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

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 com pare the effects of a 5-HT1B 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-HT1B 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-HT1B (GR 127935; 10 mg/kg, IP) and the 5-HT1A receptor (WAY 100,635; 0.1 mg/kg IP) were used. Results: CP-94,253 suppressed non-heightened aggressive behavior (ED50=7.2 mg/kg). GR 127935, but not WAY 100,635 shifted the ED50 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 (ED50=3.8 and 3.7 mg/kg, respectively). Conclusions: The current results support the hypothesis that activation of 5-HT1B receptors modulates very high levels of aggressive behavior in a pharmacologically and behaviorally specific manner.