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Mol Psychiatry. 2018 May;23(5):1328-1335. doi: 10.1038/mp.2017.80. Epub 2017 Apr 25.

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

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Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychology, The Graduate Center, City University of New York, New York, NY, USA.
Vermont Center on Behavior and Health, Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA.
Institute of Psychiatry, King's College London, London, UK.
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.
Department of Psychology, Queens College of the City University of New York, Flushing, NY, USA.


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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