Effects of SR48968, a selective non-peptide NK2 receptor antagonist on emotional processes in rodents

Rationale: It has been suggested that tachykinin NK2 receptor antagonists m ay have therapeutic utility in anxiety and/or depressive disorders. Objecti ve: The present study investigated the modulatory action of the NK2 recepto r antagonist SR48968 on emotional processes in rodents. Methods: The tests used include classical models of anxiety (punished lever pressing and punis hed drinking conflict tests, elevated plus-maze in rats), a model based on defensive behaviors of mice confronted with a natural threat (a rat), and t wo tests based on exposure of rats or mice to a natural predator (a cat) fo llowed by subsequent exposure to a cat odor cue. The prototypical anxiolyti c diazepam was used throughout as a positive control, the antidepressant im ipramine was tested in the mouse defense test battery and in both models of predatory exposure, and the selective CRF1 receptor antagonist antalarmin was used in the cat-exposure test in rats. Results: Unlike diazepam, SR4896 8 failed to increase rates of responding suppressed by punishment in both c onflict procedures. By contrast, in the elevated plus-maze test, the NK2 re ceptor antagonist (3 mg/kg, IP) elicited positive effects on traditional an d ethologically derived measures of anxiety. In the mouse defense test batt ery, SR48968 (0.03-1 mg/kg, IP) decreased flight reactions, risk assessment behavior, defensive biting and escape attempts. While the magnitude of the effects on flight, risk assessment and escape attempts of the NK2 receptor antagonist was less than that of diazepam, SR48968 appeared to be as effec tive as the BZ on defensive biting. In rats previously exposed to a cat, SR 48968 (3 mg/kg, IP), antalarmin (1 mg/kg, IP), imipramine (30 mg/kg, IP), b ut not diazepam, reduced subsequent high levels of avoidance responses when subjects are exposed to a cat odor-saturated cue 1 h later. Similar effect s of SR48968 (0.1-0.3 mg/kg, IP) were observed in mice following repeated a dministration (twice a day/5 days/IP). Importantly, the positive effects of the NK2 receptor antagonist were evident at doses that did not impair gene ral activity, unlike imipramine which displayed mainly sedative action. Mor eover, the (R)-enantiomer of SR48968, SR48965, which was tested in the elev ated plus-maze, the mouse defense test battery and the cat exposure tests, was much less active than its racemate, indicating a stereoselective action of SR48968. Conclusion: These data show that while SR48968 has limited or no efficacy in models or behavioral measures mainly sensitive to BZs, it sh ows good activity in reducing anxiety-like behaviors following traumatic st ress or upon forced and unavoidable contact with a threatening stimulus. Th is suggests that NK2 receptor antagonists may have a potential in the treat ment of some forms of anxiety disorders.