Amphetamine regulates gene expression in rat striatum via transcription factor CREB.
Amphetamine is a psychostimulant drug of abuse that can produce long-lived changes in behavior including sensitization and dependence. The neural substrates of these drug effects remain unknown, but based on their prolonged time course, we hypothesize that they involve drug-induced alterations in gene expression. It has recently been demonstrated that amphetamine regulates the expression of several genes, including c-fos, via dopamine D1 receptors in rat striatum. Here we report that amphetamine induces phosphorylation of transcription factor cAMP response element binding protein (CREB) in rat striatum in vivo and that dopamine D1 receptor stimulation induces phosphorylation of CREB within specific complexes bound to cAMP regulatory elements. In addition, we show by antisense injection that CREB is necessary for c-fos induction by amphetamine in vivo. Since CREB has been implicated in the activation of a number of immediate-early genes as well as several neuropeptide genes, CREB phosphorylation may be an important early nuclear event mediating long-term consequences of amphetamine administration.
Konradi
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C
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Charlestown 02129.
Cole
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RL
Heckers
S
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Hyman
S E
SE
D051698:Activating Transcription Factor 2; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004298:Dopamine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors
D051698:Activating Transcription Factor 2; D000662:Amphetamines; D017362:Cyclic AMP Response Element-Binding Protein; D015345:Oligonucleotide Probes; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D003042:Cocaine; D004298:Dopamine