Neurobehavioural mechanisms of addiction: vulnerability, circuits and drug memories

Drug addiction is a chronic, relapsing brain disorder that afflicts many people in the UK and internationally, placing enormous burdens on health, social and criminal justice systems. There is a major need to develop new treatments for drug addiction and to identify who may be at risk of developing addiction following exposure to drugs. Addressing these questions requires an improved psychological and brain-based explanation of the processes by which casual, or 'recreational', drug use can progress to a compulsive habit, such that drug addiction is manifested clinically as a chronic, relapsing disorder with devastating consequences for individuals, their families and the societies in which they live. Remarkably, despite understanding how addictive substances produce their pleasurable or rewarding effects through specific actions in the brain, it remains unclear why only a subset of individuals currently using drugs such as cocaine, heroin and alcohol subsequently become addicted. The proposed research uses a novel strategy to make predictions about which individuals, or group of individuals, may be more likely to develop harmful drug use in the future. It is now widely acknowledged by the scientific community that addiction is prevalent in individuals who express certain behavioural/personality traits such as novelty seeking, anxiety, impulsivity, and increased reactions to drug cues that predict the availability of drug rewards. We now wish to undertake longitudinal behavioural assessment in rat populations combined with high-resolution imaging of the brain and assess whether the resultant scans reveal anatomical and functional correlates of behavioural traits and whether they in turn can predict the development of compulsive drug use, thereby providing a better explanation of the development of addiction in vulnerable individuals. These results may have broad implications for discovering novel mechanisms and therapies to treat or even prevent the onset of addiction. Drug addiction is not a manifestation of dysfunction of a single brain structure or mechanism. Rather it reflects complex behavioural processes and equally complex brain mechanisms that are determined by aberrant activity in underlying brain circuits. A second major goal of our planned research is to identify and understand these circuits by using several contemporary techniques including brain imaging (structural, functional and molecular), electrophysiological recording and new molecular methods so as precisely to manipulate these circuits at defined points in the transition from initial to compulsive drug use. In particular, we seek to understand how initial voluntary drug use gives way to habitual, involuntary drug use that is elicited by salient drug-associated conditioned stimuli, or cues (familiar examples would be smoking a cigarette after a meal, or having a drink in a bar on the way home from work, when voluntary intention was not to do so). Ultimately these habits become maladaptive as they emerge as compulsive. Little is known about the brain basis of compulsivity and this is a key aim of our brain circuit investigations. Abstinence in drug-addicted individuals is especially difficult to attain and maintain, and relapse, often triggered by drug-associated cues in the environment is an important feature of drug addiction. We now know that retrieval of drug memories makes them vulnerable to disruption, since they undergo a process of 'reconsolidation' during which the memories are restabilised and updated by specific mechanisms in brain circuits. Therefore, we will continue to investigate the molecular and neurochemical basis of drug memories in order to enhance our ability to diminish their pervasive impact on relapse, with a longer-term goal of introducing novel psychological and, in due course, pharmacological treatments to the clinic that are designed primarily to help addicted individuals to attain and maintain abstinence from harmful drug use