Environmental Enrichment Produces a Behavioral Phenotype Mediated by Low Cyclic Adenosine Monophosphate Response Element Binding (CREB) Activity in the Nucleus Accumbens

Thomas A. Green, Imran N. Alibhai, C. Nathaniel Roybal, Catharine A. Winstanley, David E H Theobald, Shari G. Birnbaum, Ami R. Graham, Stephen Unterberg, Danielle L. Graham, Vincent Vialou, Caroline E. Bass, Ernest F. Terwilliger, Michael T. Bardo, Eric J. Nestler

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133 Scopus citations

Abstract

Background: Previous research has shown that rats reared in an enriched condition (EC) are more sensitive to the acute effects of amphetamine than rats reared in an isolated condition (IC); yet, EC rats self-administer less amphetamine than IC rats. The present study used cocaine to further explore this environmental enrichment behavioral phenotype, as well as the underlying molecular mechanisms involved. Methods: Enriched condition and IC rats were studied in a broad battery of behavioral tests, including cocaine conditioned place preference (CPP) and self-administration and several measures of anxiety- and depression-related behavior. The involvement of the transcription factor, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), in mediating EC versus IC differences was investigated. Results: Enriched condition rats exhibited less cocaine self-administration, despite showing enhanced cocaine CPP. Enriched condition rats also displayed less depression-like behavior but higher levels of anxiety-like behavior. This behavioral phenotype is consistent with low CREB activity in the nucleus accumbens, a key brain reward region. Indeed, EC rats have less phospho-CREB (the transcriptionally active form of the protein) in the nucleus accumbens than IC rats, and a selective knockdown of CREB in this brain region of normally reared rats, by use of a novel viral vector expressing a short hairpin RNA (shRNA) directed against CREB, reproduced the EC behavioral phenotype. Conclusions: These studies identify a potential molecular mechanism for how rearing environment-a nonpharmacological, nonsurgical manipulation-can modify a wide range of complex emotional behaviors.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
JournalBiological Psychiatry
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • Addiction
  • anxiety
  • craving
  • depression
  • differential rearing
  • drug abuse
  • drug addiction
  • forced swim test
  • incentive sensitization
  • relapse
  • salience

ASJC Scopus subject areas

  • Biological Psychiatry

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