Abstract
Rationale
A challenge in treating substance use disorder is that successful treatment often does not persist, resulting in relapse and continued drug seeking. One approach to persistently weaken drug-seeking behaviors is to pair exposure to drug-associated cues or behaviors with delivery of a compound that may strengthen the inhibition of the association between drug cues and behavior.
Objectives
We evaluated whether a selective histone deacetylase 3 (HDAC3) inhibitor could promote extinction and weaken contextual control of operant drug seeking after intravenous cocaine self-administration.
Methods
Male Long-Evans rats received a systemic injection of the HDAC3 inhibitor RGFP966 either before or immediately after the first extinction session. Persistence of extinction was tested over subsequent extinction sessions, as well as tests of reinstatement that included cue-induced reinstatement, contextual renewal, and cocaine-primed reinstatement. Additional extinction sessions occurred between each reinstatement test. We also evaluated effects of RGFP966 on performance and motivation during stable fixed ratio operant responding for cocaine and during a progressive ratio of reinforcement.
Results
RGFP966 administered before the first extinction session led to significantly less responding during subsequent extinction and reinstatement tests compared to vehicle-injected rats. Follow-up studies found that these effects were not likely due to a performance deficit or a change in motivation to self-administer cocaine, as injections of RGFP966 had no effect on stable responding during a fixed or progressive ratio schedule. In addition, RGFP966 administered just after the first extinction session had no effect during early extinction and reinstatement tests, but weakened long-term responding during later extinction sessions.
Conclusions
These results suggest that a systemic injection of a selective HDAC3 inhibitor can enhance extinction and suppress reinstatement after cocaine self-administration. The finding that behavioral and pharmacological manipulations can be combined to decrease drug seeking provides further potential for treatment by epigenetic modulation.
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References
Alaghband Y, Kwapis JL, López AJ, White AO, Aimiuwu OV, Al-Kachak A et al (2017) Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory. Neurobiol Learn Mem 145:94–104. https://doi.org/10.1016/j.nlm.2017.09.001
Andersen CL, Mcmullin MF, Ejerblad E, Zweegman S, Harrison C, Fernandes S et al (2013) A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia. Br J Haematol 162(4):498–508. https://doi.org/10.1111/bjh.12416
Arrar M, de Oliveira CAF, McCammon JA (2013) Inactivating mutation in histone deacetylase 3 stabilizes its active conformation. Protein Sci 22(10):1306–1312. https://doi.org/10.1002/pro.2317
Berglind WJ, See RE, Fuchs RA, Ghee SM, Whitfield TW, Miller SW, McGinty JF (2007) A BDNF infusion into the medial prefrontal cortex suppresses cocaine seeking in rats. Eur J Neurosci 26:757–766. https://doi.org/10.1111/j.1460-9568.2007.05692.x
Bieszczad KM, Bechay K, Rusche JR, Jacques V, Kudugunti S, Miao W, Weinberger NM, McGaugh JL, Wood MA (2015) Histone deacetylase inhibition via RGFP966 releases the brakes on sensory cortical plasticity and the specificity of memory formation. J Neurosci 35(38):13124–13132. https://doi.org/10.1523/JNEUROSCI.0914-15.2015
Blank M, Dornelles AS, Werenicz A, Velho LA, Pinto DF, Fedi AC, Schröder N, Roesler R (2014) Basolateral amygdala activity is required for enhancement of memory consolidation produced by histone deacetylase inhibition in the hippocampus. Neurobiol Learn Mem 111(1–8):1–8. https://doi.org/10.1016/j.nlm.2014.02.009
Bossert JM, Marchant NJ, Calu DJ, Shaham Y (2013) The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology 229:453–476. https://doi.org/10.1007/s00213-013-3120-y
Bongiovanni M, See RE (2008) A comparison of the effects of different operant training experiences and dietary restriction on the reinstatement of cocaine-seeking in rats. Pharmacol Biochem Behav 89(2):227–233.
Bousiges O, Neidl R, Majchrzak M, Muller MA, Barbelivien A, Pereira de Vasconcelos A, Schneider A, Loeffler JP, Cassel JC, Boutillier AL (2013) Detection of histone acetylation levels in the dorsal hippocampus reveals early tagging on specific residues of H2B and H4 histones in response to learning. PLoS One 8(3):e57816. https://doi.org/10.1371/journal.pone.0057816
Bouton ME, Todd TP (2014) A fundamental role for context in instrumental learning and extinction. Behav Process 104:13–19
Bowers ME, Xia B, Carreiro S, Ressler KJ (2015) The Class I HDAC inhibitor RGFP963 enhances consolidation of cued fear extinction. Learn Mem 22(4):225–231. https://doi.org/10.1101/lm.036699.114
Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. 14:268–276. https://doi.org/10.1101/lm.500907.lation
Broide RS, Redwine JM, Aftahi N, Young W, Bloom FE, Winrow CJ (2007) Distribution of histone deacetylases 1-11 in the rat brain. J Mol Neurosci 31:47–58. https://doi.org/10.1007/BF02686117
Castino MR, Cornish JL, Clemens KJ, Wittnam J, Held T, Bahr M (2015) Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats. PLoS One 10(4):e0124796. https://doi.org/10.1371/journal.pone.0124796
Crombag HS, Shaham Y (2002) Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav Neurosci 116(1):169–173. https://doi.org/10.1037/0735-7044.116.1.169
Crombag HS, Grimm JW, Shaham Y (2002) Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues. Neuropsychopharmacology 27(6):1006–1015. https://doi.org/10.1016/S0893-133X(02)00356-1
Dagnas M, Micheau J, Decorte L, Beracochea D, Mons N (2015) Post-training, intrahippocampal HDAC inhibition differentially impacts neural circuits underlying spatial memory in adult and aged mice. Hippocampus 25(7):827–837. https://doi.org/10.1002/hipo.22406
Depoortere RY, Li DH, Lane JD, Emmett-Oglesby MW (1993) Parameters of self-administration of cocaine in rats under a progressive-ratio schedule. Pharmacol Biochem Behav 45(3):539–548
Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5:981–989. https://doi.org/10.1158/1541-7786.MCR-07-0324
Farrell M R, Schoch H, Mahler SV (2018) Modeling cocaine relapse in rodents: Behavioral considerations and circuit mechanisms. Prog Neuro-Psychopharmacol Biol Psychiatry
Foley AG, Cassidy AW, Regan CM (2014) Pentyl-4-yn-VPA, a histone deacetylase inhibitor, ameliorates deficits in social behavior and cognition in a rodent model of autism spectrum disorders. Eur J Pharmacol 727:80–86. https://doi.org/10.1016/j.ejphar.2014.01.050
Fuchs RA, Tran-Nguyen LTL, Specio SE, Groff RS, Neisewander JL (1998) Predictive validity of the extinction/reinstatement model of drug craving. Psychopharmacology 135(2):151–160. https://doi.org/10.1007/s002130050496
Fuchs RA, Evans KA, Ledford CC, Parker MP, Case JM, Mehta RH, See RE (2005) The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats. Neuropsychopharmacology 30(2):296–309. https://doi.org/10.1038/sj.npp.1300579
Gabriele A, Pacchioni AM, See RE (2012) Dopamine and glutamate release in the dorsolateral caudate putamen following withdrawal from cocaine self-administration in rats. Pharmacol Biochem Behav 103(2):373–379. https://doi.org/10.1016/j.pbb.2012.09.015
Gaglio D, Capitano F, Mastrodonato A, Minicocci E, Deiana C, Fragapane P, Camilloni G, Mele A (2014) Learning induced epigenetic modifications in the ventral striatum are necessary for long-term memory. Behav Brain Res 265:61–68. https://doi.org/10.1016/j.bbr.2014.02.006
Guan J-S, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJF, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai L-H (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459(7243):55–60. https://doi.org/10.1038/nature07925
Gulick D, Gould TJ (2007) Acute ethanol has biphasic effects on short‐and long‐term memory in both foreground and background contextual fear conditioning in C57BL/6 mice. Alcoholism: Clinical and Experimental Research, 31(9): 1528–1537.
Hitchcock LN, Lattal KM (2014) Histone-mediated epigenetics in addiction. In: Akbarian S, Lubin F (eds) Progress in Molecular Biology and translational Science. Epigenetics and Neuroplasticity - Evidence and Debate, vol 128, 128th edn. Elsevier Inc, pp 51–87. https://doi.org/10.1016/B978-0-12-800977-2.00003-6
Hitchcock LN, Lattal KM (2018) Involvement of the dorsal hippocampus in expression and extinction of cocaine-induced conditioned place preference. Hippocampus 28(3):226–238
Hitchcock LN, Cunningham CL, Lattal KM (2014) Cue configuration effects in acquisition and extinction of a cocaine-induced place preference. Behav Neurosci 128(2):217–227
Jeanblanc J, Lemoine S, Jeanblanc V, Alaux-Cantin SS, Naassila MM (2015) The class I-specific HDAC inhibitor MS-275 decreases motivation to consume alcohol and relapse in heavy drinking rats. Int J Neuropsychopharmacol 18:1–9. https://doi.org/10.1093/ijnp/pyv029
Kennedy PJ, Harvey E (2015) Histone deacetylases as potential targets for cocaine addiction. CNS Neurol Disord Drug Targets 14(6):764–772
Kiefer F, Dinter C (2013) New approaches to addiction treatment based on learning and memory. Curr Top Behav Neurosci 13:671–684. https://doi.org/10.1007/7854_2011_147
Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705. https://doi.org/10.1016/j.cell.2007.02.005
Kuntz-Melcavage KL, Brucklacher RM, Grigson PS, Freeman WM, Vrana KE (2009) Gene expression changes following extinction testing in a heroin behavioral incubation model. BMC Neurosci 10:95. https://doi.org/10.1186/1471-2202-10-95
Lattal KM, Barrett RM, Wood MA (2007) Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav Neurosci 121(5):1125–1131. https://doi.org/10.1037/0735-7044.121.5.1125
Liu XF, Bagchi MK (2004) Recruitment of distinct chromatin-modifying complexes by tamoxifen-complexed estrogen receptor at natural target gene promoters in vivo. J Biol Chem 279(15):15050–15058. https://doi.org/10.1074/jbc.M311932200
Lopez-Atalaya JP, Ito S, Valor LM, Benito E, Barco A (2013) Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition. Nucleic Acids Res 41(17):8072–8084. https://doi.org/10.1093/nar/gkt590
Malvaez M, Sanchis-Segura C, Vo D, Lattal KM, Wood MA (2010) Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference. Biol Psychiatry 67(1):36–43. https://doi.org/10.1016/j.biopsych.2009.07.032
Malvaez M, McQuown SC, Rogge GA, Astarabadi M, Jacques V, Carreiro S et al (2013) HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci 110(7):2647–2652. https://doi.org/10.1073/pnas.1213364110
Malvaez M, Greenfield VY, Matheos DP, Angelillis NA, Murphy MD, Kennedy PJ, Wood MA, Wassum KM (2018) Habits are negatively regulated by histone deacetylase 3 in the dorsal striatum. Biol Psychiatry 84:383–392
Maze I, Noh K-M, Allis CD (2012) Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 38(1):3–22. https://doi.org/10.1038/npp.2012.124
McQuown SC, Wood MA (2011) HDAC3 and the molecular brake pad hypothesis. Neurobiol Learn Mem 96(1):27–34. https://doi.org/10.1016/j.nlm.2011.04.005
McQuown SC, Barrett RM, Matheos DP, Post RJ, Rogge GA, Alenghat T et al (2011) HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci 31(2):764–774. https://doi.org/10.1523/JNEUROSCI.5052-10.2011
Millan EZ, Marchant NJ, McNally GP (2011) Extinction of drug seeking. Behav Brain Res 217(2): 454–462.
Morrison FG, Ressler KJ (2014) From the neurobiology of extinction to improved clinical treatments. Depress Anxiety 31(4):279–290. https://doi.org/10.1002/da.22214
Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LTL, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20(2):798–805. https://doi.org/10.1038/466194a
Nott A, Cheng J, Gao F, Lin YT, Gjoneska E, Ko T et al (2016) Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat Neurosci 19(11):1497–1505. https://doi.org/10.1038/nn.4347
Penney J, Tsai L-H (2014) Histone deacetylases in memory and cognition. Sci Signal 7(355):re12. https://doi.org/10.1126/scisignal.aaa0069
Phan ML, Gergues MM, Mahidadia S, Jimenez-Castillo J, Vicario DS, Bieszczad KM (2017) Hdac3 inhibitor Rgfp966 modulates neuronal memory for vocal communication signals in a songbird model. Front Syst Neurosci 11:65
Pizzimenti CL, Lattal KM (2015) Epigenetics and memory: causes, consequences and treatments for post‐traumatic stress disorder and addiction. Genes, Brain and Behavior, 14(1):73–84.
Pizzimenti CL, Navis TM, Lattal K M (2017) Persistent effects of acute stress on fear and drugseeking in a novel model of the comorbidity between post-traumatic stress disorder and addiction. Learning & Memory, 24(9):422–431.
Ploense KL, Kerstetter KA, Wade MA, Woodward NC, Maliniak D, Reyes M, Kippin TE (2013) Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior. Behav. Pharmacol. 24(3):164-171
Rai M, Soragni E, Chou CJ, Barnes G, Jones S, Rusche JR, Gottesfeld JM, Pandolfo M (2010) Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from Friedreich’s ataxia patients and in a mouse model. PLoS One 5(1):e8825. https://doi.org/10.1371/journal.pone.0008825
Raybuck JD, McCleery EJ, Cunningham CL, Wood MA, Lattal KM (2013) The histone deacetylase inhibitor sodium butyrate modulates acquisition and extinction of cocaine-induced conditioned place preference. Pharmacol Biochem Behav 106:109–116. https://doi.org/10.1016/j.pbb.2013.02.009
Richardson NR, Roberts DCS (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66(1):1–11. https://doi.org/10.1016/0165-0270(95)00153-0
Rogge GA, Wood MA (2013) The role of histone acetylation in cocaine-induced neural plasticity and behavior. Neuropsychopharmacology, 38(1):94.
Rogge GA, Singh H, Dang R, Wood MA (2013) HDAC3 is a negative regulator of cocaine-context-associated memory formation. J Neurosci 33(15):6623–6632. https://doi.org/10.1523/JNEUROSCI.4472-12.2013
Romieu P, Host L, Gobaille S, Sandner G, Aunis D, Zwiller J (2008) Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats. J Neurosci 28(38):9342–9348. https://doi.org/10.1523/JNEUROSCI.0379-08.2008
Romieu P, Deschatrettes E, Host L, Gobaille S, Sandner G, Zwiller J (2011) The inhibition of histone deacetylases reduces the reinstatement of cocaine-seeking behavior in rats. Curr Neuropharmacol 9(1):21–25. https://doi.org/10.2174/157015911795017317
Rosen HJ, Pace-Savitsky K, Perry RJ, Kramer JH, Miller BL, Levenson RW (2004) Recognition of emotion in the frontal and temporal variants of frontotemporal dementia. Dement Geriatr Cogn Disord 17(4):277–281. https://doi.org/10.1159/000077154
Rosenberg T, Gal-Ben-Ari S, Dieterich DC, Kreutz MR, Ziv NE, Gundelfinger ED, Rosenblum K (2014) The roles of protein expression in synaptic plasticity and memory consolidation. Front Mol Neurosci 7:1–14. https://doi.org/10.3389/fnmol.2014.00086
Sakharkar AJ, Zhang H, Tang L, Shi G, Pandey SC (2012) Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol. Alcohol Clin Exp Res 36(1):61–71. https://doi.org/10.1111/j.1530-0277.2011.01581.x
Sarkar S, Abujamra AL, Loew JE, Forman LW, Perrine SP, Faller DV (2011) Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling. Anticancer Res 31(9):2723–2732 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21868513
Schroeder FA, Lin CL, Crusio WE, Akbarian S (2007) Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry 62(1):55–64
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20. https://doi.org/10.1007/s00213-002-1224-x
Simon-O’Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (2015) The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals. Addict Biol 20(4):676–689. https://doi.org/10.1111/adb.12161
Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ (2015) Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther 149:150–190
Stafford JM, Raybuck JD, Ryabinin AE, Lattal KM (2012) Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry 72(1):25–33. https://doi.org/10.1016/j.biopsych.2011.12.012
Tran L, Schulkin J, Ligon CO, Greenwood-Van Meerveld B (2014) Epigenetic modulation of chronic anxiety and pain by histone deacetylation. Mol Psychiatry 20:1–13. https://doi.org/10.1038/mp.2014.122
Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Cabrera SM, McDonough CB, Brindle PK, Abel T, Wood MA (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci 27(23):6128–6140. https://doi.org/10.1523/JNEUROSCI.0296-07.2007
Venniro M, Caprioli D, Shaham Y (2016) Animal models of drug relapse and craving: from drug priming-induced reinstatement to incubation of craving after voluntary abstinence. Prog Brain Res 224:25–52. https://doi.org/10.1016/bs.pbr.2015.08.004
Wang Y, Lai J, Cui H, Zhu Y, Zhao B, Wang W, Wei S (2015) Inhibition of histone deacetylase in the basolateral amygdala facilitates morphine context-associated memory formation in rats. J Mol Neurosci 55(1):269–278. https://doi.org/10.1007/s12031-014-0317-4
Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP et al (2001) Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci 937:1–26. https://doi.org/10.1111/j.1749-6632.2001.tb03556.x
Whittle N, Singewald N (2014) HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand? Biochem Soc Trans 42:569–581
Whittle N, Schmuckermair C, Gunduz Cinar O, Hauschild M, Ferraguti F, Holmes A, Singewald N (2013) Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model. Neuropharmacology 64:414–426. https://doi.org/10.1016/j.neuropharm.2012.06.001
Whittle N, Maurer V, Murphy C, Rainer J, Bindreither D, Hauschild M et al (2016) Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction. Transl Psychiatry 6(12):e974
Funding
Financial support was provided by the National Institute on Drug Abuse (NIDA) grants P50DA018165 (KML), R01DA025922 (KML and MAW) and R01DA025922S1 (KML and MAW), and T32DA007262 (LNH); the Department of Defense grant W81XWH-12-2-0048 (KML); and the American Psychological Association APA 1006636 (LNH).
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This article belongs to a Special Issue on Psychopharmacology of Extinction
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Hitchcock, L.N., Raybuck, J.D., Wood, M.A. et al. Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats. Psychopharmacology 236, 517–529 (2019). https://doi.org/10.1007/s00213-018-5122-2
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DOI: https://doi.org/10.1007/s00213-018-5122-2