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The Journal of Neuroscience, December 1, 2001, 21(23):9160-9167

Prenatal Exposure to Cocaine Disrupts D_1A Dopamine Receptor Function Via Selective Inhibition of Protein Phosphatase 1 Pathway in Rabbit Frontal Cortex

Xuechu Zhen, Claudio Torres, Hoau-Yan Wang, and Eitan Friedman

Department of Pharmacology and Physiology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania 19102

Previous work has demonstrated that in utero cocaine exposure induces an uncoupling of brain D_1A dopamine receptors (D_1ADARs) from G_s-protein. The present work is an attempt to define the mechanism underlying the uncoupling. We detected a significant elevation of phosphoserine in frontal cortical D_1ADARs of rabbits that were exposed prenatally to cocaine compared with saline controls. This increase in phosphorylation is observed at gestational day 22 and persists to postnatal day 20. The hyperphosphorylation of the D_1ADAR is accompanied by a 45% inhibition in frontal cortex (FCX) protein phsphatase-1 (PP1) activity that appears to be mediated via DARPP-32 (dopamine and cAMP-regulated phosphoprotein) as indicated by elevated FCX phospho-DARPP-32 (Thr³⁴). Furthermore, we demonstrated in both FCX and in PC2 cells that express D_1ADARs that PP1 is physically associated with D_1ADARs. We also observed a dramatic decrease in D_1ADAR-associated PP1 activity in FCX of prenatal cocaine-exposed rabbits, indicating that the reduction in PP1 activity may be responsible for the hyperphosphorylation of the receptor. Furthermore, pretreatment of cortical membranes obtained from cocaine-exposed animals with exogenous PP1 dephosphorylated the phosphorylated D_1ADAR and significantly reversed the impaired receptor-G_s coupling. This work indicates (1) that D_1ADAR dephosphorylation via PP1 is essential for receptor resensitization or reactivation and (2) an alteration in the DARPP-32/PP1 cascade appears to be a primary event responsible for D_1ADAR dysfunction in in utero cocaine-exposed rabbit progeny. The present finding of an altered DARPP-32/PP1 cascade in association with a dysfunction in D_1ADAR signal transmission in the prenatal cocaine-exposed rabbit brain may implicate novel strategies for the prevention and treatment for in utero cocaine-induced developmental and behavioral abnormalities.

Key words: signal transduction; G-protein; cocaine; dopamine receptor; coupling; protein phophatases

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21239160-08$05.00/0

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