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Vol. 301, Issue 1, 333-345, April 2002
Central Nervous System Research Department, Sanofi-Synthelabo,
Bagneux, France (G.G., B.S., P.R.); Exploratory Research Department,
Sanofi-Synthelabo, Toulouse, France (D.G., M.G., J.S.); and Discovery
Research Division, Sanofi-Synthelabo, Montpellier, France (R.S., M.J.,
P.S., J.P.M.)
The present study investigated the effects of the novel
corticotrophin-releasing factor (CRF)1 receptor
antagonist
4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on
stress-induced changes in physiological (isolation-induced
hyperthermia and tail pinch-induced cortical norepinephrine release) or
behavioral (social defeat-induced anxiety, maternal separation-induced
vocalization) parameters. Moreover, the effects of SSR125543A were
investigated in acute (forced swimming) and chronic (chronic mild
stress; CMS) models of depression. SSR125543A and the CRF1
receptor antagonist antalarmin displayed limited efficacy in
exploration-based anxiety models. In contrast, both compounds produced
clear-cut anxiolytic-like activity in models involving inescapable
stress, including the conflict procedures, the social defeat-induced
anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or
p.o.). These effects paralleled those of the anxiolytic diazepam. In
addition, SSR125543A and antalarmin antagonized stress-induced
hyperthermia, distress vocalization, and cortical norepinephrine
release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to
30 mg/kg p.o. antalarmin produced clear antidepressant-like
effects. These latter results were strengthened by the findings from
the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state,
the reduction of body weight gain, and anxiety produced by stress.
Together, these data indicate that SSR125543A shows good activity in
acute and chronic tests of unavoidable stress exposure, suggesting that
it may have a potential in the treatment of depression and some forms
of anxiety disorders.
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