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

Abstract

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.

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

“…1a) (Malvaez et al 2011;White et al 2016). Both saline-reinstated and cocaine-reinstated animals equally acquired and extinguished a conditioned preference (Fig.…”

Involvement of phosphorylated Apis mellifera CREB in gating a honeybee's behavioral response to an external stimulus

“…Because an enhanced phosphorylation of CREB at S133 results in an enhanced binding of CBP (Du et al 2000) and CBP is a transcriptional coactivator with acetyltransferase activity (for review, see Valor et al 2013), these results are in line with the notion of a causal relationship between CREB phosphorylation and the bee's stimulus responsiveness. Further support for the idea that the level of phosphorylated CREB is important for gating the response to an external stimulus comes from studies in vertebrates where CREB, CBP and histone acetylation play a role in behavioral sensitization (Kumar et al 2005;Levine et al 2005;Renthal et al 2007;Fasano et al 2009;Sanchis-Segura et al 2009a,b;Malvaez et al 2011;Bilbao et al 2014). Behavioral sensitization is a process in which repeated exposure to addictive drugs leads to a longlasting enhancement of drug-induced behavior (Robinson and Berridge 1993;Stewart et al 1993;Vanderschuren et al 2001).…”

Possible contributions of a novel form of synaptic plasticity inAplysiato reward, memory, and their dysfunctions in mammalian brain

“…Drugs of abuse also produce regulation of genes related to LTP in NAc, including Fos B, c-fos, NR2B and NR4A, CamKII, and dynorphin (Carlezon et al 1998;Hyman et al 2006;Lee et al 2006;Brown et al 2011;Malvaez et al 2011;Damez-Werno et al 2012;Pitchers et al 2013;Robison et al 2013;Rogge et al 2013). That regulation involves a variety of mechanisms, including activation of CREB and epigenetic changes in histone acetylation and methylation (Carlezon et al 1998;Brown et al 2011;Malvaez et al 2011;Maze et al 2011;Damez-Werno et al 2012;Sun et al 2012;Taniguchi et al 2012;Rogge et al 2013).…”

“…That regulation involves a variety of mechanisms, including activation of CREB and epigenetic changes in histone acetylation and methylation (Carlezon et al 1998;Brown et al 2011;Malvaez et al 2011;Maze et al 2011;Damez-Werno et al 2012;Sun et al 2012;Taniguchi et al 2012;Rogge et al 2013). In addition, drugs of abuse produce synaptic growth and structural changes related to L-LTP in NAc, including increases in dendritic branching, spine density, and spine size (Lee et al 2006;Ren et al 2010;Dobi et al 2011;Shen et al 2011;Dietz et al 2012;Dumitriu et al 2012;Gipson et al 2013a,b;Pitchers et al 2013;Robison et al 2013), as well as increases in pre-and postsynaptic proteins (Subramaniam et al 2001;Gipson et al 2013b).…”