We examined the effects of chronic in vivo antipsychotic drug treatments on G protein function and regulation. Mice were treated with typical antipsychotic haloperidol (6 mg/kg per day) and atypical agent olanzapine (20 mg/kg per day) for 14 days via mini-osmotic pumps. G protein-activated adenylyl cyclase activity in brain tissues was measured in the presence of guanine nucleotide analogue guanosine-5'-O(3-thiotriphosphate) tetralithium salt, or GTPgammaS. In frontal cortex, haloperidol treatment produced 21% increases in the GTPgammaS -mediated adenylyl cyclase Emax value (vs. vehicle controls) while olanzapine produced 20% reductions in this value (vs. controls); these effects were significant. In striatum, olanzapine treatment produced significant 31 and 27% decreases in Emax values compared with vehicle and haloperidol treatment, respectively. Chronic haloperidol treatment produced significant 24% reductions in the immunoreactivity of cortical, but not striatal, Gialpha1,2 subunits. There were no effects of chronic olanzapine treatment on G(i)alpha1,2 levels and no effects of either antipsychotic on G(s)alpha, levels. Chronic haloperidol and olanzapine treatments differentially regulate G protein-mediated adenylyl cyclase responses in brain regions possibly relating to their unique effects on G protein-coupled receptors.