Preclinical Studies Shed Light on Individual Variation in Addiction
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HOT TOPICS ............................................................................................................................................................... 249 tin, with resulting H4K16ac hypo- acetylation and decreased H4K16ac binding onto GluA1 and GluA2 DNA sequences. In addition, a METH-in- duced MeCP2-CoREST-HDAC2 com- plex might preferentially be involved in the hypoacetylation of histone H4 at lysines 5 and 12. The present obser- vations add to the accumulating evi- dence that psychostimulants can cause substantial transcriptional and epig- enetic changes in the brain. These results also suggest that therapeutic approaches that involved the use of epigenetic agents might be important areas for future investigations. Figure 1. Models illustrating METH-induced epigenetic modifications in the dorsal striatum. Under 1 normal conditions, a balance exists between histone acetyltransferases (HATs) and histone Jean Lud Cadet and 1 deacetylases (HDACs) that regulate the histone acetylation/deacetylation status that control the Subramaniam Jayanthi mRNA expression of AMPA receptor subunits (a). Chronic METH exposure (b) increases the 1Molecular Neuropsychiatry Research Branch, expression of HDAC2, SIRT2, CoREST, and MeCP2. This is followed by the formation of protein National Institute on Drug Abuse/NIH/DHHS, repressor complexes that cause histone H4 hypoacetylation. Histone H4 hypoacetylation Bayview Boulevard, Baltimore, MD, USA then produces decreased expression of GluA1 and GuA2 in the dorsal striatum of chronically E-mail: [email protected] METH-exposed rats. DISCLOSURE The authors declare no conflict of interest. ........................................................................................... Gene transcription is regulated by duced decreased binding of acetylated Krasnova IN, Cadet JL (2009). Methamphetamine complex epigenetic changes that include H4K5, H4K12, and H4K16 on GluA1 toxicity and messengers of death. Brain Res Rev post-translational histone modifications and GluA2 DNA sequences. In addition, 60: 379–407. Mehler MF (2008). Epigenetic principles and and DNA methylation (Mehler, 2008). chronic METH administration enhan- mechanisms underlying nervous system functions There is evidence that epigenetic ced the recruitment of corepressor of in health and disease. Prog Neurobiol 86: 305– phenomena are intimately involved RE1 silencing transcription (CoREST) 341. McCoy MT, Jayanthi S, Wulu JA, Beauvais G, in the development and the clinical factor onto GluA1 and GluA2 DNA Ladenheim B, Martin TA et al (2011). Chronic course of complex neuropsychiatric sequences. METH also caused CoREST methamphetamine exposure suppresses the stria- diseases including addiction (Robison co-immunoprecipitation with histone tal expression of members of multiple families of immediate early genes (IEGs) in the rat: normal- and Nestler, 2011). Therefore, we deacetylase 2 (HDAC2) and sirtuin 2 ization by an acute methamphetamine injection. thought it likely that METH might (SIRT2). Moreover, METH increased Psychopharmacology 215: 353–365. engender transcriptional and epi- enrichment of methyl CpG binding Robison AJ, Nestler EJ (2011). Transcriptional and epigenetic mechanisms of addiction. Nat Rev genetic alterations that are unique to protein 2 (MeCP2) on the promoters Neurosci 12: 623–637. this clinically devastating drug. of both GluA1 and GluA2, with co- Wolf ME, Ferrario CR (2010). AMPA receptor As a first step toward clarifying immunoprecipitation studies revealing plasticity in the nucleus accumbens after repeated exposure to cocaine. Neurosci Biobehav Rev 35: the effects of METH on glutamatergic METH-induced MeCP2 interactions 185–211. function, we treated rats with an esca- with HDAC2. Finally, we demonstrated lating METH dose paradigm that that the FDA-approved HDAC inhibi- Neuropsychopharmacology Reviews (2013) 38, 248–249; started at METH (0.5 mg/kg twice/ tor, valproic acid, prevented METH- doi:10.1038/npp.2012.169 day) and ended with METH (3 mg/kg induced downregulation of GluA1 and four times per day) over a period of GluA2 mRNA levels. 2weeks(McCoyet al,2011).Wefound In summary, the present study Preclinical Studies Shed that chronic METH caused significant provides direct evidence for epigenetic decreases in mRNA and protein levels regulation of chronic transcriptional Light on Individual of both GluA1 and GluA2 AMPA effects of METH in the dorsal stria- Variation in Addiction receptor subunits. We also found that tum. Figure 1 provides a scheme Vulnerability METH caused significant decreases in that describes a potential role of acetylation of histone H4 at lysine 5 CoREST, HDAC2, MeCP2, and SIRT2 (H4K5), lysine 12 (H4K12), and lysine in the mediation of METH-induced Cues associated with drug use attract 16 (H4K16). Using chromatin immu- downregulation of GluA1 and GluA2 the attention of addicts, draw them to noprecipitation-PCR assay, we found mRNA levels. Specifically, CoREST locations where drugs are located, and that repeated METH injections pro- might recruit SIRT2 onto the chroma- motivate drug-seeking—often leading .............................................................................................................................................. Neuropsychopharmacology HOT TOPICS ............................................................................................................................................................... 250 to relapse—even in the face of an et al, 2012). First, there are neurobio- Lomanowska AM, Lovic V, Rankine MJ, Mooney SJ, expressed desire to remain abstinent. logical differences between STs and Robinson TE, Kraemer GW (2011). Inadequate early social experience increases the incentive There is, however, considerable indi- GTs, including differences in dopami- salience of reward-related cues in adulthood. vidual variation in the ability of nergic systems (Flagel et al, 2011; Behav Brain Res 220: 91–99. reward cues to gain motivational Flagel et al, 2010). Second, the varia- Meyer PJ, Lovic V, Saunders BT, Yager LM, Flagel control over behavior. Emerging evi- tion is heritable (Flagel et al, 2010), SB, Morrow JD et al (2012). Quantifying individual variation in the propensity to attribute incentive dence from preclinical studies sug- indicating that some unknown genetic salience to reward cues. PLoS One 7: e38987. gests that such variation is due, at differences contribute to variation in Saunders BT, Robinson TE (2010). A cocaine cue least in part, to intrinsic differences in reward cue processing. Third, the acts as an incentive stimulus in some but not others: implications for addiction. Biol Psychiatry the extent to which reward cues are extent to which rats become STs or 67: 730–736. attributed with incentive salience, GTs is influenced by early life experi- Saunders BT, Robinson TE (2011). Individual variation thereby acquiring the properties of ences (Lomanowska et al, 2011), in the motivational properties of cocaine. Neuro- incentive stimuli. When a Pavlovian suggesting that environmental factors psychopharmacology 36: 1668–1676. conditional stimulus (CS) reliably also contribute to how individuals Neuropsychopharmacology Reviews (2013) 38, 249–250; predicts delivery of a food reward, process and respond to reward cues doi:10.1038/npp.2012.161 for some rats (sign-trackers; STs), the in adulthood. In conclusion, this line CS itself becomes attractive, in that of research provides a novel approach these rats approach and interact with to understanding the interplay be- the CS, and becomes ‘wanted’, in that tween genetic, epigenetic, environ- Fractionating the these rats will work just to obtain the mental, and neural-systems-level Impulsivity Construct CS. For other rats (goal-trackers; factors that confer susceptibility (and in Adolescence GTs), the CS itself is not attractive, resilience) to impulse-control disor- but instead evokes conditioned ap- ders, such as addiction. Implications proach towards the location of food for the development of clinical inter- The teenage years are often associ- delivery (rather than the CS), and GTs vention strategies include: (1) greater ated with ‘impulsive’ behavior; that is, will not work avidly to get the CS attention to individual differences in behavior with diminished regard to (Meyer et al, 2012). Importantly, the psychological factors that control potential negative consequences. variation in the propensity to attribute pathological motivation for drugs, and Adolescent impulsivity, while often incentive salience to a food cue pre- (2) greater recognition that, in sus- adaptive, can manifest itself in a range dicts the extent to which drug cues ceptible individuals, drug cues may be of sub-optimal behaviors, including gain motivational control over beha- especially insidious in instigating and use of nicotine, alcohol, or illicit vior. For example, a cocaine-asso- maintaining drug-seeking behavior. substances, symptoms associated with ciated cue is more effective in attention deficit hyperactivity disorder maintaining self-administration beha- (ADHD), or poorer performance on ACKNOWLEDGEMENTS vior, and instigates more robust re- laboratory assays of impulse control. lapse behavior, in STs than GTs This research was supported by the Although these maladaptive behaviors (Saunders and Robinson, 2010). Addi- National Institute on Drug Abuse are often co-morbid, their correlation tionally, STs will exert more effort grants to BTS (F31 DA030801), LMY is not perfect. It is therefore increas-