Role of CREB-binding protein on histone acetylation and cocaine-associated behaviors

Evidence shows that cocaine exposure triggers altered gene expression within the nucleus accumbens, contributing to the development and persistence of drug addiction. Chromatin modification is emerging as a major molecular mechanism involved in the regulation of gene expression critical for long lasting forms of synaptic plasticity, memory processes, and drug-induced neural and behavioral change. Cocaine induces specific chromatin modifications, such as histone acetylation, that modulate histone-DNA interactions and the recruitment of transcriptional regulatory complexes, leading to changes in transcription that may underlie aspects of cocaine addiction. Although changes in histone acetylation in response to cocaine have been documented, relatively little is known about the specific histone acetylation enzymes involved in cocaine-induced plasticity. The enzymes that regulate levels of histone acetylation are histone acetyltransferases (HATs) and histone deacetylases (HDACs), which generally promote or silence gene expression, respectively. 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.