The neurokinin NK2 antagonist, saredutant, ameliorates stress-induced conditions without impairing cognition

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2011-05, Vol.98 (3), p.405-411
• Main Authors: Rogacki, Nancy, Lopez-Grancha, Matilde, Naimoli, Vanessa, Potestio, Lisa, Stevens, Rachel J., Pichat, Philippe, Bergis, Olivier E., Cohen, Caroline, Varty, Geoffrey B., Griebel, Guy
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - pharmacology; Anxiety; Benzamides - pharmacology; Benzodiazepine; Biological and medical sciences; Cognition - drug effects; Learning; Male; Medical sciences; Memory; Mice; Mice, Inbred C57BL; Mouse; Piperidines - pharmacology; Rats; Rats, Wistar; Receptors, Neurokinin-2 - antagonists & inhibitors; Stress, Physiological - drug effects; Tachykinin
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2010.11.017

The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3–30mg/kg, per os, p.o.) was tested for anxiolytic-like potential in three mouse models: holeboard, stress-induced hyperthermia (SIH) and four-plate. In the holeboard model saredutant (30mg/kg) showed a trend to increase head dipping without affecting general activity. In the SIH model, saredutant demonstrated a significant reduction in stress-induced temperature at 30mg/kg, while the number of punished crossings in the four-plate was increased at all doses tested (3–30mg/kg). While chlordiazepoxide (CDP) demonstrated anxiolytic-like effects in these models, the adverse side effects of benzodiazepines, such as sedation, disinhibition and cognitive deficits are well-documented. Saredutant produced no detrimental effect in three models of cognition: Morris Water Maze (MWM) in rats, spontaneous alternation in a Y-maze in mice and novel objection recognition in mice. In contrast, the benzodiazepine, diazepam (DZM), produced cognitive impairments. NK2 receptor antagonists like saredutant may therefore yield beneficial effects for mood disorders without the adverse effects of current treatments. ► The NK2 antagonist saredutant is anxiolytic in animal models of anxiety. ► This is the first report of an NK2 antagonist's lack of effect on models of cognition. ► The NK2 antagonist saredutant may ameliorate anxiety without disrupting cognition.