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

Neuron. 1995 Apr;14(4):813-23. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Cyclic AMP Response Element-Binding Protein
  • Enkephalins
  • Protein Precursors
  • RNA, Messenger
  • Transcription Factor AP-1
  • DNA
  • preproenkephalin
  • Amphetamine
  • Cyclic AMP
  • Dopamine