The 5-HT3 receptor antagonists ICS 205-930 and GR38032F, putative anxiolytic drugs, differ from diazepam in their...

The pharmacological profile of the two 5-HT(3) (5-hydroxytryptamine) receptor antagonists, the putative anxiolytics ICS 205-930 and GR38032F was compared with that of diazepam in four standard behavioural tests in rats. All the investigated drugs induced an anxiolytic effect in the passive avoidance test, having reduced the latency to re-enter the chamber previously associated with an inescapable footshock, and increased the time spent in that chamber. On the basis of the lowest effective dose, both ICS 205-930 and GR38032F were about 20 times more potent than diazepam, though the anxiolytic activity of either 5- HT(3) receptor antagonist was confined to a narrow dose range (ICS 205-930: 93.7-187.5 μg/ kg, GR38032F: 125-375 μg/kg), their higher doses having been ineffective. The anxiolytic effect of diazepam, but not of ICS 205-930, was abolished by flumazenil. In contrast to diazepam, neither ICS 205-930 nor GR38032F-both given in doses up to 20 mg/kg-showed any activity in the pentylenetetrazol-induced seizures, open field, and rota-rod tests. These results suggest that the 5-HT(3) receptor antagonists may represent a new class of anxiolytic drugs devoid of anticonvulsant, sedative or muscle-relaxant properties, and that their anxi olytic activity is not mediated by benzodiazepine receptors.