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Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability


Impulsivity, a multifaceted behavioral hallmark of attention-deficit/hyperactivity disorder (ADHD), strongly influences addiction vulnerability and other psychiatric disorders that incur enormous medical and societal burdens yet the neurobiological underpinnings linking impulsivity to disease remain poorly understood. Here we report the critical role of ventral striatal cAMP-response element modulator (CREM) in mediating impulsivity relevant to drug abuse vulnerability. Using an ADHD rat model, we demonstrate that impulsive animals are neurochemically and behaviorally more sensitive to heroin and exhibit reduced Crem expression in the nucleus accumbens core. Virally increasing Crem levels decreased impulsive action, thus establishing a causal relationship. Genetic studies in seven independent human populations illustrate that a CREM promoter variant at rs12765063 is associated with impulsivity, hyperactivity and addiction-related phenotypes. We also reveal a role of Crem in regulating striatal structural plasticity. Together, these results highlight that ventral striatal CREM mediates impulsivity related to substance abuse and suggest that CREM and its regulated network may be promising therapeutic targets.

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  1. Daruna JH, Barnes PA . A neurodevelopmental view of impulsivity. In: McCown WG, Johnson J, Shure MB (eds). The Impulsive Client: Theory, Research, and Treatment. American Psychological Association: Washington, DC, USA, 1993, pp 23–37.

    Chapter  Google Scholar 

  2. Nigg JT, Wong MM, Martel MM, Jester JM, Puttler LI, Glass JM et al. Poor response inhibition as a predictor of problem drinking and illicit drug use in adolescents at risk for alcoholism and other substance use disorders. J Am Acad Child Adolesc Psychiatry 2006; 45: 468–475.

    Article  PubMed  Google Scholar 

  3. Tarter RE, Kirisci L, Mezzich A, Cornelius JR, Pajer K, Vanyukov M et al. Neurobehavioral disinhibition in childhood predicts early age at onset of substance use disorder. Am J Psychiatry 2003; 160: 1078–1085.

    Article  PubMed  Google Scholar 

  4. Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ . High impulsivity predicts the switch to compulsive cocaine-taking. Science 2008; 320: 1352–1355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Laane K et al. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 2007; 315: 1267–1270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Diergaarde L, Pattij T, Poortvliet I, Hogenboom F, de Vries W, Schoffelmeer AN et al. Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats. Biol Psychiatry 2008; 63: 301–308.

    Article  CAS  PubMed  Google Scholar 

  7. Perry JL, Nelson SE, Carroll ME . Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats. Exp Clin Psychopharmacol 2008; 16: 165–177.

    Article  PubMed  Google Scholar 

  8. Zeng H, Lee TM, Waters JH, So KF, Sham PC, Schottenfeld RS et al. Impulsivity, cognitive function, and their relationship in heroin-dependent individuals. J Clin Exp Neuropsychol 2013; 35: 897–905.

    Article  CAS  PubMed  Google Scholar 

  9. Peles E, Schreiber S, Sutzman A, Adelson M . Attention deficit hyperactivity disorder and obsessive-compulsive disorder among former heroin addicts currently in methadone maintenance treatment. Psychopathology 2012; 45: 327–333.

    Article  PubMed  Google Scholar 

  10. Dissabandara LO, Loxton NJ, Dias SR, Dodd PR, Daglish M, Stadlin A . Dependent heroin use and associated risky behaviour: the role of rash impulsiveness and reward sensitivity. Addict Behav 2014; 39: 71–76.

    Article  PubMed  Google Scholar 

  11. SAMHSA Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health. Office of Applied Studies, NSDUH Series H-50, HHS Publication No. SMA 15-4927: Rockville, MD, USA, 2015.

  12. Dalley JW, Mar AC, Economidou D, Robbins TW . Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry. Pharmacol Biochem Behav 2008; 90: 250–260.

    Article  CAS  PubMed  Google Scholar 

  13. Bechara A, Van Der Linden M . Decision-making and impulse control after frontal lobe injuries. Curr Opin Neurol 2005; 18: 734–739.

    Article  PubMed  Google Scholar 

  14. Cardinal RN, Pennicott DR, Sugathapala CL, Robbins TW, Everitt BJ . Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 2001; 292: 2499–2501.

    Article  CAS  PubMed  Google Scholar 

  15. Jentsch JD, Ashenhurst JR, Cervantes MC, Groman SM, James AS, Pennington ZT . Dissecting impulsivity and its relationships to drug addictions. Ann N Y Acad Sci 2014; 1327: 1–26.

    PubMed  PubMed Central  Google Scholar 

  16. da Costa Araujo S, Body S, Hampson CL, Langley RW, Deakin JF, Anderson IM et al. Effects of lesions of the nucleus accumbens core on inter-temporal choice: further observations with an adjusting-delay procedure. Behav Brain Res 2009; 202: 272–277.

    Article  CAS  PubMed  Google Scholar 

  17. Pothuizen HH, Jongen-Relo AL, Feldon J, Yee BK . Double dissociation of the effects of selective nucleus accumbens core and shell lesions on impulsive-choice behaviour and salience learning in rats. Eur J Neurosci 2005; 22: 2605–2616.

    Article  PubMed  Google Scholar 

  18. Sesia T, Temel Y, Lim LW, Blokland A, Steinbusch HW, Visser-Vandewalle V . Deep brain stimulation of the nucleus accumbens core and shell: opposite effects on impulsive action. Exp Neurol 2008; 214: 135–139.

    Article  PubMed  Google Scholar 

  19. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Koob GF . Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology 2009; 56 (Suppl 1): 18–31.

    Article  CAS  PubMed  Google Scholar 

  21. Stefanik MT, Moussawi K, Kupchik YM, Smith KC, Miller RL, Huff ML et al. Optogenetic inhibition of cocaine seeking in rats. Addict Biol 2013; 18: 50–53.

    Article  CAS  PubMed  Google Scholar 

  22. Ward LD, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 2012; 40 (Database issue): D930–D934.

    Article  CAS  PubMed  Google Scholar 

  23. Albertson DN, Schmidt CJ, Kapatos G, Bannon MJ . Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology 2006; 31: 2304–2312.

    Article  CAS  PubMed  Google Scholar 

  24. Jacobs MM, Okvist A, Horvath M, Keller E, Bannon MJ, Morgello S et al. Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels. Mol Psychiatry 2013; 18: 1205–1210.

    Article  CAS  PubMed  Google Scholar 

  25. Drakenberg K, Nikoshkov A, Horvath MC, Fagergren P, Gharibyan A, Saarelainen K et al. Mu opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers. Proc Natl Acad Sci USA 2006; 103: 7883–7888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Edenberg HJ, Bierut LJ, Boyce P, Cao M, Cawley S, Chiles R et al. Description of the data from the Collaborative Study on the Genetics of Alcoholism (COGA) and single-nucleotide polymorphism genotyping for Genetic Analysis Workshop 14. BMC Genet 2005; 6 (Suppl 1): S2.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rajendran K, Rindskopf D, O'Neill S, Marks DJ, Nomura Y, Halperin JM . Neuropsychological functioning and severity of ADHD in early childhood: a four-year cross-lagged study. J Abnorm Psychol 2013; 122: 1179–1188.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Trampush JW, Jacobs MM, Hurd YL, Newcorn JH, Halperin JM . Moderator effects of working memory on the stability of ADHD symptoms by dopamine receptor gene polymorphisms during development. Dev Sci 2014; 17: 584–595.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Schumann G, Loth E, Banaschewski T, Barbot A, Barker G, Buchel C et al. The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology. Mol Psychiatry 2010; 15: 1128–1139.

    Article  CAS  PubMed  Google Scholar 

  30. Jutras-Aswad D, Jacobs MM, Yiannoulos G, Roussos P, Bitsios P, Nomura Y et al. Cannabis-dependence risk relates to synergism between neuroticism and proenkephalin SNPs associated with amygdala gene expression: case-controlstudy. PLoS ONE 2012; 7: e39243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H, Wallis D et al. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry 2010; 15: 1053–1066.

    Article  CAS  PubMed  Google Scholar 

  32. Carlezon WA Jr, Duman RS, Nestler EJ . The many faces of CREB. Trends Neurosci 2005; 28: 436–445.

    Article  CAS  PubMed  Google Scholar 

  33. Laoide BM, Foulkes NS, Schlotter F, Sassone-Corsi P . The functional versatility of CREM is determined by its modular structure. EMBO J 1993; 12: 1179–1191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rauen T, Hedrich CM, Tenbrock K, Tsokos GC . cAMP responsive element modulator: a critical regulator of cytokine production. Trends Mol Med 2013; 19: 262–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Maldonado R, Smadja C, Mazzucchelli C, Sassone-Corsi P . Altered emotional and locomotor responses in mice deficient in the transcription factor CREM. Proc Natl Acad Sci USA 1999; 96: 14094–14099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wallis D, Hill DS, Mendez IA, Abbott LC, Finnell RH, Wellman PJ et al. Initial characterization of mice null for Lphn3, a gene implicated in ADHD and addiction. Brain Res 2012; 1463: 85–92.

    Article  CAS  PubMed  Google Scholar 

  37. Ranaivoson FM, Liu Q, Martini F, Bergami F, von Daake S, Li S et al. Structural and mechanistic insights into the Latrophilin3-FLRT3 complex that mediates glutamatergic synapse development. Structure 2015; 23: 1665–1677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lange M, Norton W, Coolen M, Chaminade M, Merker S, Proft F et al. The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development. Mol Psychiatry 2012; 17: 946–954.

    Article  CAS  PubMed  Google Scholar 

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The study was supported by the National Institute on Drug Abuse (NIDA) grants R01-DA015446 (YLH), R01-DA030359 (YLH), R01-DA006470 (MJB), F30-DA038954 (MLM), F31-DA031559 (CVM) and T32-DA007135 (NAW); the National Institute of Mental Health (NIMH) grants R01-MH068286 (JMH) and R01-MH060698 (JMH); the National Institute of General Medical Sciences grant T32-GM007280 (MLM). The Collaborative Study on the Genetics of Alcoholism (COGA) is supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) grant U10-AA008401. We thank Nayana Patel, James Sperry and Joseph A. Landry for technical assistance; Dr. Rachael L. Neve for generating the viral particles; Dr. Thomas A. Green for providing Crem plasmid.

Author contributions

YLH, YR and MLM designed the experiments. MLM, YR, HS, NAW, GE and CT performed the experiments and/or analyzed the data. JMH, AM, MJB, BC, HG, GS and IMAGEN Consortium provided access to materials and resources. MK performed analyses in the COGA data set. MLM, HS and YLH wrote the paper. All co-authors reviewed the manuscript and provided comments.

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Correspondence to Y L Hurd.

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Miller, M., Ren, Y., Szutorisz, H. et al. Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23, 1328–1335 (2018).

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