Genotype-by-diagnosis interaction influences self-control in human cocaine addiction

Abstract

Not everyone who uses drugs loses control over their intake, which is a hallmark of addiction. Although familial risk studies suggest significant addiction heritability, the genetic basis of vulnerability to drug addiction remains largely unknown. In the present study, we investigate the relationship between self-control, cocaine use, and the rs36024 single nucleotide polymorphism of the noradrenaline transporter gene (SLC6A2). We hypothesize that C-allele-carrying adults show impaired self-control, as measured by the stop-signal task and demonstrated previously in adolescents, and further exacerbated by chronic cocaine use. Patients with cocaine use disorder (CUD, n = 79) and healthy unrelated participants with no history of drug abuse (n = 54) completed the stop-signal task. All participants were genotyped for rs36024 allelic variants (CC/TT homozygotes, CT heterozygotes). We measured mean stop-signal reaction time, reflecting the ability to inhibit ongoing motor responses, reaction times to go stimuli, and the proportion of successful stops. CUD patients showed prolonged stop-signal reaction time, however, there was no main effect of rs36024 genotype. Importantly, there was a significant genotype-by-diagnosis interaction such that CUD patients with CC genotype had longer stop-signal reaction time and fewer successful stops compared with CC healthy controls and TT CUD patients. CT CUD patients showed an intermediate performance. Self-control deficits were associated with cocaine use disorder diagnosis, which interacts with the noradrenaline transporter rs36024 polymorphism. Our findings suggest that rs36024 may represent a potential genetic vulnerability marker, which facilitates the transition from first cocaine use to addiction by weakening the inhibitory control over behavior.