Neurobiological correlates of trait impulsivity and drug abuse vulnerability

It is becoming increasingly recognised that many people in society can apparently use drugs such as cocaine for prolonged periods of time without ever becoming dependent on the drug. For example, it has been estimated that less than 20% of people who use cocaine actually become addicted; or in other words, show an escalating pattern of drug consumption, a persistence of drug taking despite adverse consequences (e.g., marital and family breakdown, unemployment, ill health and the threat of incarceration) and ultimately a loss of control over drug intake. Recent research also indicates that certain personality traits (e.g., sensation- and novelty-seekers), as well as people diagnosed with attention-deficit hyperactivity disorder (ADHD), depression and other brain disorders, are more likely to abuse drugs and progress ultimately to the advanced stages of drug addiction. This research focuses on underlying abnormalities in brain chemistry associated with certain personality traits and investigates how these changes confer vulnerability for drug abuse and addiction. A powerful non-invasive brain imaging technique will be used (positron emission tomography or ?PET?) to visualise a particular chemical receptor in the brain which previous research has linked to certain impulsive traits (i.e., behaviour that is poorly planned and controlled and occurs without due consideration or foresight), as well as the long-term effects of cocaine and other drugs of abuse on the brain. Our specific objective is to elucidate the brain mechanisms associated with the increased risk for cocaine addiction of individuals showing high levels of impulsive behaviour ? a core symptom of ADHD ?and thereby address why these individuals are more likely to become addicted to cocaine and other drugs of abuse. A key to this research is that we are able to assess in the same individual the progression from first drug exposure to the emergence of drug addictive behaviour, thereby determining changes in brain chemistry that potentially underlie the transition from recreational drug use to repeated use and addiction. This research has important implications for understanding the neurobiology of, and inter-relationship between, ADHD and drug addiction and thus in discovering new ways of treating these debilitating and frequently co-morbid brain disorders. It also addresses the contentious issue whether the ?paradoxical? treatment of ADHD with stimulant drugs such as methylphenidate (or Ritalin?) alters the progression from casual to compulsive drug use, thereby enabling the development of novel therapies.

Despite the complexity of the problem, the costs to the UK economy and healthcare system of chronic drug abuse and addiction are too enormous to ignore. Notwithstanding intensive research efforts we still do not understand why some individuals use or become dependent on drugs nor do we have effective treatments to prevent or ameliorate this pervasive and devastating brain disorder. However, an important clue to the aetiology of drug addiction is that it tends to be linked to certain personality traits (e.g., risk-takers, sensation- or novelty-seekers), and people diagnosed with certain brain disorders (e.g., depression and attention-deficit hyperactivity disorder or ADHD). However, from studies of human drug addicts alone, it is difficult to resolve whether cognitive dysfunction and co-morbid disorders pre-date the onset of drug use or emerge as a consequence of chronic drug exposure. It is also unclear how personality traits linked to risk taking and impulsivity confer vulnerability to addiction. A prominent theory in recent years is that the transition from voluntary to habitual and compulsive drug use reflects a progression from ventral to more dorsal regions of the striatum. This research tests the hypothesis that the emergence of addiction (or compulsive drug seeking) is accentuated by pre-existing abnormalities in dopamine function in the ventral striatum of subjects exhibiting spontaneously high levels of impulsivity, leading to a loss of control over drug intake and a progressive disruption of DA function in the dorsal striatum. Our specific research plan is to use positron emission tomography (PET) to assess longitudinally changes in DA D2/3 receptor availability (inferred by [18F]fallypride binding) in the ventral and dorsal striatum prior to, and following, extended exposure of low and high impulsive subjects to cocaine. We also aim to investigate whether the transition to compulsive cocaine use ? defined by the persistence of responding for drug under punishment ? can be attenuated or even blocked by treatment with drugs with proven or putative efficacy in ADHD. This research is fundamentally important because it examines for the first time the neurobiology of drug addiction vulnerability and the processes underlying the transition from first drug use to repeated use and addiction. This research also allows direct translation to analogous imaging studies in human drug addicts and ADHD patients, thereby facilitating the discovery of novel brain mechanisms relevant to the aetiology and treatment of these debilitating and often co-morbid brain disorders.