title: CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants.
abstract: BACKGROUND
  The transcription factor cAMP responsive element-binding protein 1 (CREB1) has a complex influence on behavioural responses to drugs of abuse which varies depending on the brain region in which it is expressed. In response to drug exposure, CREB1 is phosphorylated in the striatum, a structure that is critically involved in reward-related learning.
  
  
  OBJECTIVE
  The present study assessed the role of striatal CREB1 and its coactivator CREB-binding protein (CBP) in behavioural responses to psychostimulants.
  
  
  METHODS
  Using the 'cre/lox' recombination system, we generated mice with a postnatal deletion of CREB1 or CBP directed to medium spiny neurons of the striatum. qRT-PCR and immunohistochemistry were used to confirm the deletion, and mice were assessed with respect to their locomotor response to acute cocaine (20 mg/kg), cocaine sensitization (10 mg/kg), amphetamine-induced stereotypies (10 mg/kg) and ethanol-induced hypnosis (3.5 g/kg).
  
  
  RESULTS
  Here we show that CREB1 mutant mice have increased sensitivity to psychostimulants, an effect that does not generalise to ethanol-induced hypnosis. Furthermore, in the absence of CREB1, there is rapid postnatal upregulation of the related transcription factor CREM, indicating possible redundancy amongst this family of transcription factors. Finally striatal deletion of CBP, a coactivator for the CREB1/CREM signalling pathway, results in an even more increased sensitivity to psychostimulants.
  
  
  CONCLUSIONS
  These data suggest that striatal CREB1 regulates sensitivity to psychostimulants and that CREM acting via CBP is able to partially compensate in the absence of CREB1 signalling.
authors.affiliation: Florey Neuroscience Institutes, Parkville, VIC, Australia.
authors.forename: Heather B
authors.initials: HB
authors.lastname: Madsen
authors.forename: Srigala
authors.initials: S
authors.lastname: Navaratnarajah
authors.forename: Jessica
authors.initials: J
authors.lastname: Farrugia
authors.forename: Elvan
authors.initials: E
authors.lastname: Djouma
authors.forename: Michelle
authors.initials: M
authors.lastname: Ehrlich
authors.forename: Theo
authors.initials: T
authors.lastname: Mantamadiotis
authors.forename: Jan
authors.initials: J
authors.lastname: Van Deursen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000431:Ethanol; D000661:Amphetamine; D050882:CREB-Binding Protein; D003042:Cocaine