Prenatal cocaine exposure alters signal transduction in the brain D1 dopamine receptor system.
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]GTP gamma S binding to G alpha S without affecting binding of the nucleotide to G alpha I 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 G alpha s did not result from a decrease in concentration of membrane G alpha s 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 post-translational modifications of the D1 dopamine receptor or of Gs alpha 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.
Department of Pharmacology, MCP Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19129, USA.
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000633:toxicity; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D019966:Substance-Related Disorders
D017447:Receptors, Dopamine D1; D019204:GTP-Binding Proteins; D003042:Cocaine