Non-peptide vasopressin V1b receptor antagonists as potential drugs for the treatment of stress-related disorders.

Since vasopressin has been shown to be critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active non-peptide V(1b) receptor antagonist, SSR149415, opened a new era for examining the role of vasopressin in animal models of anxiety and depression. In rats, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. hyperthermia) responses following various stress exposures. Moreover, the drug was able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. These latter were highly effective and reliably produced robust effects in most anxiety tests, while SSR149415 showed clear-cut effects only in particularly stressful situations. Experiments with mice or hamsters indicated that V(1b) receptor blockade is associated with reduced aggressiveness, suggesting that SSR149415 could prove useful for treating aggressive behavior. It is important to note that SSR149415 is devoid of adverse effects on motor functions or cognitive processes, and it did not produce tolerance to its anxiolytic- or antidepressant-like activity. Altogether, these findings suggest that V(1b) receptor antagonists represent a promising alternative to agents currently used for the treatment of depression and some forms of anxiety disorders.

The vasopressin V1b receptor as a therapeutic target in stress-related disorders.

The complexity of the stress response would appear to provide multiple opportunities for intervention, but treatment strategies are often centered on the improvement of symptoms rather than attempting to "treat" the stress response. However, recent efforts have begun to focus on the development of pharmacological agents that can attenuate the stress response itself, rather than the symptoms associated with stress. Although CRF, which is the main regulator of the stress system, is the focus of current interest, there is an accumulating body of evidence suggesting that the vasopressinergic system may play an equal role in the regulation of the stress response, and that V(1b) receptor antagonists may be of potential therapeutic benefit. The availability of SSR149415, the first selective antagonist for the V(1b) receptor has allowed us to evaluate this hypothesis. SSR149415 is able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. The latter were active in a wide range of anxiety models, whereas the V(1b) receptor antagonist showed clear-cut effects only in particularly stressful situations. It is important to note that SSR149415 is devoid of central depressant effects, even at high doses, and does not affect cognitive processes, suggesting a large therapeutic window. Altogether, these findings suggest that V(1b) receptor antagonists might be useful as a treatment for major depression and stress disorders that result from traumatic events.