Less stress?

A potential new approach to the development of anxiolytic and antidepressant drugs might emerge from results showing that an antagonist of the vasopressin V_1b receptor is effective in rodent models of both anxiety and depression. Griebel et al. tested the antagonist SSR149415 in a variety of rat and mouse models, and concluded that it shows both anxiolytic- and antidepressant-like properties.

Although arginine vasopressin (AVP) is produced in the hypothalamus and is involved in the regulation of the secretion of corticotropin by the pituitary gland, the presence of AVP-containing neurons that project to the limbic system, and of vasopressin receptors (V_1a and V_1b) in structures such as the septum and hippocampus, has led to the idea that AVP might also be important in emotional processes such as stress responses. In support of this, a mixed (V_1a/b) peptide vasopressin receptor antagonist has anxiolytic effects in rats, and stress resulting from chronic immobilization increases the levels of V_1b receptor messenger RNA. These results indicate a possible role for the V_1b receptor in emotional processes.

Now, the availability of a selective antagonist for the V_1b receptor has allowed Griebel et al. to test this idea. They used a battery of mouse and rat models of anxiety and depression to test the effects of SSR149415. In 'classical' models of anxiety, such as the elevated plus-maze and the light/dark test (which measures how long mice spend in a lit box as opposed to a dark one), the new compound was less effective than the benzodiazepine anxiolytic diazepam. But in models of exposure to traumatic stress, such as the social-defeat paradigm (in which a mouse is exposed to aggression from a resident mouse in a test cage, which normally increases anxiety as assessed in the elevated plus-maze), SSR149415 had clear anxiolytic effects. The authors suggest that V_1b receptor antagonists might be useful as a treatment for stress disorders that result from traumatic events, rather than for generalized anxiety disorder.

To test the antidepressant effects of SSR149415, Griebel and colleagues used two models of depression: the acute forced-swimming test, and the chronic mild-stress test (in which a mouse is exposed to a sequence of mildly stressful events, such as water deprivation and restraint, for several weeks, leading to a decline in grooming that is thought to parallel the reduction in personal hygiene in depressed humans). SSR149415 reduced all of the measures of 'depression' in these rodent models, which are normally good predictors of antidepressant efficacy in humans.

Although these results might be therapeutically useful, they do not tell us where in the brain SSR149415 acts to reduce anxiety or depression. However, the fact that it is still effective in hypophysectomized rats indicates that the effects do not depend on blocking the hypothalamic V_1b receptors, and supports the idea that the receptors in limbic structures are more important for these effects. Further studies using selective vasopressin receptor antagonists, perhaps targeted to specific regions such as the amygdala, septum or hippocampus, should help to clarify the role of AVP in anxiety and stress.