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Psychopharmacology

, Volume 219, Issue 3, pp 699–713 | Cite as

CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants

  • Heather B. Madsen
  • Srigala Navaratnarajah
  • Jessica Farrugia
  • Elvan Djouma
  • Michelle Ehrlich
  • Theo Mantamadiotis
  • Jan Van Deursen
  • Andrew J. LawrenceEmail author
Original Investigation

Abstract

Rationale

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.

Keywords

CBP CREB DARPP-32 Psychostimulants Striatum 

Notes

Acknowledgements

AJL is a senior fellow of the National Health and Medical Research Council of Australia. This work was also supported by the Victocrian Government's Operational Infrastructure Support Program. All experiments performed comply with current Australian laws.

Conflict of interest

There are no conflicts of interest to report.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Heather B. Madsen
    • 1
  • Srigala Navaratnarajah
    • 1
  • Jessica Farrugia
    • 1
    • 2
  • Elvan Djouma
    • 2
  • Michelle Ehrlich
    • 3
  • Theo Mantamadiotis
    • 4
  • Jan Van Deursen
    • 5
  • Andrew J. Lawrence
    • 1
    • 6
    • 7
    Email author
  1. 1.Florey Neuroscience InstitutesParkvilleAustralia
  2. 2.Department of Human Physiology and AnatomyLa Trobe UniversityMelbourneAustralia
  3. 3.Departments of Neurology, Pediatrics, and Genetics and Genomic SciencesMount Sinai School of MedicineNew YorkUSA
  4. 4.Laboratory of PhysiologyUniversity of PatrasPatrasGreece
  5. 5.Department of Pediatric and Adolescent MedicineMayo Clinic College of MedicineRochesterUSA
  6. 6.Centre for NeuroscienceUniversity of MelbourneParkvilleAustralia
  7. 7.Addiction NeuroscienceFlorey Neuroscience InstitutesParkvilleAustralia

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