Our translational study provides direct neurobiological evidence for a causal relationship between the transcription factor Crem in the AcbC and motor impulsivity relevant to ADHD and SUD. Studying a genetically homogeneous inbred animal model and various human cohorts, we demonstrate that (i) impulsivity was associated with vulnerability to heroin abuse and reduced AcbC Crem expression, (ii) AcbC Crem specifically mediated impulsive action, and (iii) striatal Crem regulated spine morphology and neuroplasticity. While Crem expression in the AcbC was not a sufficient regulator of opiate reward sensitivity, it may contribute to factors related to severity and predisposition given that impulsivity mediated the genetic association between CREM and substance use. The fact that CREM genotype was not specific to one drug type suggests it relates to more general aspects of addiction vulnerability.
