Neurocognitive Endophenotypes of Stimulant Drug Dependence

We know that about 15% of people who try cocaine will become dependent on it within 10 years of their first use. The likelihood of developing cocaine dependence is further increased for people who have a family history of substance use disorders. Thus the addictive potential of cocaine is magnified by genetic risk factors but we currently know little about how the risks for drug dependence are inherited.

We aim to discover more about the genetic basis for cocaine dependence, by using brain imaging and cognitive testing to assess people with a clinical diagnosis of cocaine dependence and their non-dependent first degree relatives, as well as healthy normal volunteers. In this way, we aim to identify heritable traits or endophenotypes in brain organization and cognitive processing that may mediate the genetic predisposition to develop drug addiction.

Identification of such endophenotypes would make an important contribution to understanding of drug addiction, by clarifying the distinction between those brain and cognitive abnormalities that are the effects of long-term drug abuse, versus those that represent predisposing causes of drug abuse. Delineating the neurobiological causes and effects of stimulant drug dependence will be fundamental to future development of more effective therapeutic and preventative interventions.

This project aims to define neurocognitive endophenotypes of drug addiction by examining two key aspects of brain function, reward sensitivity and inhibitory control, in currently stimulant-dependent individuals, their non-drug using siblings, and unrelated healthy controls (n=40 per group). The groups will be characterized in terms of psychopathology, cognitive function, and MRI-based measurements of brain structure and function; the fMRI paradigms are chosen to activate cortico-subcortical circuits implicated in inhibitory and reward processing. By comparing behavioural and imaging measurements between drug-dependent individuals and healthy volunteers, we will be able to test the hypothesis that reward sensitivity, inhibitory control, and the brain circuits subserving these functions, are abnormal in drug dependence. Moreover, the inclusion of a non-dependent sibling group will additionally allow us to test the hypothesis, supported by the high heritability of drug dependence syndromes, that there will be abnormalities of inhibitory and/or reward processing in first degree relatives of dependent individuals. In other words, the study is designed to test the candidacy of cognitive and imaging markers of inhibitory and reward processing as intermediate phenotypes or endophenotypes that mediate genetic risk for stimulant-dependence. The identification of such neurocognitive endophenotypes would immediately make an important contribution to biological understanding of drug-dependence syndromes by segregating those abnormalities expected in dependent individuals compared to healthy controls which are effects of long-term stimulant drug abuse (and therefore not seen in non-dependent relatives) from those which are predisposing causes of drug abuse (and therefore also seen to some extent in relatives). Clarification of this distinction between neurocognitive causes and effects of stimulant drug dependence has been difficult to achieve in clinical studies yet is fundamental to rational development of future therapeutic and preventative interventions.