Repeated cocaine administration induces gene expression changes through the dopamine D1 receptors.
Drug addiction involves compulsive drug-seeking and drug-taking despite known adverse consequences. The enduring nature of drug addiction suggests that repeated exposure to abused drugs leads to stable alterations that likely involve changes in gene expression in the brain. The dopamine D1 receptor has been shown to mediate the long-term behavioral effects of cocaine. To examine how the persistent behavioral effects of cocaine correlate with underlying changes in gene expression, we have used D1 receptor mutant and wild-type mice to identify chronic cocaine-induced gene expression changes mediated via the D1 receptors. We focused on the caudoputamen and nucleus accumbens, two key brain regions that mediate the long-term effects of cocaine. Our analyses demonstrate that repeated cocaine administration induces changes in the expression of 109 genes, including those encoding the stromal cell-derived factor I, insulin-like growth factor binding protein 6, sigma 1 receptor, regulators of G-protein signaling protein 4, Wnt1 responsive Cdc42 homolog, Ca2+/calmodulin-dependent protein kinase II alpha subunit, and cyclin D2, via the D1 receptors. Moreover, the seven genes contain AP-1 binding sites in their promoter regions. These results suggest that genes encoding certain extracellular factors, membrane receptors and modulators, and intracellular signaling molecules, among others, are regulated by cocaine via the D1 receptor, and these AP-1 transcription complex-regulated genes might contribute to persistent cocaine-induced behavioral changes.
Zhang
Dongsheng
D
Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
Zhang
Lu
L
Tang
Yang
Y
Zhang
Qi
Q
Lou
Danwen
D
Sharp
Frank R
FR
Zhang
Jianhua
J
Xu
Ming
M
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D018801:CD2 Antigens / Q000235:genetics / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004399:Dynorphins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046228:Microarray Analysis / Q000379:methods; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors
D001552:Benzazepines; D018801:CD2 Antigens; D056741:Cyclin D; D016213:Cyclins; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018976:Insulin-Like Growth Factor Binding Protein 6; D011506:Proteins; D020710:RGS Proteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; C098799:RGS4 protein; D004399:Dynorphins; D003042:Cocaine