CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine.
The neuronal circuitry underlying stress- and drug-induced reinstatement of cocaine-seeking has been relatively well characterized; however, less is known regarding the long-term molecular changes following cocaine administration that may promote future reinstatement. The transcription factor cAMP response element-binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned reward, suggesting that different molecular mechanisms may underlie these two types of reinstatement. To explore the relationship between this transcription factor and reinstatement, we utilized the place-conditioning paradigm to examine alterations in gene expression in the amygdala, a neural substrate critically involved in stress-induced reinstatement, following the development of cocaine reward and subsequent extinction. Our findings demonstrate that the amygdala transcriptome was altered by CREB deficiency more than by previous cocaine experience, with an over-representation of genes involved in the immune response. However, a subset of genes involved in stress and immune response demonstrated a drug×genotype interaction, indicating that cocaine produces different long-term alterations in gene expression depending on the presence or absence of CREB. This profile of gene expression in the context of addiction enhances our understanding of the long-term molecular changes that occur throughout the addiction cycle and identifies novel genes and pathways that might lead to the creation of better therapeutic agents.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Laurel E
LE
Ecke
Jessica N
JN
Cleck
Peter
P
White
Jonathan
J
Schug
Lauren
L
Mifflin
Julie A
JA
Blendy
D000679:Amygdala / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000276:immunology; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D012201:Reward; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D059467:Transcriptome
D017362:Cyclic AMP Response Element-Binding Protein; D018765:Dopamine Uptake Inhibitors; D014157:Transcription Factors; D003042:Cocaine