COMPARISON OF POTENCIES OF 5-HT3 RECEPTOR ANTAGONISTS AT INHIBITING AVERSIVE BEHAVIOR TO ILLUMINATION AND THE VON BEZOLD-JARISCH REFLEX IN THE MOUSE

The inhibitory effects of ondansetron and R and S zacopride on aversive behavior to light and the von Bezold-Jarisch reflex have been compared in mouse. The potencies (ID50, mu g/kg i.v.) of compounds at inhibiting the von Bezold-Jarisch reflex, elicited by 2-methyl-5-HT (mouse 100 mu g/kg, i.v.; rat 10-80 mu g/kg i.v.) were: S zacopride (0.02), granisetron (0.17), R zacopride (0:30) ondansetron (3.16). A similar rank order of ID50 values was observed in rat, i.e. S zacopride (0.02), granisetron (0.36), R zacopride (0.25) and ondansetron (2.65). These data suggest that the activity of compounds at 5-HT3 receptors mediating this effect was similar in both mouse and rat. In mouse behavioral studies, ondansetron and R and S zacopride potently inhibited aversive behavior to light (0.0003-30 mu g/kg, p.o.), when the amount of time spent in the dark and locomotor activity were measured. Thus, at 0.3 ng/kg, the mean percentage time spent in the dark significantly decreased from 84 to 72, for both R and S zacopride, respectively. The maximal effects of these compounds were modest in comparison to the 'anxiolytic' effects of diazepam (0.3-1.4 mg/kg, i.p.; at 0.3 mg/kg the mean percentage time spent in the dark significantly decreased from 84 to 36) or chlordiazepoxide (3-40 mg/kg, i.p.; at 3 mg/kg, the mean percentage time spent in the dark significantly decreased from 85 to 40). The doses of the 5-HT3 antagonists were approx 1000-foId lower than those effective inhibitory doses determined in the von Bezold-Jarisch reflex studies, in either mouse or rat. R and S zacopride did not exhibit stereospecificity in the behavioral studies, compared with a 10-fold higher potency of the S over the R isomer in the von Bezold-Jarisch studies. It is concluded that, in mouse, 5-HT3 receptor antagonists exhibited differential potencies at inhibiting the von Bezold-Jarisch reflex and aversive behavior to light. These findings were inconsistent with an interaction at a single, homogeneous population of 5-HT3 receptors. The definitive mechanism by which 'anxiolytic' effects are induced in mouse, by 5-HT3 receptor antagonists, thus remains to be established.