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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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.
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.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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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). https://doi.org/10.1038/mp.2017.80
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