Dysregulation of the endocannabinoid and dopamine systems has been implicated in schizophrenia. The purpose of this study was to examine the effects of sub-chronic treatment with two antipsychotics on CB 1 receptor-mediated in vitro and in vivo effects. Adult and adolescent male and female rats were injected twice daily with haloperidol (0.3mg/kg), clozapine (10mg/kg), or saline for 10 days. Subsequently, CB 1 receptor number and function were assessed by [ 3 H]SR141716 and WIN55,212-2-stimulated [ 35 S]GTPγS binding, respectively. The effects of sub-chronic antipsychotic treatment on the in vivo actions of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) were also evaluated. In adult female rats, antipsychotic treatment attenuated maximal stimulation of CB 1 receptor-mediated G-protein activity in the striatum (clozapine) and prefrontal cortex (both antipsychotics), but not in the ventral midbrain. Associated changes in CB 1 receptor number were not observed, suggesting that this attenuation was not due to downregulation. In vivo, sub-chronic treatment with clozapine, but not haloperidol, attenuated Δ 9 -THC-induced suppression of activity in adult females, whereas neither drug altered hypothermia or catalepsy. In contrast, antipsychotic treatment did not change CB 1 receptor-mediated G-protein activation in any brain region in adult male rats and in adolescents of either sex. In vivo, haloperidol, but not clozapine, enhanced Δ 9 -THC-mediated suppression of activity and hypothermia in adult male rats whereas neither antipsychotic affected Δ 9 -THC-induced in vivo effects in adolescent rats. These findings suggest that modulation of the endocannabinoid system might contribute in a sex- and age-selective manner to differences in motor side effects of clozapine versus haloperidol.