Advertisement

Adaptations in nucleus accumbens neuron subtypes mediate negative affective behaviors in fentanyl abstinence

      Abstract

      Background

      Opioid discontinuation generates a withdrawal syndrome marked by increased negative affect. Increased symptoms of anxiety and dysphoria during opioid discontinuation are a significant barrier to achieving long-term abstinence in opioid-dependent individuals. While adaptations in the nucleus accumbens are implicated in the opioid abstinence syndrome, the precise neural mechanisms are poorly understood. Additionally, our current knowledge is limited to changes following natural and semi-synthetic opioids, despite recent increases in synthetic opioid use and overdose.

      Methods

      We used a combination of cell subtype specific viral-labeling and electrophysiology in male and female mice to investigate structural and functional plasticity in nucleus accumbens medium spiny neuron (MSNs) subtypes after fentanyl abstinence. We characterized molecular adaptations after fentanyl abstinence with subtype specific RNAseq and Weighted Gene Co-expression Network Analysis. We used viral-mediated gene transfer to manipulate the molecular signature of fentanyl abstinence in D1-MSNs.

      Results

      Here we show fentanyl abstinence increases anxiety-like behavior, decreases social interaction, and engenders MSN subtype-specific plasticity in both sexes. D1, but not D2-MSNs exhibit dendritic atrophy and an increase in excitatory drive. We identified a cluster of co-expressed dendritic morphology genes downregulated selectively in D1-MSNs that are transcriptionally co-regulated by E2F1. E2f1 expression in D1-MSNs protects against loss of dendritic complexity, altered physiology, and negative affect-like behaviors caused by fentanyl abstinence.

      Conclusion

      Our findings indicate fentanyl abstinence causes unique structural, functional, and molecular changes in nucleus accumbens D1-MSNs that can be targeted to alleviate negative affective symptoms during abstinence.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Drug Enforcement Administration (2016): Counterfeit prescription pills containing fentanyls: A global threat. DEA Intelligence Brief. Retrieved April 13, 2022, from https://www.safemedicines.org/2018/06/fentanyl-has-created-a-new-kind-of-21st-century-drug-kingpin.html

      2. Ahmad F, Rossen L, Sutton P (2021): Provisional drug overdose death counts. National Center for Health Statistics. Des by LM Rossen, A Lipphardt, FB Ahmad, JM Keralis, Y Chong Natl Cent Heal Stat. Retrieved from https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm

        • Volkow N.D.
        • Koob G.F.
        • McLellan A.T.
        Neurobiologic Advances from the Brain Disease Model of Addiction.
        N Engl J Med. 2016; 374: 363-371
        • Koob G.F.
        Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement.
        Biol Psychiatry. 2020; 87: 44-53
      3. Jordan CJ, Xi ZX (2022): Identification of the Risk Genes Associated With Vulnerability to Addiction: Major Findings From Transgenic Animals. Front Neurosci 15. https://doi.org/10.3389/FNINS.2021.811192

      4. Reiner DJ, Fredriksson I, Lofaro OM, Bossert JM, Shaham Y (2019, February 6): Relapse to opioid seeking in rat models: behavior, pharmacology and circuits. Neuropsychopharmacology, vol. 44. Nature Publishing Group, pp 465–477.

      5. Browne CJ, Godino A, Salery M, Nestler EJ (2020, January 1): Epigenetic Mechanisms of Opioid Addiction. Biological Psychiatry, vol. 87. Elsevier USA, pp 22–33.

        • Rossetti Z.L.
        • Hmaidan Y.
        • Gessa G.L.
        Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats.
        Eur J Pharmacol. 1992; 221: 227-234
        • Acquas E.
        • Carboni E.
        • Di Chiara G.
        Profound depression of mesolimbic dopamine release after morphine withdrawal in dependent rats.
        Eur J Pharmacol. 1991; 193: 133-134
        • Pothos E.
        • Rada P.
        • Mark G.P.
        • Hoebel B.G.
        Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment.
        Brain Res. 1991; 566: 348-350
        • Fox M.E.
        • Nathan Rodeberg T.
        • Mark Wightman R.
        • Rodeberg N.T.
        • Wightman R.M.
        Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal.
        Neuropsychopharmacology. 2017; 42: 671-681
        • Cahill M.E.
        • Browne C.J.
        • Wang J.
        • Hamilton P.J.
        • Dong Y.
        • Nestler E.J.
        Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure.
        J Neurochem. 2018; 147: 84-98
        • Sun H.S.
        • Martin J.A.
        • Werner C.T.
        • Wang Z.J.
        • Damez-Werno D.M.
        • Scobie K.N.
        • et al.
        BAZ1B in nucleus accumbens regulates reward-related behaviors in response to distinct emotional stimuli.
        J Neurosci. 2016; 36: 3954-3961
        • Mayberry H.L.
        • Bavley C.C.
        • Karbalaei R.
        • Peterson D.R.
        • Bongiovanni A.R.
        • Ellis A.S.
        • et al.
        Transcriptomics in the nucleus accumbens shell reveal sex- and reinforcer-specific signatures associated with morphine and sucrose craving.
        Neuropsychopharmacology. 2022; https://doi.org/10.1038/S41386-022-01289-2
        • Ferguson D.
        • Koo J.W.
        • Feng J.
        • Heller E.
        • Rabkin J.
        • Heshmati M.
        • et al.
        Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action.
        J Neurosci. 2013; 33: 16088-16098
        • Spijker S.
        • Houtzager S.W.J.
        • De Gunst M.C.M.
        • De Boer W.P.H.
        • Schoffelmeer A.N.M.
        • Smit A.B.
        Morphine exposure and abstinence define specific stages of gene expression in the rat nucleus accumbens.
        FASEB J. 2004; 18: 848-850
        • Martin J.A.
        • Werner C.T.
        • Mitra S.
        • Zhong P.
        • Wang Z.J.
        • Gobira P.H.
        • et al.
        A novel role for the actin-binding protein drebrin in regulating opiate addiction.
        Nat Commun. 2019; 10: 4140
        • Townsend E.A.
        • Kim R.K.
        • Robinson H.L.
        • Marsh S.A.
        • Banks M.L.
        • Hamilton P.J.
        Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription.
        Biol psychiatry Glob open Sci. 2021; 1: 112
        • Hofford R.S.
        • Mervosh N.L.
        • Euston T.J.
        • Meckel K.R.
        • Orr A.T.
        • Kiraly D.D.
        Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to morphine.
        Neuropsychopharmacology. 2021; 46: 2062-2072
        • McDevitt D.S.
        • Jonik B.
        • Graziane N.M.
        Morphine Differentially Alters the Synaptic and Intrinsic Properties of D1R- and D2R-Expressing Medium Spiny Neurons in the Nucleus Accumbens.
        Front Synaptic Neurosci. 2019; 11https://doi.org/10.3389/fnsyn.2019.00035
        • Graziane N.M.
        • Sun S.
        • Wright W.J.
        • Jang D.
        • Liu Z.
        • Huang Y.H.
        • et al.
        Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses.
        Nat Neurosci. 2016; 19: 915-925
        • Wu X.
        • Shi M.
        • Ling H.
        • Wei C.
        • Liu Y.
        • Liu Z.
        • Ren W.
        Effects of morphine withdrawal on the membrane properties of medium spiny neurons in the nucleus accumbens shell.
        Brain Res Bull. 2013; 90: 92-99
        • Madayag A.C.
        • Gomez D.
        • Anderson E.M.
        • Ingebretson A.E.
        • Thomas M.J.
        • Hearing M.C.
        Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal.
        Brain Struct Funct. 2019; 224: 2311-2324
        • Wu X.
        • Shi M.
        • Wei C.
        • Yang M.
        • Liu Y.
        • Liu Z.
        • et al.
        Potentiation of synaptic strength and intrinsic excitability in the nucleus accumbens after 10 days of morphine withdrawal.
        J Neurosci Res. 2012; 90: 1270-1283
        • Hearing M.C.
        • Jedynak J.
        • Ebner S.R.
        • Ingebretson A.
        • Asp A.J.
        • Fischer R.A.
        • et al.
        Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement.
        Proc Natl Acad Sci U S A. 2016; 113: 757-762
        • Spiga S.
        • Puddu M.C.
        • Pisano M.
        • Diana M.
        Morphine withdrawal-induced morphological changes in the nucleus accumbens.
        Eur J Neurosci. 2005; 22: 2332-2340
        • Diana M.
        • Spiga S.
        • Acquas E.
        Persistent and reversible morphine withdrawal-induced morphological changes in the nucleus accumbens.
        Annals of the New York Academy of Sciences. 2006; 1074 1074: 446-457
        • Robinson T.E.
        • Kolb B.
        Structural plasticity associated with exposure to drugs of abuse.
        Neuropharmacology. 2004; 47: 33-46
        • Heng L.-J.
        • Yang J.
        • Liu Y.-H.
        • Wang W.-T.
        • Hu S.-J.
        • Gao G.-D.
        Repeated morphine exposure decreased the nucleus accumbens excitability during short-term withdrawal.
        Synapse. 2008; 62: 775-782
      6. Thompson BL, Oscar-Berman M, Kaplan GB (2021, January 1): Opioid-induced structural and functional plasticity of medium-spiny neurons in the nucleus accumbens. Neuroscience and Biobehavioral Reviews, vol. 120. Elsevier Ltd, pp 417–430.

        • Matsubara T.
        • Matsuo K.
        • Nakashima M.
        • Nakano M.
        • Harada K.
        • Watanuki T.
        • et al.
        Morphine alters the structure of neurons in the nucleus accumbens and neocortex of rats.
        Synapse. 1999; 85: 160-162
        • Pal A.
        • Das S.
        Chronic morphine exposure and its abstinence alters dendritic spine morphology and upregulates Shank1.
        Neurochem Int. 2013; 62: 956-964
        • Gerfen C.R.
        • Surmeier D.J.
        Modulation of Striatal Projection Systems by Dopamine.
        Annu Rev Neurosci. 2011; 34: 441-466
        • Kupchik Y.M.
        • Brown R.M.
        • Heinsbroek J.A.
        • Lobo M.K.
        • Schwartz D.J.
        • Kalivas P.W.
        Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.
        Nat Neurosci. 2015; 18: 1230-1232
        • Smith R.J.
        • Lobo M.K.
        • Spencer S.
        • Kalivas P.W.
        Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways).
        Current Opinion in Neurobiology. 2013, August; 23: 546-552
        • Calipari E.S.
        • Bagot R.C.
        • Purushothaman I.
        • Davidson T.J.
        • Yorgason J.T.
        • Peña C.J.
        • et al.
        In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward.
        Proc Natl Acad Sci. 2016; 113: 2726-2731
        • Lobo M.K.
        • Covington H.E.
        • Chaudhury D.
        • Friedman A.K.
        • Sun H.S.
        • Damez-Werno D.
        • et al.
        Cell type - Specific loss of BDNF signaling mimics optogenetic control of cocaine reward.
        Science. 2010; 330: 385-390
        • Hauser S.R.
        • Deehan G.A.
        • Dhaher R.
        • Knight C.P.
        • Wilden J.A.
        • McBride W.J.
        • Rodd Z.A.
        D1 receptors in the nucleus accumbens-shell, but not the core, are involved in mediating ethanol-seeking behavior of alcohol-preferring (P) rats.
        Neuroscience. 2015; 295: 243-251
        • Koo J.W.
        • Lobo M.K.
        • Chaudhury D.
        • Labonté B.
        • Friedman A.
        • Heller E.
        • et al.
        Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition.
        Neuropsychopharmacology. 2014; 39: 2646-2653
        • Kravitz A.V.
        • Tye L.D.
        • Kreitzer A.C.
        Distinct roles for direct and indirect pathway striatal neurons in reinforcement.
        Nat Neurosci. 2012; 15: 816-818
        • James A.S.
        • Chen J.Y.
        • Cepeda C.
        • Mittal N.
        • Jentsch J.D.
        • Levine M.S.
        • et al.
        Opioid self-administration results in cell-type specific adaptations of striatal medium spiny neurons.
        Behav Brain Res. 2013; 256: 279-283
        • Hikida T.
        • Kimura K.
        • Wada N.
        • Funabiki K.
        • Nakanishi S.
        Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior.
        Neuron. 2010; 66: 896-907
        • Tai L.H.
        • Lee A.M.
        • Benavidez N.
        • Bonci A.
        • Wilbrecht L.
        Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value.
        Nat Neurosci. 2012; 15: 1281-1289
        • Gallo E.F.
        • Meszaros J.
        • Sherman J.D.
        • Chohan M.O.
        • Teboul E.
        • Choi C.S.
        • et al.
        Accumbens dopamine D2 receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum.
        Nat Commun. 2018; 9https://doi.org/10.1038/s41467-018-03272-2
        • Soares-Cunha C.
        • Coimbra B.
        • David-Pereira A.
        • Borges S.
        • Pinto L.
        • Costa P.
        • et al.
        Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation.
        Nat Commun. 2016; 711829
        • Soares-Cunha C.
        • de Vasconcelos N.A.P.
        • Coimbra B.
        • Domingues A.V.
        • Silva J.M.
        • Loureiro-Campos E.
        • et al.
        Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.
        Mol Psychiatry. 2019; : 1-15
        • Gibson G.D.
        • Prasad A.A.
        • Jean-Richard-dit-Bressel P.
        • Yau J.O.Y.
        • Millan E.Z.
        • Liu Y.
        • et al.
        Distinct Accumbens Shell Output Pathways Promote versus Prevent Relapse to Alcohol Seeking.
        Neuron. 2018; 98 (e6): 512-520
        • Natsubori A.
        • Tsutsui-Kimura I.
        • Nishida H.
        • Bouchekioua Y.
        • Sekiya H.
        • Uchigashima M.
        • et al.
        Ventrolateral striatal medium spiny neurons positively regulate food-incentive, goal-directed behavior independently of D1 and D2 selectivity.
        J Neurosci. 2017; 37: 2723-2733
        • Cui G.
        • Jun S.B.
        • Jin X.
        • Pham M.D.
        • Vogel S.S.
        • Lovinger D.M.
        • Costa R.M.
        Concurrent Activation of Striatal Direct and Indirect Pathways During Action Initiation.
        Nature. 2013; 494: 238
        • Soares-Cunha C.
        • Coimbra B.
        • Domingues A.V.
        • Vasconcelos N.
        • Sousa N.
        • Rodrigues A.J.
        Nucleus Accumbens Microcircuit Underlying D2-MSN-Driven Increase in Motivation.
        eNeuro. 2018; 5https://doi.org/10.1523/ENEURO.0386-18.2018
        • Vicente A.M.
        • Galvão-Ferreira P.
        • Tecuapetla F.
        • Costa R.M.
        Direct and indirect dorsolateral striatum pathways reinforce different action strategies.
        Curr Biol. 2016; 26: R267-R269
        • Engeln M.
        • Fox M.E.
        • Lobo M.K.
        Housing conditions during self-administration determine motivation for cocaine in mice following chronic social defeat stress.
        Psychopharmacology (Berl). 2021; 238: 41-54
        • Kennedy B.C.
        • Panksepp J.B.
        • Runckel P.A.
        • Lahvis G.P.
        Social influences on morphine-conditioned place preference in adolescent BALB/cJ and C57BL/6J mice.
        Psychopharmacology (Berl). 2012; 219: 923-932
        • Bozarth M.A.
        • Murray A.
        • Wise R.A.
        Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats.
        Pharmacol Biochem Behav. 1989; 33: 903-907
        • Westenbroek C.
        • Perry A.N.
        • Becker J.B.
        Pair housing differentially affects motivation to self-administer cocaine in male and female rats.
        Behav Brain Res. 2013; 252: 68-71
        • Fox M.E.
        • Chandra R.
        • Menken M.S.
        • Larkin E.J.
        • Nam H.
        • Engeln M.
        • et al.
        Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior.
        Mol Psychiatry. 2020; 25: 1022-1034
        • Francis T.C.
        • Gaynor A.
        • Chandra R.
        • Fox M.E.
        • Lobo M.K.
        The Selective RhoA Inhibitor Rhosin Promotes Stress Resiliency Through Enhancing D1-Medium Spiny Neuron Plasticity and Reducing Hyperexcitability.
        Biol Psychiatry. 2019; 85: 1001-1010
        • Francis T.C.
        • Chandra R.
        • Gaynor A.
        • Konkalmatt P.
        • Metzbower S.R.
        • Evans B.
        • et al.
        Molecular basis of dendritic atrophy and activity in stress susceptibility.
        Mol Psychiatry. 2017; 22: 1512-1519
        • Ueno H.
        • Takahashi Y.
        • Suemitsu S.
        • Murakami S.
        • Kitamura N.
        • Wani K.
        • et al.
        Effects of repetitive gentle handling of male C57BL/6NCrl mice on comparative behavioural test results.
        Sci Reports. 2020; 101 (2020): 1-13
        • Franco D.
        • Wulff A.B.
        • Lobo M.K.
        • Fox M.E.
        Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice.
        Front Behav Neurosci. 2022; 16https://doi.org/10.3389/fnbeh.2022.821080
        • Wemm S.E.
        • Sinha R.
        Drug-induced stress responses and addiction risk and relapse.
        Neurobiol Stress. 2019; 10100148
        • Saunders A.
        • Johnson C.A.
        • Sabatini B.L.
        Novel recombinant adeno-associated viruses for Cre activated and inactivated transgene expression in neurons.
        Front Neural Circuits. 2012; 6https://doi.org/10.3389/FNCIR.2012.00047
        • Engeln M.
        • Song Y.
        • Chandra R.
        • La A.
        • Fox M.E.M.E.
        • Evans B.
        • et al.
        Individual differences in stereotypy and neuron subtype translatome with TrkB deletion.
        Mol Psychiatry. 2020; 26: 1-14
        • Maere S.
        • Heymans K.
        • Kuiper M.
        BiNGO: A Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks.
        Bioinformatics. 2005; 21: 3448-3449
      7. Janky R, Verfaillie A, Imrichová H, Sande B Van de, Standaert L, Christiaens V (2014): PLoS Comput Biol. PLoS Computational Biology, vol. 10. Public Library of Science, p e1003731.

        • Francis T.C.
        • Chandra R.
        • Friend D.M.
        • Finkel E.
        • Dayrit G.
        • Miranda J.
        • et al.
        Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress.
        Biol Psychiatry. 2015; 77: 212-222
        • Bai Y.
        • Li Y.
        • Lv Y.
        • Liu Z.
        • Zheng X.
        Complex motivated behaviors for natural rewards following a binge-like regimen of morphine administration: mixed phenotypes of anhedonia and craving after short-term withdrawal.
        Front Behav Neurosci. 2014; 8: 23
        • Becker J.A.J.
        • Kieffer B.L.
        • Le Merrer J.
        Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol.
        Addict Biol. 2017; 22: 1205-1217
        • Bravo I.M.
        • Luster B.R.
        • Flanigan M.E.
        • Perez P.J.
        • Cogan E.S.
        • Schmidt K.T.
        • McElligott Z.A.
        Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice.
        Eur J Neurosci. 2020; 51: 742-754
        • Ingham C.A.
        • Hood S.H.
        • Arbuthnott G.W.
        Spine density on neostriatal neurones changes with 6-hydroxydopamine lesions and with age.
        Brain Res. 1989; 503: 334-338
        • Meredith G.E.
        • Ypma P.
        • Zahm D.S.
        Effects of dopamine depletion on the morphology of medium spiny neurons in the shell and core of the rat nucleus accumbens.
        J Neurosci. 1995; 15: 3808-3820
        • Leite-Morris K.A.
        • Kobrin K.L.
        • Guy M.D.
        • Young A.J.
        • Heinrichs S.C.
        • Kaplan G.B.
        Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core.
        Behav Brain Res. 2014; 263: 51-59
        • Fox M.E.
        • Figueiredo A.
        • Menken M.S.
        • Lobo M.K.
        Dendritic spine density is increased on nucleus accumbens D2 neurons after chronic social defeat.
        Sci Rep. 2020; 1012393
        • Kobrin K.L.
        • Moody O.
        • Arena D.T.
        • Moore C.F.
        • Heinrichs S.C.
        • Kaplan G.B.
        Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons.
        Addict Biol. 2016; 21: 1086-1096
        • Zhu Y.
        • Wienecke C.F.R.
        • Nachtrab G.
        • Chen X.
        A thalamic input to the nucleus accumbens mediates opiate dependence.
        Nature. 2016; 530: 219-222
        • Heshmati M.
        • Aleyasin H.
        • Menard C.
        • Christoffel D.J.
        • Flanigan M.E.
        • Pfau M.L.
        • et al.
        Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.
        Proc Natl Acad Sci U S A. 2018; 115: 1111-1116
        • Francis T.C.
        • Lobo M.K.
        Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression.
        Biol Psychiatry. 2017; 81: 645-653
        • LeGates T.A.
        • Kvarta M.D.
        • Tooley J.R.
        • Francis T.C.
        • Lobo M.K.
        • Creed M.C.
        • Thompson S.M.
        Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses.
        Nature. 2018; 564: 258-262
        • Lefevre E.M.
        • Pisansky M.T.
        • Toddes C.
        • Baruffaldi F.
        • Pravetoni M.
        • Tian L.
        • et al.
        Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system.
        Neuropsychopharmacology. 2020; 45: 1-13
        • Seney M.L.
        • Kim S.M.
        • Glausier J.R.
        • Hildebrand M.A.
        • Xue X.
        • Zong W.
        • et al.
        Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder.
        Biol Psychiatry. 2021; 90: 550-562
        • Ting J.H.
        • Marks D.R.
        • Schleidt S.S.
        • Wu J.N.
        • Zyskind J.W.
        • Lindl K.A.
        • et al.
        Targeted gene mutation of E2F1 evokes age-dependent synaptic disruption and behavioral deficits.
        J Neurochem. 2014; 129: 850-863
        • Cates H.M.
        • Heller E.A.
        • Lardner C.K.
        • Purushothaman I.
        • Peña C.J.
        • Walker D.M.
        • et al.
        Transcription Factor E2F3a in Nucleus Accumbens Affects Cocaine Action via Transcription and Alternative Splicing.
        Biol Psychiatry. 2018; 84: 167-179
      8. Cates HM, Lardner CK, Bagot RC, Neve RL, Nestler EJ (2019): Fosb Induction in Nucleus Accumbens by Cocaine Is Regulated by E2F3a. eNeuro 6. https://doi.org/10.1523/ENEURO.0325-18.2019

        • Feng J.
        • Wilkinson M.
        • Liu X.
        • Purushothaman I.
        • Ferguson D.
        • Vialou V.
        • et al.
        Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens.
        Genome Biol. 2014; 15https://doi.org/10.1186/GB-2014-15-4-R65
        • Tencheva Z.S.
        • Praskova M.D.
        • Velichkova A.A.
        • Mitev V.I.
        δ-Opioid agonist induced regulation of E2F1 DNA binding activity in NG108-15 cells.
        Mol Brain Res. 2005; 136: 271-274
        • Wang Y.
        • Shyam N.
        • Ting J.H.
        • Akay C.
        • Lindl K.A.
        • Jordan-Sciutto K.L.
        E2F1 localizes predominantly to neuronal cytoplasm and fails to induce expression of its transcriptional targets in Human Immunodeficiency Virus-induced neuronal damage.
        Neurosci Lett. 2010; 479: 97
        • Zhang Y.
        • Song X.
        • Herrup K.
        Context-Dependent Functions of E2F1: Cell Cycle, Cell Death, and DNA Damage Repair in Cortical Neurons.
        Mol Neurobiol. 2020; 57: 2377-2390