Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders.
The limbic localization of the arginine vasopressin V(1b) receptor has prompted speculation as to a potential role of this receptor in the control of emotional processes. To investigate this possibility, we have studied the behavioral effects of SSR149415, the first selective and orally active non-peptide antagonist of vasopressin V(1b) receptors, in a variety of classical (punished drinking, elevated plus-maze, and light/dark tests) and atypical (fear/anxiety defense test battery and social defeat-induced anxiety) rodent models of anxiety, and in two models of depression [forced swimming and chronic mild stress (CMS)]. When tested in classical tests of anxiety, SSR149415 produced anxiolytic-like activity at doses that ranged from 1 to 30 mg/kg (i.p. or p.o.), but the magnitude of these effects was overall less than that of the benzodiazepine anxiolytic diazepam, which was used as a positive control. In contrast, SSR149415 produced clear-cut anxiolytic-like activity in models involving traumatic stress exposure, such as the social defeat paradigm and the defense test battery (1-30 mg/kg, p.o.). In the forced swimming test, SSR149415 (10-30 mg/kg, p.o.) produced antidepressant-like effects in both normal and hypophysectomized rats. Moreover, in the CMS model in mice, repeated administration of SSR149415 (10 and 30 mg/kg, i.p.) for 39 days improved the degradation of the physical state, anxiety, despair, and the loss of coping behavior produced by stress. These findings point to a role for vasopressin in the modulation of emotional processes via the V(1b) receptor, and suggest that its blockade may represent a novel avenue for the treatment of affective disorders.
Griebel
Guy
G
Sanofi-Synthelabo Recherche, Avenue P. V.-Couturier, 92220 Bagneux, France. guy.griebel@sanofi-synthelabo.com
Simiand
Jacques
J
Serradeil-Le Gal
Claudine
C
Wagnon
Jean
J
Pascal
Marc
M
Scatton
Bernard
B
Maffrand
Jean-Pierre
JP
Soubrie
Philippe
P
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D065092:Antidiuretic Hormone Receptor Antagonists; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy*; D005247:Feeding Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018570:Risk Assessment; D013312:Stress, Physiological; D013315:Stress, Psychological; D013997:Time Factors
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; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; D005473:Fluoxetine; D007099:Imipramine