Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94,253

Abstract

Rationale Models of heightened aggression may be particularly relevant in exploring pharmacological options for the clinical treatment of aggressive and impulsive disorders. Objectives To investigate and compare the effects of a 5-HT(1B) selective agonist, CP-94,253, on aggression that was heightened as a result of 1) social instigation or 2) alcohol treatment. Methods Male CFW mice were administered 1.0 g/kg EtOH and were subsequently confronted by an intruder in their home cage. In a separate experimental procedure, resident male mice were instigated to aggressive behavior by brief exposure to a provocative stimulus male. To test the hypothesis that activation of the 5-HT(1B )receptor subtype would preferentially attenuate heightened aggression, in comparison to the moderate levels of species-typical aggressive behaviors, the selective agonist, CP-94,253 (1.0-30 mg/kg, IP), and antagonists to the 5-HT(1B) (GR 127935; 10 mg/kg, IP) and the 5-HT(1A) receptor (WAY 100,635; 0.1 mg/kg IP) were used. Results CP-94,253 suppressed non-heightened aggressive behavior (ED(50)=7.2 mg/kg ). GR 127935, but not WAY 100,635 shifted the ED(50) for CP-94,253 to 14.5 mg/kg. Importantly, the anti-aggressive effects of CP-94,253 were not accompanied by locomotor sedation. Alcohol-heightened and instigation-heightened aggression were suppressed at lower doses than those necessary to suppress non-heightened aggression (ED(50)=3. 8 and 2.7 mg/kg, respectively). Conclusions The current results support the hypothesis that activation of 5-HT(1B) receptors modulates very high levels of aggressive behavior in a pharmacologically and behaviorally specific manner.