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. Lawrence

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)699-713
Number of pages15
JournalPsychopharmacology
Volume219
Issue number3
DOIs
StatePublished - Feb 2012

Fingerprint

CREB-Binding Protein
Corpus Striatum
Carrier Proteins
Neurons
Transcription Factors
Hypnosis
Cocaine
Ethanol
Street Drugs
Amphetamine
Reward
Genetic Recombination
Up-Regulation
Immunohistochemistry
Learning
Polymerase Chain Reaction

Keywords

  • CBP
  • CREB
  • DARPP-32
  • Psychostimulants
  • Striatum

ASJC Scopus subject areas

  • Pharmacology

Cite this

Madsen, H. B., Navaratnarajah, S., Farrugia, J., Djouma, E., Ehrlich, M., Mantamadiotis, T., ... Lawrence, A. J. (2012). CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants. Psychopharmacology, 219(3), 699-713. https://doi.org/10.1007/s00213-011-2406-1

CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants. / Madsen, Heather B.; Navaratnarajah, Srigala; Farrugia, Jessica; Djouma, Elvan; Ehrlich, Michelle; Mantamadiotis, Theo; Van Deursen, Jan; Lawrence, Andrew J.

In: Psychopharmacology, Vol. 219, No. 3, 02.2012, p. 699-713.

Research output: Contribution to journalArticle

Madsen, HB, Navaratnarajah, S, Farrugia, J, Djouma, E, Ehrlich, M, Mantamadiotis, T, Van Deursen, J & Lawrence, AJ 2012, 'CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants', Psychopharmacology, vol. 219, no. 3, pp. 699-713. https://doi.org/10.1007/s00213-011-2406-1
Madsen, Heather B. ; Navaratnarajah, Srigala ; Farrugia, Jessica ; Djouma, Elvan ; Ehrlich, Michelle ; Mantamadiotis, Theo ; Van Deursen, Jan ; Lawrence, Andrew J. / CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants. In: Psychopharmacology. 2012 ; Vol. 219, No. 3. pp. 699-713.
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