Abstract

Olanzapine (LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine) is a novel "atypical" antipsychotic agent with 5-hydroxytryptamine2.dopamine D1/D2 antagonist activity and anticholinergic properties. In behavioral studies, olanzapine (1.25-10 mg/kg, p.o.) antagonizes apomorphine-induced climbing behavior in mice, demonstrating that the compound possesses D1/D2 antagonist activity in vivo. Olanzapine (0.3-20 mg/kg, p.o.) antagonizes 5-hydroxytryptophan-induced head twitches in mice at doses much lower than those required to block the climbing response, confirming that in vivo, the compound is a more potent 5-hydroxytryptamine2 antagonist than dopamine antagonist. Olanzapine (2.5-10 mg/kg, p.o.) also antagonized oxotremorine-induced tremor in mice. In a conditioned avoidance paradigm in rats, olanzapine inhibits the avoidance response with an ED50 of 4.7 mg/kg p.o; however, unlike other antipsychotic agents, catalepsy is only observed at much higher doses (ED50 39.4 mg/kg, p.o.). These data would suggest that the compound will be less likely to produce undesirable extrapyramidal symptoms. Unlike "typical" antipsychotics, olanzapine (1.25-5 mg/kg p.o.) increases responding during the conflict component of a modified Geller Seifter test, demonstrating that the compound may also possess anxiolytic activity. In another series of experiments, olanzapine (1.25 mg/kg, i.p.) produced clozapine-appropriate responding in a drug discrimination model in which animals had been trained to discriminate clozapine (5 mg/kg, i.p.) from vehicle. On the basis of these results, it would therefore be predicted that olanzapine will have an atypical profile and will be less likely to induce undesirable extrapyramidal symptoms than currently available drugs.