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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Animals
  • Attention Deficit and Disruptive Behavior Disorders / metabolism*
  • Attention Deficit and Disruptive Behavior Disorders / psychology
  • Behavior, Addictive / metabolism*
  • Behavior, Addictive / psychology
  • Brain / metabolism
  • Cyclic AMP Response Element Modulator / metabolism*
  • Disease Models, Animal
  • Humans
  • Impulsive Behavior / physiology
  • Male
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Substance-Related Disorders / metabolism*
  • Substance-Related Disorders / psychology
  • Ventral Striatum / metabolism*


  • CREM protein, human
  • Crem protein, rat
  • Cyclic AMP Response Element Modulator