CBP in the Nucleus Accumbens Regulates Cocaine-Induced Histone Acetylation and Is Critical for Cocaine-Associated Behaviors

University of California, Irvine, Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, Irvine, California 92697-3800, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2011; 31(47):16941-8. DOI: 10.1523/JNEUROSCI.2747-11.2011
Source: PubMed


Cocaine exposure triggers molecular events that lead to long-lasting changes in brain structure and function. These changes can lead to the development of persistent and robust behavioral adaptations that characterize addiction. Recent evidence suggests the regulation of transcription via chromatin modification, such as histone acetylation, has an important role in the development of addictive behavior. Histone acetylation is regulated by histone acetyltransferases (HATs), which acetylate histones and promote transcription, and histone deacetylases (HDACs), which remove acetyl groups and silence transcription. Studies have demonstrated that HDACs may negatively regulate cocaine-induced behaviors, but very little is known about the role of specific HATs in long-lasting drug-induced plasticity. The histone acetyltransferase CREB-binding protein (CBP) mediates transcriptional activation by recruiting basal transcription machinery and acetylating histones. CBP is a critically important chromatin-modifying enzyme involved in regulating gene expression required for long-term plasticity and memory. However, the role of CBP in cocaine-induced behaviors remains largely unknown. We examined the role of CBP in drug-induced plasticity using CBP-FLOX genetically modified mice in combination with adeno-associated virus expressing Cre-recombinase to generate focal homozygous deletions of Cbp in the nucleus accumbens (NAc). A complete loss of CBP in NAc neurons results in decreased histone acetylation and significantly altered c-fos expression in response to cocaine. Furthermore, the deletion of CBP in the NAc correlates with significant impairments in cocaine sensitivity and context-cocaine associated memory. This is the first study to demonstrate a definitive role for CBP in modulating gene expression that may subserve drug-seeking behaviors.

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Available from: Emanuela Mhillaj, Jan 12, 2015
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    • "Similar findings in other tasks and with other class I HDAC inhibitors support the idea that removing an epigenetic " brake " on gene expression allows a permissive state for memory to consolidate from short-to long-term memory. Evidence from studies using other types of learned information, including spatial contexts associated with drugs of abuse, also supports the idea that HDAC inhibition engages plasticity in the selective brain regions or populations of neurons that are critical for task performance, such as the nucleus accumbens (NAc) for drug-related memory3536373839. Taken together, these studies support at least two apparent roles of class I HDACs, and maybe in particular of HDAC3, in memory formation: (1) to modulate the strength of memory formation with respect to its durability over time, especially beyond 24 hours, and (2) to selectively act within neural brain regions (and neurons) that have behaviorally relevant information of the tasks to-be-remembered. "
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