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