Effect of prenatal cocaine on dopamine receptor-G protein coupling in mesocortical regions of the rabbit brain.

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.