5-HT3 receptor ligands lack discriminative stimulus properties

The putative discriminative stimulus of the 5-HT3 receptor antagonists ondansetron and (DL)-11-[(2-methyl-1H-imidazol-1-yl)methyl]-4,5,6,7,10,11,12-octahydroazepinol[3,2,1-jk]-carbazol-12-one hydrochloride (DU122932), and of the 5-HT3 receptor agonists 2-methyl-5-HT and 3,4-dichlorophenylbiguanide (3,4DCPB) were investigated in a standard two-lever, food-reinforced drug-saline discrimination procedure with groups of rats (N= 10 per group). In three groups of rats after 80 sessions with training doses ranging from 0.1 to 4.0 mg/kg po, stimulus control by ondansetron, DU122932 and 2-methyl-5-HT was still absent. The same 30 animals thereafter rapidly learned to discriminate chlordiazepoxide (CDP) from vehicle. In three other groups of rats, stimulus control by CDP was first established. Then, the vehicle was gradually (from 0.1 to 2.0 mg/kg po) replaced by either ondansetron, DU122932 or 2-methyl-5-HT. Finally, the dose of CDP was gradually decreased. In all three groups, stimulus control disappeared. A seventh group was trained to discriminate 3,4DCPB (5.0 mg/kg po) from saline. When training was not successful, dose and route were changed but discrimination was not attained. It is concluded that in the rat, using the classical two lever discrimination procedure, the 5-HT3 receptor ligands ondansetron, DU122932, 2-methyl-5-HT and 3,4DCPB are incapable of producing an internal state that can act as a stimulus to control responding.