Genetic influences underlying impulsivity and risk for drug addiction

Despite intensive research efforts we still do not understand why some people use or become dependent on drugs such as crack cocaine nor do we have effective treatments to prevent or ameliorate this widespread and debilitating brain disorder. An important clue to the cause of drug addiction is that it tends to be associated with people who are naturally impulsive or who enjoy taking risks, as well as people diagnosed with certain childhood brain disorders such as attention deficit hyperactivity disorder (ADHD). Such traits and disorders appear to play an important role in determining the likelihood of future problem drug use by influencing the various stages of the pathway to addiction, including the chances of first coming into contact with drugs, the transition from occasional to regular drug use and the propensity for repeated episodes of drug binging and withdrawal. This research investigates the biological basis of such traits using a sophisticated gene hunting technique to determine the hereditary risk for drug addiction in close family members. Our research will be conducted using a colony of impulsive rats which carry a strongly increased risk for developing a drug taking habit. We will search over 10,000 known gene variations across the entire rat genetic code to pinpoint genes that underlie the impulsive trait. In so doing, we will provide a much fuller understanding of the genetic basis of risk for drug addiction, not only in our rat model but also in humans. This research will facilitate the discovery of new brain mechanisms and therapies to treat drug abuse and addiction as well as ADHD and related brain disorders.

Drug addiction is a devastating brain disorder that wrecks the lives of individuals, families and the wider community with serious and growing repercussions for public health and crime rate in the UK. Although the precise cause of dug addiction is unknown it is widely hypothesised to be influenced by complex genetic and environmental factors that interact with direct drug-induced effects to affect the final pathway to addiction. Indeed, genetic influences are postulated to account for a substantial proportion of vulnerability to drug abuse and addiction, especially those that underlie complex personality traits such as impulsivity and risk taking and brain disorders frequently co-morbid with drug addiction, including attention deficit hyperactivity disorder (ADHD) and conduct disorder. This pilot study focuses on a spontaneously occurring form of impulsivity in rats that not only predisposes to excessive cocaine intake and the development of compulsive cocaine seeking it is also a marker for vulnerability to relapse. We aim to investigate the genetic basis of impulsivity by carrying out a genome-wide linkage analysis across 10,000 SNPs using a large sample of selectively inbred, multi-generational, impulsive rats. Genome-wide linkage analysis for impulsivity phenotypes (i.e., high versus low impulsivity) will be carried out using selected animals from three successive generations of inbreeding (in total n=250) for which a substantial heritable genetic variation has been determined. We will also investigate the influence of early environmental factors on impulsivity by cross-fostering rat offspring with dams of the opposite extreme phenotype (i.e., low impulsive pups reared by high impulsive dams and visa versa), thus addressing directly the contribution of genetic versus environmental determinants of vulnerability to drug addiction. This pilot study benefits from an already existing archive of tissue harvested from this multi-generation pedigree and the formation of a strategic new partnership between the MRC and Wellcome Trust funded Behavioural and Clinical Neuroscience Institute at Cambridge University and Tim Aitman?s genomics laboratory at the MRC Clinical Sciences Centre at Imperial College. The outcome of this pilot study will be the demonstration of linkage to discrete chromosomal regions that habour genetic determinants of impulsivity and related phenotypes and the identification of genes and pathways underlying heritable risk for drug abuse and addiction. This proof-of-principle study is especially important because it will enable comparative genetic analysis of strong translational relevance for human drug addiction and thereby identify potential new targets and therapies to promote abstinence and reduce the propensity to relapse.