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

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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.

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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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Authors and Affiliations

  1. Florey Neuroscience Institutes, Parkville, VIC, Australia

    Heather B. Madsen, Srigala Navaratnarajah, Jessica Farrugia & Andrew J. Lawrence

  2. Department of Human Physiology and Anatomy, La Trobe University, Bundoora, Melbourne, VIC, Australia

    Jessica Farrugia & Elvan Djouma

  3. Departments of Neurology, Pediatrics, and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    Michelle Ehrlich

  4. Laboratory of Physiology, University of Patras, 26500, Patras, Greece

    Theo Mantamadiotis

  5. Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

    Jan Van Deursen

  6. Centre for Neuroscience, University of Melbourne, Parkville, VIC, Australia

    Andrew J. Lawrence

  7. Addiction Neuroscience, Florey Neuroscience Institutes, Royal Parade, Parkville, VIC, 3010, Australia

    Andrew J. Lawrence

Authors
  1. Heather B. Madsen
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  2. Srigala Navaratnarajah
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  3. Jessica Farrugia
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  4. Elvan Djouma
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  5. Michelle Ehrlich
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  6. Theo Mantamadiotis
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  7. Jan Van Deursen
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  8. Andrew J. Lawrence
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Correspondence to Andrew J. Lawrence.

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Madsen, H.B., Navaratnarajah, S., Farrugia, J. et al. CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants. Psychopharmacology 219, 699–713 (2012). https://doi.org/10.1007/s00213-011-2406-1

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