Prenatal exposure to cocaine selectively reduces D1 dopamine receptor-mediated activation of striatal Gs proteins.
The effect of in utero exposure to cocaine on striatal dopamine receptors was assessed at postnatal days 10 through 100 by examining receptor-mediated increases in GTP binding to G alpha proteins. Pregnant Dutch-belted rabbits were injected with 4 mg/kg i.v. of cocaine HCl twice a day on gestational days 8 through 29, and striatal membranes were prepared from their progenies on days 10 through 100. Dopamine-stimulated [35S]GTP gamma S binding to membrane alpha subunits was measured and found to increase binding to G alpha s and G alpha i. Pharmacological characterization of the dopamine response revealed that enhanced [35S]GTP gamma S binding to G alpha s is associated with D1 receptor stimulation, whereas binding to G alpha i is linked to D2 receptor activation. The abilities of dopamine to stimulate the binding of [35S]GTP gamma S to G alpha s but not to G alpha i was reduced in striata obtained from cocaine-exposed animals when examined at 10, 50 or 100 days of age. Similarly, prenatal cocaine exposure also reduced dopamine-stimulated [alpha-32P]GTP binding to G alpha s without influencing binding to G alpha i. Fetal cocaine exposure did not change carbachol-induced increases in [35S]GTP gamma S binding to G alpha i and G alpha o. Immunoblot analyses showed no changes in the amounts of these alpha subunits in membranes from cocaine-exposed animals vs. controls. Moreover, prenatal cocaine did not affect [3H]SCH23390 binding to D1 dopamine receptors in the caudate, putamen or substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
H Y
HY
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia, USA.
Runyan
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S
Yadin
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Friedman
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D000367:Age Factors; D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity*; D003342:Corpus Striatum / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D011817:Rabbits; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000502:physiology
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins; D003042:Cocaine