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.
Griebel
Guy
G
Sanofi-Synthelabo Recherche, Bagneux, France. guy.griebel@sanofi-synthelabo.com
Simiand
Jacques
J
Stemmelin
Jeanne
J
Gal
Claudine Serradeil-Le
CS
Steinberg
Régis
R
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D065092:Antidiuretic Hormone Receptor Antagonists; D001008:Anxiety Disorders / Q000188:drug therapy / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000639:trends; D005544:Forecasting; D005849:Gerbillinae; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017483:Receptors, Vasopressin / Q000187:drug effects*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology
C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; D017483:Receptors, Vasopressin