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

Abstract.

Rationale: It has been suggested that tachykinin NK₂ receptor antagonists may have therapeutic utility in anxiety and/or depressive disorders. Objective: The present study investigated the modulatory action of the NK₂ receptor antagonist SR48968 on emotional processes in rodents. Methods: The tests used include classical models of anxiety (punished lever pressing and punished drinking conflict tests, elevated plus-maze in rats), a model based on defensive behaviors of mice confronted with a natural threat (a rat), and two tests based on exposure of rats or mice to a natural predator (a cat) followed by subsequent exposure to a cat odor cue. The prototypical anxiolytic diazepam was used throughout as a positive control, the antidepressant imipramine 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, SR48968 failed to increase rates of responding suppressed by punishment in both conflict procedures. By contrast, in the elevated plus-maze test, the NK₂ receptor antagonist (3 mg/kg, IP) elicited positive effects on traditional and ethologically derived measures of anxiety. In the mouse defense test battery, 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 effective as the BZ on defensive biting. In rats previously exposed to a cat, SR48968 (3 mg/kg, IP), antalarmin (1 mg/kg, IP), imipramine (30 mg/kg, IP), but not diazepam, reduced subsequent high levels of avoidance responses when subjects are exposed to a cat odor-saturated cue 1 h later. Similar effects of SR48968 (0.1–0.3 mg/kg, IP) were observed in mice following repeated administration (twice a day/5 days/IP). Importantly, the positive effects of the NK₂ receptor antagonist were evident at doses that did not impair general activity, unlike imipramine which displayed mainly sedative action. Moreover, the (R)-enantiomer of SR48968, SR48965, which was tested in the elevated 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 shows good activity in reducing anxiety-like behaviors following traumatic stress or upon forced and unavoidable contact with a threatening stimulus. This suggests that NK₂ receptor antagonists may have a potential in the treatment of some forms of anxiety disorders.