Vulnerability to substance dependence

The purpose of the current studies was to examine associations with genetic variation, impulsive sensation seeking (ImpSS) and responsiveness to substance-related stimuli among four hundred individuals (100 alcoholics, 100 heroin abusers, 100 smokers and 100 controls), who each completed questionnaires measuring demographics; substance history; ImpSS levels; addiction severity and mood status. Participants provided a sample of their DNA, genotyped using PCR, and completed a modified Stroop task. Heroin users were found to be significantly higher impulsive sensation seekers than all other groups and all substance-using groups were found to be significantly higher sensation seekers than controls. The pleasure/reward seeking characteristics of high ImpSS are thought to be governed by the mesolimbic dopamine reward pathway, this system appears unregulated in substance abusers, encouraging them to seek out substances to satisfy their neurochemical urge for pleasure. The dopamine reward pathway is where D4 receptors are most densely populated and having the long variant at the DRD4 gene was found to predispose individuals to a high lmpSS personality type. Moreover, genotype alone predicted ImpSS behaviour amongst the heroin group, shedding light onto the controversy surrounding the influence of DRD4 on ImpSS behaviour and illustrates the importance of other factors (e. g. age, sex and mood status) on this association. lmpSS could mediate the genetic influence on addiction; the DRD4 gene variant predisposed individuals to heroin and nicotine dependence, but not alcohol dependence. Therefore, the dopaminergic polymorphisms contribute to individual differences in addiction and lmpSS behaviour. High impulsive sensation seekers were significantly faster to respond to stimuli on the emotional Stroop task and both heroin and smoking groups were distracted by stimuli that were associated with their drug of choice. Individuals with the long variant at the DRD4 gene spent longer responding to words related to heroin and cigarettes. Therefore, the DRD4 gene polymorphism represents a genetic mechanism that could be associated with substance-specific cue-associated responding to drug-related environmental stimuli, whilst demonstrating individual differences in susceptibility to sensitisation. Ultimately, the thesis demonstrates the importance of genetic variation in substance dependence; it advances our understanding of the personalities of substance abusers and increases our knowledge of neurobehavioural influences on addiction. thus offering a multidisciplinary approach to studying vulnerability factors to substance dependence