Behavioural profiles in the mouse defence test battery suggest anxiolytic potential of 5-HT1A receptor antagonists

Rationale: Compounds varying in selectivity as 5-HT1A receptor antagonists have recently been reported to produce anxiolytic-like effects comparable t o those of benzodiazepines in the mouse elevated plus-maze procedure. Objec tive: In view of the potential clinical significance of these findings, the present experiments compared the behavioural effects of diazepam (0.5-3.0 mg/kg) with those of several non-selective 5-HT1A receptor antagonists [NAN -190, 0.1-3.0 mg/kg, MM-77, 0.03-1.0 mg/kg, (S)-UH-301, 0.3-3.0 mg/kg and p indobind-5-HT1A, 0.03-1.0 mg/kg], and three selective 5-HT1A receptor antag onists (WAY100635, 0.01-3.0 mg/kg, p-MPPI, 0.1-3.0 mg/kg and SL88.0338, 0.3 -3.0 mg/kg) in the mouse defence test battery (MDTB). Methods: In this well -validated anxiolytic screening test, Swiss mice are directly confronted wi th a natural threat (a rat) as well as situations associated with this thre at. Primary measures taken during and after rat confrontation were flight, risk assessment (RA), defensive threat/attack and escape attempts. Results: Diazepam significantly decreased flight reactions after the rat was introd uced into the runway, reduced RA activities of mice chased by the rat, incr eased RA responses displayed when subjects were constrained in a straight a lley and reduced defensive upright postures and biting upon forced contact. All the selective 5-HT1A receptor antagonists and NAN-190 also reduced fli ght, RA in the chase test, and defensive threat and attack behaviours. (S)- UH-301 and pindobind-5-HT1A reduced RA in the chase test, but only partiall y modified defensive threat and attack. Unlike the other drugs tested, MM-7 7 produced significant effects only at doses which also markedly reduced sp ontaneous locomotor activity, suggesting a behaviourally non-specific actio n. In contrast to diazepam, the 5-HT1A receptor ligands failed to affect RA in the straight alley test. Following removal of the rat from the test are a, only diazepam and (S)-UH-301 reduced escape behaviour (contextual defenc e) at doses which did not decrease locomotion. Overall, the present finding s indicate that except for one RA behaviour and escape responses, the 5-HT1 A receptor ligands studied modified the same defensive behaviours as diazep am, suggesting potential therapeutic efficacy in the management of anxiety disorders. However, the magnitude of the effects of the 5-HT1A compounds on defence was generally smaller than that of the benzodiazepine. Conclusion: As all of the 5-HT1A compounds tested in this series share antagonistic ac tivity in models of postsynaptic 5-HT1A receptor function, it is proposed t hat this action accounts for their effects on defence.