5-HT1A agonists modulate mouse antipredator defensive behavior differently from the 5-HT2A antagonist pirenperone

The mouse defense test battery (MDTB) has been designed to investigate defensive reactions in Swiss-Webster mice to situations associated with a natural predator, the rat, such as flight, avoidance, defensive threat, defensive attack, and risk assessment activities. The present study evaluated the ability of 8-OH-DPAT (0.05-10 mg/kg, SC, 5) and gepirone (2.5-10 mg/kg, IP, 30), a full- and a partial agonist at 5-HT1A sites, as well as pirenperone (0.25-1 mg/kg, IP, 30), a preferential 5-HT2A receptor antagonist, to exert an anxiolytic-like action in the MDTB. The most consistent effect of both 5-HT1A receptor agonists across tests was a marked reduction in predator assessment activity and defensive attack behavior. In contrast, neither of the two ligands was able to reduce flight responses to the approaching predator, and both failed to reduce in a specific manner contextual defense behaviors after the predator was removed. The 5-HT2A receptor antagonist pirenperone did not provide significant indication of an anxiolytic effect on predator assessment activity and postpredator potentiation of contextual defense responses, and had negligible influence on antipredator defensive behavior. The most interesting exception to this profile was a dose-related reduction in flight-related measures. In view of previous results indicating that the panic-promoting drug yohimbine increases flight/escape reactions and that the panicolytic compound alprazolam reduces these responses, we tentatively suggest that the preferential 5-HT2A receptor antagonist pirenperone may have some efficacy in improving panic attacks. In addition, the lack of effect of the 5-HT1A receptor agonists on these flight responses is consistent with clinical findings indicating that these agents are of limited use in the treatment of panic disorder. These findings suggest that the MDTB provides behavioural measures capable of differentiating between various classes of antianxiety drugs.