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The Role of Histone Acetylation in Cocaine-Induced Neural Plasticity and Behavior

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The Role of Histone Acetylation in Cocaine-Induced Neural Plasticity and Behavior Neuropsychopharmacology REVIEWS (2013) 38, 94–110 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 ............................................................................................................................................................... REVIEW 94 www.neuropsychopharmacology.org The Role of Histone Acetylation in Cocaine-Induced Neural Plasticity and Behavior 1 ,1 George A Rogge and Marcelo A Wood* 1 Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, 301 Qureshey Research Lab, Irvine, CA, USA How do drugs of abuse, such as cocaine, cause stable changes in neural plasticity that in turn drive long-term changes in behavior? What kind of mechanism can underlie such stable changes in neural plasticity? One prime candidate mechanism is epigenetic mechanisms of chromatin regulation. Chromatin regulation has been shown to generate short-term and long-term molecular memory within an individual cell. They have also been shown to underlie cell fate decisions (or cellular memory). Now, there is accumulating evidence that in the CNS, these same mechanisms may be pivotal for drug-induced changes in gene expression and ultimately long-term behavioral changes. As these mechanisms are also being found to be fundamental for learning and memory, an exciting new possibility is the extinction of drug-seeking behavior by manipulation of epigenetic mechanisms. In this review, we critically discuss the evidence demonstrating a key role for chromatin regulation via histone acetylation in cocaine action. Neuropsychopharmacology Reviews (2013) 38, 94–110; doi:10.1038/npp.2012.154; published online 22 August 2012 Keywords: epigenetics; acetylation; HDAC; HAT; CBP; cocaine INTRODUCTION maintaining cellular memory (eg, cell fate) and may underlie the strengthening and maintenance of synaptic connections Substance abuse disorders are characterized by compulsive required for long-term changes in behavior (Maze and drug seeking and drug use despite the associated negative Nestler, 2011). consequences that can be quite severe. Addiction is a chronic Chromatin modification refers to the post-translational condition such that even after extended periods of absti- modification of histones including, but not limited to, nence, addicted individuals have a high rate of relapse (Koob acetylation, methylation, and phosphorylation (see other and Le Moal, 2005). Drugs of abuse are known to affect reviews, in this special issue of NPP reviews). In neuroscience, neuronal structure and function in specific brain regions, the best-studied enzymes involved in chromatin modification resulting in stable and persistent changes from the cellular thus far are the histone acetyltransferases (HATs) and histone level to the behavioral level (Nestler, 2001). A key question is deacetylases (HDACs), which in general facilitate gene expres- what mechanisms are involved in initiating and establishing sion and repress gene expression (Kouzarides, 2007). A pre- these stable changes at the cellular level that manifest in long- vailing idea is that gene expression is necessary for stable term behavioral changes? cellular changes manifesting in stable changes in behavior. A prime candidate for such a mechanism involves Thus, one hypothesis is that epigenetic mechanisms, known to epigenetic mechanisms of chromatin regulation. Chromatin be involved in establishing long-lasting cellular changes, regulation may provide transient and potentially stable regulate gene expression required for stable changes in cell epigenetic marks in the service of activating and/or main- function, and ultimately stable changes in behavior. taining transcriptional processes. These in turn may ulti- This review focuses on mechanisms of cocaine action, and mately participate in the molecular mechanisms required for in particular the role of histone acetylation in regulating neuronal changes subserving long-lasting changes in beha- cocaine-induced changes in neural plasticity and behavior. vior. As an epigenetic mechanism of transcriptional control, That is not to suggest that other drugs of abuse or other chromatin modification has been shown to participate in mechanisms of chromatin modification are not as impor- tant, but with regard to drugs of abuse and epigenetic *Correspondence: Dr MA Wood, Department of Neurobiology and mechanisms, there is simply more known about cocaine Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, 301 Qureshey Research Lab, Irvine, CA 92697-3800, and histone acetylation allowing us to hopefully draw better USA, Tel: þ 1 949 824 2259; E-mail: [email protected] overall conclusions and perhaps determine fundamental Received 5 March 2012; revised 7 May 2012; accepted 7 May 2012 aspects of how substance abuse disorders arise and persist. .............................................................................................................................................. Neuropsychopharmacology REVIEWS Cocaine action and histone acetylation REVIEW GA Rogge and MA Wood ............................................................................................................................................................... 95 The review has four main sections. The first section the VTA-originating mesocorticolimbic DA pathway (brain discusses the evidence demonstrating that cocaine affects reward pathway). That is not to say that SERT and NET are histone acetylation (Section I). This is followed by a not involved in cocaine action. In fact, many groups have discussion of the individual HDACs (Section II) and HATs examined the effects of knocking out SERT and NET on (Section III) that are involved in regulating histone acetyla- behavioral responses to cocaine, such as self-administration tion changes induced by cocaine. Finally, we draw from the (Hall et al, 2004). An important frontier for addiction learning and memory field to discuss the extinction of neurobiology is to determine the precise, differential and/or cocaine-seeking behavior (Section IV). But first, how does overlapping roles DAT, SERT and NET play in the cocaine affect neuronal function? development of cocaine addiction. Since a large body of literature has examined the molecular/behavioral conse- Cocaine mechanism of action quences of cocaine binding to DAT, though, this review focuses on the effects of cocaine on dopaminergic One of the cocaine0s primary molecular actions is to block neurotransmission in the reward pathway. presynaptic dopamine (DA) reuptake transporters (DAT) DA-producing neurons of the reward pathway originate (Ritz et al, 1987, 1988; Kuhar et al, 1988) (see Figure 1). in the VTA and release DA in the NAc, medial prefrontal Although cocaine has an affinity for presynaptic norepi- cortex and limbic areas like the thalamus and amygdala. nephrine- and serotonin-reuptake transporters as well, it is DAT in the NAc region bridging NAc and VTA neurons believed that the reinforcing and rewarding properties of appears to be the primary target mediating cocaine0s cocaine are caused partly by indirect elevation of DA along rewarding and reinforcing effects (see Nestler, 2004 for Ventral tegmental area VENTRAL TEGMENTAL AREA NEURON Frontal cortex Nucleus accumbens 1 Cocaine site of action: blocks DAT DAT Neuroplastic changes in Cocaine VTA, NAc and mPFC DA 4 Gαs β γ 3 Gene activity 2 Protein production Signaling to nucleus Transcriptionally Transcriptionally inactive state active state Ac N Ac Ac N Ac Ac N A Ac C Ac Ac A T HATs C T G N C (eg. CBP) Ac G N A C A N G Ac T Ac N G Ac T E E N R R C HDACs (e.g. HDACs Ac Ac C Ac N 4 and 5) Ac Ac N N Ac TSA, SAHA, NaBut, VPA Figure 1. Cocaine causes transcription-dependent neuroplasticity in the reward pathway. (Brain top right): Cocaine alters the dynamics of numerou neurotransmitter systems in the mesocorticolimbic ‘reward pathway’ of the brain, which includes the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). These brain regions are critical for reward, reinforcement, and higher cognitive functions. (Main panel): Cocaine indirectly enhances the levels of the neurotransmitter DA at the interface between VTA cells and NAc cells by binding to and blocking DAT (top left). The subsequent activation of D1- and D2-like DA receptors stimulates intracellular signaling cascades that direct TF binding to DNA, facilitating neuroplasticity in response to cocaine intake. (DNA inset): Nucleosomes are in equilibrium between transcriptionally inactive and active states. HATs and HDACs have opposing actions to push the equilibrium one way or the other. Histone acetylation (by HATs) generally allows for TF binding and gene expression while histone deacetylation (by HDACs) represses transcription. Adapted from Nestler (2005) and McQuown and Wood (2010). .............................................................................................................................................. Neuropsychopharmacology REVIEWS Cocaine action and histone acetylation GA Rogge and MA Wood REVIEW ............................................................................................................................................................... 96 review). For a review of reward pathway anatomy and this review by discussing the evidence demonstrating that physiology please see Koob and Volkow (2010). Blockade of cocaine regulates gene expression via histone acetylation.
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