Genetics, drugs, and cognitive control: uncovering individual differences in substance dependence

Abstract

Why is it that only some people who use drugs actually become addicted? In fact, addiction depends on a complicated process involving a confluence of risk factors related to biology, cognition, behaviour, and personality. Notably, all addictive drugs act on a neural system for reinforcement learning called the midbrain dopamine system, which projects to and regulates the brain's system for cognitive control, called frontal cortex and basal ganglia. Further, the development and expression of the dopamine system is determined in part by genetic factors that vary across individuals such that dopamine related genes are partly responsible for addiction-proneness. Taken together, these observations suggest that the cognitive and behavioral impairments associated with substance abuse result from the impact of disrupted dopamine signals on frontal brain areas involved in cognitive control: By acting on the abnormal reinforcement learning system of the genetically vulnerable, addictive drugs hijack the control system to reinforce maladaptive drug-taking behaviors. The goal of this research was to investigate this hypothesis by conducting a series of experiments that assayed the integrity of the dopamine system and its neural targets involved in cognitive control and decision making in young adults using a combination of electrophysiological, behavioral, and genetic assays together with surveys of substance use and personality. First, this research demonstrated that substance dependent individuals produce an abnormal Reward-positivity, an electrophysiological measure of a cortical mechanism for dopamine-dependent reward processing and cognitive control, and behaved abnormally on a decision making task that is diagnostic of dopamine dysfunction. Second, several dopamine-related neural pathways underlying individual differences in substance dependence were identified and modeled, providing a theoretical framework for bridging the gap between genes and behavior in drug addiction. Third, the neural mechanisms that underlie individual differences in decision making function and dysfunction were identified, revealing possible risk factors in the decision making system. In sum, these results illustrate how future interventions might be individually tailored for specific genetic, cognitive and personality profiles.