Prenatal Cocaine Exposure Alters Signal Transduction in the Brain D₁ Dopamine Receptor System^a

Cocaine use during pregnancy may result in persistent behavioral abnormalities in the newborn. Animal studies show behavioral and neurochemical alterations in offspring that were exposed to cocaine prenatally. The monoamine neurons, including those containing dopamine, appear and become operational prenatally and mature during early postnatal life. It is therefore conceivable that exposure to cocaine during gestation may critically affect normal development and subsequently cause protracted postnatal neurochemical and behavioral changes. The data we obtained demonstrate that prenatal exposure to cocaine in the rabbit impairs signal transduction via the D₁ but not the D₂ dopamine receptor system. This is reflected in impaired dopamine-stimulated [³⁵S]GTPγS binding to Gαs without affecting binding of the nucleotide to Gαi in both cortex and striatum of rabbit offspring. This selective reduction in D₁ dopamine receptor-mediated activation of Gs protein increased in severity as the dose of cocaine administered to the pregnant dams was increased. Maximal impairment was observed after treatment with two daily injections of 3 mg/kg of cocaine HC1. The reduction in dopamine-stimulated GTP binding to Gαs did not result from a decrease in concentration of membrane Gαs protein or D₁ dopamine receptors. The data also indicate that in utero cocaine exposure causes persistent uncoupling of the D₁ dopamine receptors from their associated Gs protein which appears as early as gestational day 22 and persists to postnatal day 100. The reduction in D₁ dopamine receptor-mediated signal transduction may be mediated by posttranslational modifications of the D₁ dopamine receptor or of Gsα such as phosphorylation, which result in altered coupling between these membrane components. The resultant attenuated D₁ dopamine receptor-mediated signaling may ultimately underlie both long-lasting behavioral dysfunction and morphologic changes which are associated with prenatal cocaine exposure in the rabbit.