ssr-125543a and Cognition-Disorders

The selective CRF1 (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus.. The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD.. Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study.. Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine.. These findings confirm that the CRF1 receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress.

Topics: Animals; Behavior, Animal; Cognition Disorders; Cycloserine; Electroshock; Hippocampus; Hydrocarbons, Halogenated; Male; Mice; Paroxetine; Receptors, Corticotropin-Releasing Hormone; Selective Serotonin Reuptake Inhibitors; Stress, Psychological; Thiazines; Time Factors

The selective antagonist at the CRF₁ receptor, SSR125543, has been shown to produce anxiolytic-like effects in a number of animal models. The aim of the present study was to verify whether these effects are mediated by an action on the hypothalamic pituitary adrenal (HPA) axis. SSR125543 effects were evaluated in a mouse model of post-traumatic stress disorder. Animals received two unavoidable electric foot-shocks (1.5 mA/2 s). Two weeks later they were placed in the shock context and fecal and plasma corticosterone levels were measured by enzyme-immunoassay. Their cognitive performances were evaluated using the object recognition task following administration of SSR125543 at 3, 10 and 30 mg/kg or paroxetine at 20 mg/kg (i.p.), used as positive control. To assess the involvement of the HPA axis in the drug effects, a separate group of animals was subjected to the same procedure and drug regimen, but was treated with dexamethasone to blunt the HPA axis. Stressed mice had higher levels of corticosterone following re-exposure to the context and displayed impaired cognitive performance as compared to control animals. Corticosterone levels were normalized in stressed mice by SSR125543 and the cognitive deficit was significantly attenuated by SSR125543 and paroxetine, whether the HPA axis was blunted or not. These findings confirm that SSR125543 is able to attenuate the deleterious effects of stressful exposure. Importantly, the observation that these effects were still present in dexamethasone-treated mice indicates that this action does not necessarily involve pituitary-adrenal axis blockade, thereby suggesting that extra-pituitary CRF₁ receptors may play a role in these effects.

Topics: Animals; Cognition Disorders; Corticosterone; Dexamethasone; Electroshock; Feces; Hydrocarbons, Halogenated; Hypothalamo-Hypophyseal System; Male; Mice; Paroxetine; Pituitary-Adrenal System; Receptors, Corticotropin-Releasing Hormone; Recognition, Psychology; Selective Serotonin Reuptake Inhibitors; Stress, Psychological; Thiazines

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 animals. In the present study, their effects on stress-induced deficit in cognitive performances as assessed in a modified object recognition test were investigated in mice. The object recognition task measures the ability of a mouse to remember an object it has previously explored in a learning trial. During this acquisition session, the mouse was stressed by the presence of a pair of rats under the grid floor of the apparatus. One hour later, it was placed again in the environment with the known and a novel object, but in the absence of the rats. While non-exposed mice spent more time exploring the new object, mice that had been exposed to the rats during acquisition failed to discriminate between the known and the new object during retrieval. This cognitive impairment in stressed mice was prevented by the administration of SSR149415 (10 mg/kg, ip), SSR125543 (10 mg/kg, ip) and the selective serotonin reuptake inhibitor, fluoxetine (10 mg/kg, ip). Under similar conditions, the cognitive enhancer donepezil (1 mg/kg, ip) failed to reverse object recognition deficit. These results indicate that the effects of SSR149415 and SSR125543 in the modified object recognition test, in stressed mice, involve the ability of mice to cope with stress rather than an effect on cognition per se. Together, these data suggest that SSR149415 and SSR125543 may be of interest to reduce the cognitive deficits following exposure to stress-related events, such as acute stress disorder.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Cognition Disorders; Hydrocarbons, Halogenated; Indoles; Male; Mice; Pyrrolidines; Rats; Receptors, Corticotropin-Releasing Hormone; Stress, Psychological; Thiazines