Transcriptomic Dysregulation in Animal Models of Attention-Deficit Hyperactivity Disorder and Substance Use Suggests Shared Neural Mechanisms

Attention-Deficit/Hyperactivity Disorder (ADHD) is highly heritable and increases the likelihood of substance abuse. The self-medication hypothesis of nicotine use in ADHD proposes that ADHD patients seek nicotine for its ability to improve their symptoms, and they have less success quitting, possibly due to the worsening of ADHD symptoms in withdrawal (Liebrenz et. al., 2014). By comparing the transcriptome of rodent models of ADHD to those of nicotine dependence (ND), the present analysis identified novel differentially expressed genes that may contribute to their high co-occurrence (PRKAG2, MAPK1), and genes with known associations to either ADHD or ND (ANK3, CALD1, CHRNA4, CHRNA7, CMTM8, DLG4, DUSP6, GNG3, GNG11, GRIK5, GRINA2, ICAM2, KCNJ6, PRKAB1, SYNPO, VAMP2). In addition, MAPK signaling pathways (R-HSA-5673001, R-HSA-5684996) and synaptic transmission (R-HSA-112315) were enriched in both ADHD and ND. These pathways mediate neurological mechanisms that contribute to ND. The association of analogous differently expressed genes and common signaling pathways suggests an important causal relationship between ND and ADHD that may be clinically important.