Human drug dependence: Cognitive predisposition and neural mechanisms

Although a large percentage of the population have tried addictive drugs, only a small percentage become pathologically addicted in that they bring about significant harm to their health and social relationships. Others, by contrast, maintain casual drug use, but ultimately stop before incurring serious damage. Although the risk of becoming addicted largely depends upon whether one has an ?addictive personality?, the exact nature of this personality remains unclear. To improve our understanding of the risk factors for addiction, we plan to test whether addicts, in contrast to casual users, are less able to inhibit drug seeking behaviour in the laboratory in the face of knowledge that this behaviour is no longer rewarding, is actively causing harm, or is inappropriate in the context. Such experimental data would confirm the clinical impression that addiction is caused by an inability to inhibit drug seeking in the face of knowledge of the negative consequences of this behaviour. In addition, the laboratory methods developed in the project could provide a screening instrument for the addictive personality, and the insight gained into addiction would justify funding for treatments that target addicts? perception of drug harm.
The frontal cortex is a brain region that sits just behind the eyes, where options are considered before action judged beneficial is undertaken. It has been suggested that addicts have damage in this area, which reduces the weight given to the negative consequences when considering whether to engage in drug seeking. To test this hypothesis, we will measure activity in the frontal cortex while addicts and casual drug users consider undertaking drug seeking that is potentially harmful. If addicts show a reduced signal for this harm compared to causal users, which predicts the continuation of drug seeking despite the harm, we will be able to conclude that a flaw in the frontal cortex confers a neurobiological risk factor for the addictive personality and addiction. This conclusion would support pharmacological treatments that seek to correct this brain abnormality.
The final part of the project aims to test whether our laboratory measure of the addictive personality provides an accurate screening instrument for adolescents who are at risk of becoming drug addicted. These data would support a prevention strategy that identifies and informs these adolescents of their susceptibility before they become addicted, and in particular, seeks to enhance their understanding of the negative consequences of drug seeking.

A key diagnostic of human drug dependence is that drug seeking continues despite this behaviour causing medical and social harm. Such perseveration has recently been observed in a sub-population of animals that are unable to inhibit drug seeking when this behaviour is extinguished or punished. The implication is that humans who meet clinical criteria for drug dependence should demonstrate such perseveration under similar conditioning schedules. To test this hypothesis, clinically dependent and non-dependent smokers will be assessed for their perseveration of tobacco and money seeking under extinction, punishment and conditioned inhibition, versus none of these challenges. These experiments will indicate whether dependence related perseveration is general to reward seeking or specific to drug seeking. In addition, comparison of the three paradigms and measurement of visual attention will indicate whether perseveration is mediated by a failure to attend to or to encode the negative consequences of drug seeking, or a failure to apply inhibitory control on the basis of this knowledge. This work would refine the clinical assessment of dependence, and specify treatments that act upon the inhibitory control deficit.
It has been argued that the neurobiological basis of drug dependence is a failure of the orbital frontal cortex (OFC) to encode the expectation of negative consequences that would normally moderate harmful drug seeking. To test this, we will use an MRI scanner to measure the OFC BOLD signal in dependent and non-dependent smokers engaged in punished and non-punished tobacco and money seeking. The finding of a reduced OFC signal for punishment in the dependent group, which is associated with perseveration of tobacco seeking under punishment, would confirm the OFC as an important neurobiological substrate of dependence, strengthening neuropharmacological interventions that act upon this abnormality.
The final aim of the project is to develop a screening instrument for the risk of substance dependence in adolescence. To this end, we will examine whether behavioural perseveration of reward seeking is associated with an established psychometric index of dependence risk in young offenders. This relationship would suggest that behavioural perseveration is a risk factor for dependence rather than the consequence of chronic drug use, and would strengthen interventions that enhance the insight of the high risk cohort into the negative consequences of drug seeking. We hope to follow this work with funding for a prospective design to assess the predictive validity of behavioural perseveration as a screening instrumental for subsequent dependence.