Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum.

Cole RL, Konradi C, Douglass J, Hyman SE
Neuron. 1995 14 (4): 813-23

PMID: 7718243 · PMCID: PMC4207064 · DOI:10.1016/0896-6273(95)90225-2

Induction of prodynorphin gene expression by psychostimulant drugs may represent a compensatory adaptation to excessive dopamine stimulation and may contribute to the aversive aspects of withdrawal. We therefore investigated the molecular mechanisms by which dopamine psychostimulant drugs induce prodynorphin gene expression in vivo and in rat primary striatal cultures. We demonstrate that three recently described cAMP response elements (CREs), rather than a previously reported noncanonical AP-1 site, are critical for dopamine induction of the prodynorphin gene in striatal neurons. CRE-binding protein (CREB) binds to these CREs in striatal cell extracts and is phosphorylated on Ser-133 after dopamine stimulation in a D1 dopamine receptor-dependent manner. Surprisingly, following chronic administration of amphetamine, levels of phosphorylated CREB are increased above basal in rat striatum in vivo, whereas c-fos mRNA is suppressed below basal levels. D1 receptor-mediated CREB phosphorylation appears to mediate adaptations to psychostimulant drugs in the striatum.

MeSH Terms (21)

Amphetamine Animals Binding Sites Cells, Cultured Corpus Striatum Cyclic AMP Cyclic AMP Response Element-Binding Protein DNA Dopamine Drug Tolerance Enkephalins Gene Expression Regulation Genes, fos Male Neurons Phosphorylation Protein Precursors Rats Rats, Sprague-Dawley RNA, Messenger Transcription Factor AP-1

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