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The Journal of Neuroscience, January 3, 2007, 27(1):152-157; doi:10.1523/JNEUROSCI.4591-06.2007

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Neurobiology of Disease
Prenatal Exposure to Cocaine Produces Unique Developmental and Long-Term Adaptive Changes in Dopamine D₁ Receptor Activity and Subcellular Distribution

Gregg D. Stanwood and Pat Levitt

Vanderbilt Kennedy Center for Research on Human Development and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Correspondence should be addressed to Gregg D. Stanwood, 8110A MRBIII, Nashville, TN 37232. Email: gregg.stanwood{at}vanderbilt.edu

Low-dose intravenous cocaine administration to pregnant rabbits causes permanent structural alterations in dopamine-rich cerebral cortical areas, substantially reduced dopamine D₁ receptor coupling to G_s-protein, and deficits in cognitive function. The developmental influences of reduced D₁–G_s coupling and the underlying cellular basis are unknown. Using primary neuronal cultures derived from the medial frontal cortex and striatum of in utero saline- and cocaine-exposed embryos, spontaneous neurite outgrowth of in utero-exposed cortical neurons was greater than in control neurons. In contrast, striatal neurons exposed to cocaine in utero exhibited an entirely opposite adaptive response, with diminished spontaneous neurite outgrowth compared with saline-exposed controls. Control neurons isolated from the two structures also exhibited opposite regulatory responses to the D₁ receptor agonist SKF38393 (1-phenyl-2,3,4-5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride), inhibiting outgrowth in cortical cultures and stimulating outgrowth in striatal cultures. The agonist was ineffective in modulating neurite outgrowth of neurons from either structure isolated from cocaine-exposed fetuses, reflecting the reduced D₁–Gs coupling. Total D₁ receptor number was indistinguishable in neurons from the cocaine- and saline-exposed animals, but cell imaging and receptor binding of differentially isolated membranes showed that the lack of responsiveness was because of greatly reduced cell-surface localization of D₁ receptors. These data suggest that prenatal exposure to cocaine causes a novel, long-lasting adaptive response in the subcellular distribution of D₁ receptors, resulting in alterations in signaling capacity that have developmental and behavioral consequences.

Key words: cortex; striatum; dendrite; neurite; in utero; rabbit

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Received Sept. 7, 2006; revised Nov. 27, 2006; accepted Nov. 28, 2006.

Correspondence should be addressed to Gregg D. Stanwood, 8110A MRBIII, Nashville, TN 37232. Email: gregg.stanwood{at}vanderbilt.edu

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