The effects of in utero exposure to cocaine on dopamine receptors in the frontal and cingulate areas of the developing rabbit cortex were assessed by examining receptor-mediated stimulations in GTP binding to alpha-subunits of G proteins. Pregnant Dutch-belted rabbits received intravenous injections of 4 mg/kg of cocaine HCl twice a day on gestational days 8-29, cortical membranes were prepared from their progenies on postnatal days 10-100 and dopamine-stimulated [35S] guanosine-5'-[gamma-thio]triphosphate (GTP gamma S) binding to membrane G alpha proteins was measured. Dopamine increased [35S]GTP gamma S binding to G alpha s and G alpha i. These increases in [35S]GTP gamma S binding reflect the stimulation of D1- and D2-dopamine receptors, respectively. The ability of dopamine to stimulate the binding of [35S]GTP gamma S to G alpha s but not to G alpha i was reduced in both frontal and cingulate cortices obtained from cocaine-exposed animals when examined at 10, 50 or 100 days of age. Prenatal cocaine exposure was also shown to reduce dopamine-stimulated [alpha-32P]GTP binding to G alpha s without influencing binding to G alpha i. The muscarinic cholinergic receptor-evoked increases in [35S]GTP gamma S binding to G alpha i and G alpha o were not altered. Immunoblot analyses revealed no differences in the levels of these alpha subunits in membranes from cocaine-exposed animals vs controls. Furthermore, prenatal cocaine did not affect [3H]8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7- olhemimaleate binding to cortical D1 dopamine receptors. The results suggest that prenatal exposure of rabbits to cocaine selectively uncouples the D1 dopamine receptor from its G protein in mesocortical brain areas and that this change persists through postnatal day 100.