Abstract

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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Acknowledgements

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.

Author information

Affiliations

  1. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • M L Miller
    • , Y Ren
    • , H Szutorisz
    • , N A Warren
    • , C Tessereau
    • , G Egervari
    • , C V Morris
    • , J M Halperin
    •  & Y L Hurd
  2. Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • M L Miller
    • , Y Ren
    • , H Szutorisz
    • , N A Warren
    • , C Tessereau
    • , G Egervari
    • , M Kapoor
    • , C V Morris
    • , A M Goate
    •  & Y L Hurd
  3. Department of Psychology, The Graduate Center, City University of New York, New York, NY, USA

    • A Mlodnicka
    •  & J M Halperin
  4. Vermont Center on Behavior and Health, Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA

    • B Chaarani
    •  & H Garavan
  5. Institute of Psychiatry, King's College London, London, UK

    • G Schumann
  6. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA

    • M J Bannon
  7. Department of Psychology, Queens College of the City University of New York, Flushing, NY, USA

    • J M Halperin

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  1. IMAGEN Consortium

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Y L Hurd.

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DOI

https://doi.org/10.1038/mp.2017.80

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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