ABSTRACT
1 Dept. Physiology and Pharmacology, Sapienza University of Rome, Italy
2 Dept. Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, USA
Exposure to cocaine 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 that the regulation of transcription via chromatin modification, a form of epigenetic gene regulation, has an important role in the development of addictive behavior. One of the best-studied chromatin modifications is acetylation of histones, which is carried out by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Current research on the neurobiology of learning and memory indicates that HATs and HDACs play a pivotal role in memory processes including acquisition and extinction (Malvaez et al., 2009). Similarly, in drug addiction studies, increasing histone acetylation via HDAC inhibition enhances acquisition of drug-associated memories and decreasing histone acetylation reduces sensitization to chronic cocaine (Renthal et al., 2007; Kumar et al., 2005). Very little is known about the role of specific chromatin modifying enzymes involved in regulation of histone acetylation in the NAc. 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 formation (Barrett and Wood, 2008). In our study we will incorporate behavioral and molecularapproaches to investigate the role of CBP in regulation of cocaine-induced plasticity in the nucleus accumbens. We used CBP-FLOX genetically modified mice in combination with AAV expressing Cre recombinase to generate focal homozygous deletions of CBP in the nucleus accumbens (NAc) and examine the effects on histone modifications and context-drug associated memory formation. One animal model used to study the formation of context-drug associated memories is the conditioned place preference (CPP) paradigm, in which an association is formed between a particular context and the effects of the drug, leading to a preference for the drug-paired context. Immunohistochemistry in the NAc of WT and CBP-FLOX mice using acetyl histone-H3K14 primary antibody showed significant and long-lasting increases in H3 acetylation in WT mice upon chronic injection of cocaine; this does not occur in CBP-FLOX mice. Loss of CBP in the nucleus accumbens core resulted in reduced histone acetylation and impairments in the cocaine-induced conditioned place preference paradigm. These results show that the chromatin modifying enzyme CBP has a significant role in context-drug associated memory formation, and provide evidence that CBP is critical for cocaine-induced histone acetylation.
Malvaez et al. (2009) Mamm Genome. 20, 612–23
Renthal et al. (2007) Neuron. 56, 517-29
Kumar et al. (2005). Neuron. 48, 303-14
Barrett and Wood (2008) Learn Mem. 15(7), 460-7