Variation on the CRH Gene Determines the Different Performance of Opioid Addicts and Healthy Controls in the IOWA Gambling Task


The hypothalamus-pituitary-adrenal (HPA) axis, the biological substrate of stress reactivity, and related genetic variations play a crucial role in the initiation and maintenance of drug addiction. On the behavioral level, substance abusers are characterized by impulsivity and the inability to pursue long-term goals. The neural substrate of these behaviors is assumed to be related to the ventromedial prefrontal cortex (VMPFC). One of the most established paradigms to assess VMPFC deficiency is the IOWA gambling task (IGT).


The aim of this study was to investigate the interplay between the HPA axis-related genetic variation on corticotropin-releasing hormone (CRH; secreted from the hypothalamus and constituting the starting point of the HPA axis) gene and opioid addiction, with respect to IGT performance. There is some evidence that stress and pathological HPA axis hyperactivity, in the same way as drug addiction, is related to a poorer IGT performance.


In total, 138 long-term opioid addicts (mean age 38.63 years [SD 9.15]) and 160 healthy controls (mean age 22.57 years [SD 5.86]) performed the IGT and were genotyped for 6 SNPs covering the CRH gene and adjacent regions (rs3176921, rs6999780, rs7816410, rs1870393, rs1814583, and rs11996294). The first 5 of these 6 SNPs build a haplotype block spanning 15 kb on the CRH gene.


We found a significant group difference in the total IGT score, with higher scores in controls than in opioids. Most interestingly, there was a 3-way interaction, group × haplotype × block. Carriers homozygous for the TGTAA-haplotype differed in IGT performance dependent on group. In the control group, carriers homozygous for the TGTAA-haplotype showed a linear learning curve across blocks of trials, which was not observed in participants without this homozygosity. There were diametric effects in opioid addicts. Controlling for age and gender did not change the findings.


This study provides genetic evidence for the interplay between stress, decision-making, and opioid addiction.