Inhibition of histone deacetylases in rats self-administering cocaine regulates lissencephaly gene-1 and reelin gene expression, as revealed by microarray technique.
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.
Inserm, U575, Centre de Neurochimie, Strasbourg, France.
Lionel
L
Host
Patrick
P
Anglard
Pascal
P
Romieu
Christelle
C
Thibault
Doulaye
D
Dembele
Dominique
D
Aunis
Jean
J
Zwiller
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D019295:Computational Biology / Q000379:methods; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D000091042:Reelin Protein; D012646:Self Administration / Q000379:methods; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D015816:Cell Adhesion Molecules, Neuronal; D018765:Dopamine Uptake Inhibitors; D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; C012589:trichostatin A; D012697:Serine Endopeptidases; D006655:Histone Deacetylases; D003042:Cocaine