1192U90 IN ANIMAL TESTS THAT PREDICT ANTIPSYCHOTIC EFFICACY, ANXIOLYSIS, AND EXTRAPYRAMIDAL SIDE-EFFECTS

1192U90 was developed on the assumption that antagonism of 5-HT2 recep tors efficacy yields more potently than D-2 receptors against positive and negative symptoms of schizophrenia with minimal liability for ext rapyramidal side effects (EPSs), and that 5-HT1A agonism further reduc es EPSs and provides anxiolytic and antidepressant activity. 1192U90 w as submitted to four tests that predict antipsychotic efficacy (antago nism of apomorphine-induced climbing in mouse, antagonism of apomorphi ne-induced circling in rats with unilateral 6-OHDA lesions, antagonism of amphetamine-induced hyperlocomotion in rat, and inhibition of cond itioned avoidance in rat), two tests of 5-HT2 function (antagonism of 5-MeODMT-induced head twitches in mouse and antagonism of 5-HTP-induce d wet dog shakes in rat), and three tests that predict EPS liability ( antagonism of apomorphine-induced stereotypy in mouse and rat and indu ction of catalepsy in mouse). ED(50)s (mg/kg PO) were as follows: clim bing 10.1, circling 7.9, hyperlocomotion 6.6, and avoidance 5.7; head twitches 5 and wet dog shakes 4.6; stereotypy in mouse 91.1, stereotyp y in rat 133.4, and catalepsy 192.4. The ratio of ED(50) for stereotyp y antagonism to ED(50) for climbing antagonism was 9 (compared to 4, 3 , and 4 for clozapine, risperidone, and haloperidol). The ratio of ED( 50) for catalepsy induction to ED(50) for climbing antagonism was 19 ( compared to 7, 2, and 17 for clozapine, risperidone, and haloperidol). 1192U90 was also submitted to three tests that predict anxiolysis: It produced only a small increase in punished lever pressing for food in rat (Geller-Seifter conflict test), which is specific for rapid-onset efficacy, but produced large increases in punished key pecking for fo od in pigeon and cork gnawing in rat, which identify the delayed onset 5-HT1A agonists such as buspirone. The results suggest that 1192U90 w ould be effective for positive and negative symptoms of schizophrenia, with minimal liability for EPSs, and may also have anxiolytic propert ies.