Comparative effects of novel 5-HT1A receptor ligands, LY293284, LY315712 and LY297996, on plus-maze anxiety in mice

In contrast to the variable efficacy of 5-HT1A receptor full and partial agonists in animal models of anxiety, recent findings in our laboratory have revealed remarkably consistent anxiolytic-like effects for 5-HT1A receptor antagonists in the murine elevated plus-maze paradigm. In the present study, ethological techniques were used directly to compare the plus-maze profiles of three novel ligands varying in intrinsic efficacy at 5-HT1A receptors: LY293284 (full agonist; 0.01-0.3 mg/kg), LY315712 (partial agonist; 0.3-3.0 mg/kg); and LY297996 (antagonist; 0.03-10.0 mg/kg). At the lowest dose tested, LY293284 tended to enhance several indices of anxiety, whereas higher doses suppressed all active behaviours. Although few behavioural effects were observed with LY315712 under present test conditions, a selective reduction in risk assessment was apparent at 1.0-3.0 mg/kg. In contrast to these profiles, LY297996 (3.0-10.0 mg/kg) produced robust anxiolytic-like effects on conventional and ethological parameters but, importantly, did not alter general activity levels. These results provide further support for the anxiolytic potential of 5-HT1A receptor antagonists and are discussed in relation to possible factors underlying inter-laboratory variation in the effects of these agents in animal models of anxiety.