Species differences in the mechanism through which the serotonergic agonists indorenate and ipsapirone produce their anxiolytic action

The effect of three anxiolytic drugs, indorenate, ipsapirone and diazepam, on the burying behaviour of rats and mice was studied. All three drugs induced a reduction in burying behaviour interpreted as a reduction in anxiety. However, a species difference in the diazepam sensitivity was found: rats showed a clear effect after 1.0 mg/kg while already at 0.25 mg/kg an action was observed in mice. The serotonergic anxiolytics produced similar responses at similar doses (2.5-5.0 mg/kg) in both species. The serotonergic antagonists, pindolol (3.1 mg/kg), alprenolol (5.0 mg/kg) and methiotepin (0.31 mg/kg), induced a slight reduction in the time spent burying but effectively counteracted the anxiolytic action of the serotonergic agonists in mice but not in rats. By contrast, in rats, the beta blocker, practolol (0.5 mg/kg), was the only drug effective in preventing the anxiolytic actions of ipsapirone. The combined treatment of indorenate and methiotepin resulted in an impairment of motor coordination and ambulatory behaviour in both species studied, thereby suggesting that the lack of effect of such combination was mediated by altering the motor behaviour. Finally, the reduction in ambulatory behaviour in mice produced by ipsapirone was effectively prevented by the antagonists methiotepin, pindolol and alprenolol indicating the involvement of a serotonergic receptor in this effect. From these results it is concluded that a different mechanism underlies the anxiolytic actions of indorenate and ipsapirone in mice and rats.