Inhibition of histone deacetylases in rats self-administering cocaine regulates lissencephaly gene-1 and reelin gene expression, as revealed by microarray technique

J Neurochem. 2010 Apr;113(1):236-47. doi: 10.1111/j.1471-4159.2010.06591.x. Epub 2010 Feb 2.

Abstract

Injection of the histone deacetylase inhibitor trichostatin A (TsA) to rats has been shown to decrease their motivation to self-administer cocaine. In the present study, we investigated alterations in gene expression patterns in the anterior cingulate cortex and nucleus accumbens of rats self-administering cocaine and treated with TsA. Using oligonucleotide microarrays, we identified 722 probe sets in the cortex and 136 probe sets in the nucleus accumbens that were differentially expressed between vehicle and TsA-treated rats that self-administered cocaine. Microarray data were validated by real-time PCR for seven genes. Using immunohistochemistry, we further investigated the expression of Lis1 and reelin genes, because (i) they were similarly regulated by TsA at the mRNA level; (ii) they belong to the same signal transduction pathway; (iii) mutations within both genes cause lissencephaly. Cocaine self-injection was sufficient to activate the two genes at both the mRNA and protein levels. TsA treatment was found to up-regulate both Lis1 and reelin protein expression in the cortex and to down-regulate it in the nucleus accumbens of rats self-administering cocaine. The data suggest that the two proteins contribute to establish neurobiological mechanisms underlying brain plasticity whereby TsA lowers the motivation for cocaine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain / anatomy & histology
  • Brain / drug effects
  • Brain / metabolism
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Classical Lissencephalies and Subcortical Band Heterotopias / genetics
  • Classical Lissencephalies and Subcortical Band Heterotopias / metabolism*
  • Cocaine / administration & dosage*
  • Computational Biology / methods
  • Conditioning, Operant / drug effects
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism*
  • Hydroxamic Acids / pharmacology
  • Male
  • Microdialysis / methods
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis / methods
  • Rats
  • Rats, Wistar
  • Self Administration / methods
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Time Factors

Substances

  • Cell Adhesion Molecules, Neuronal
  • Dopamine Uptake Inhibitors
  • Extracellular Matrix Proteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Nerve Tissue Proteins
  • trichostatin A
  • Serine Endopeptidases
  • reelin protein
  • Histone Deacetylases
  • Cocaine