Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Abstract

The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIa, but not CaMKIIb, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIa, but not CaMKIIb, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIa, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement. Neuropsychopharmacology (2010) 35, 913-928; doi:10.1038/npp.2009; published online 9 December 2009 Keywords: histone acetylation; nucleus accumbens; motivation; cocaine self-administration; addiction; CaMKIIa INTRODUCTIONDrug addiction is a debilitating psychiatric disorder characterized by (1) a compulsion to seek and take the drug, (2) a loss of control in limiting intake, and (3) the emergence of a negative emotional state when access to the drug is prevented (Hyman et al, 2006;Kalivas et al, 2005;Koob and Kreek, 2007). The complex behavioral changes leading to drug addiction are thought to result from molecular and cellular adaptation in specific brain regions (Brami-Cherrier et al, 2005). One area of intensive research to clarify neuroadaptation addresses the regulation of gene expression induced by the drug (Nestler, 2001). The drug induces changes in gene expression in key brain reward regions, such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral tegmental area (VTA). For instance, the expression of the immediate early gene c-Fos and several other Fos family proteins is upregulated in the nucleus accumbens, striatum (Courtin et al, 2006) and frontal cortex (Thiriet et al, 2000) after acute cocaine treatment. T...

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

“…These findings are interesting given that dopamine D1-like agonists increase AMPAR insertion into NAC MSNs through a process involving CAMKIIa (Anderson et al, 2008;Sun et al, 2008) and that both dopamine and CAMKIIa have been shown to be important for the expression of psychostimulant sensitization and drugseeking behavior (Licata and Pierce, 2003;Loweth et al, 2008;Pierce et al, 1998). In fact, lentiviral-mediated knockdown of CAMKIIa in the NACsh reduced motivation to self-administer cocaine on a PR schedule (Wang et al, 2010a). Collectively, these data support a hypothesis in which mTORC1 acts as a key effector in the molecular pathway controlling the dynamic regulation of synaptic proteins within the NAC that are required for the expression and maintenance of drug reward.…”

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

“…Histone acetylation plays an important role in learning and memory (Alarcon et al 2004;Vecsey et al 2007) as well as in drug addiction (Levine et al 2005(Levine et al , 2011Renthal and Nestler 2008;Wang et al 2010). Our previous work has found that the administration of the HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) can simulate the priming effect of nicotine on cocaine in the expression of LTP in the NAc and amygdala (Levine et al 2011;Huang et al 2013).…”

Epigenetic Readers of Lysine Acetylation Regulate Cocaine-Induced Plasticity

“…In drug addiction, for example, repeated cocaine administration elevates global histone acetylation levels in reward-related brain regions, such as the nucleus accumbens (NAc) . Furthermore, manipulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs) by pharmacological inhibition, viralmediated gene transfer, and/or knock-out models has confirmed that histone acetylation is critically involved in behavioral and molecular responses to cocaine (Kumar et al, 2005;Sun et al, 2008;Im et al, 2010;Malvaez et al, 2010Malvaez et al, , 2011Malvaez et al, , 2013Wang et al, 2010;Kennedy et al, 2013;. As a consequence, HAT and HDAC inhibitors have emerged as attractive targets for the treatment of drug addiction; however, additional reg-ulators of histone lysine acetylation have recently come to light.…”