Antidepressant-like effects of the corticotropin-releasing factor 1 receptor antagonist, SSR125543, and the vasopressin 1b receptor antagonist, SSR149415, in a DRL-72 s schedule in the rat.
The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animal models. Presently, SSR149415 and SSR125543 were evaluated in a differential reinforcement of low-rate 72 s (DRL-72 s) schedule, a procedure known to respond differentially to antidepressants and anxiolytics. Male Wistar rats were trained to lever-press for food reinforcement, but only lever-presses occurring after a 72 s delay were reinforced; otherwise, presses were not rewarded, and the timer was reset to 0 s. The selective serotonin reuptake inhibitor, fluoxetine, and the benzodiazepine anxiolytic, diazepam, were tested in parallel. SSR149415 (10-30 mg/kg, i.p.) and SSR125543 (30 mg/kg, i.p.) increased the percentage of responses emitted in the inter-response time (IRT) bin (49-96 s), which resulted in a greater number of reinforced presses. Both compounds shifted the frequency distribution of responses toward longer IRT durations, with a preservation of the bell shape of the IRT distribution curve. Fluoxetine (10 mg/kg, i.p.) had an effect on DRL-72 s similar to that of SSR149415 and SSR125543. By contrast, diazepam increased the number of responses in IRT bin (0-12 s), and the IRT distribution curve was shifted toward shorter IRT durations and flattened. In summary, these results show that SSR149415 and SSR125543 displayed antidepressant-like activity in a DRL-72 s schedule in rat, confirming their therapeutic potential for the treatment of pathological states induced by chronic frustration such as depression.
Louis
Caroline
C
CNS Research Department, Sanofi-Aventis, Bagneux, France. caroline.louis@sanofi-aventis.com
Cohen
Caroline
C
Depoortère
Ronan
R
Griebel
Guy
G
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D065092:Antidiuretic Hormone Receptor Antagonists; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013843:Thiazines / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D003975:Diazepam; D005473:Fluoxetine; D006846:Hydrocarbons, Halogenated; D007211:Indoles; D011759:Pyrrolidines; D018019:Receptors, Corticotropin-Releasing Hormone; D017367:Selective Serotonin Reuptake Inhibitors; D013843:Thiazines; D000099052:CRF Receptor, Type 1; 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; C502407:SSR125543