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

This programme has three overarching aims: (i) to test the hypothesis that loss-of-control over drug seeking habits is the basis of compulsive drug use; (ii) to specify the underlying circuitry and mechanisms; (iii) to define vulnerability traits that predict the propensity compulsively to seek drugs, and identify their neural correlates; (iv) further investigate the mechanisms of drug memory plasticity, especially reconsolidation, extinction and interactions between them, at molecular and systems levels.
In (i), we propose to use our refined models of compulsive cocaine, heroin and alcohol seeking and in (ii) investigate causal mechanisms in underlying circuitry using chemogenetic (DREADDs) and optogenetic techniques, as well as in vivo electrophysiology. By comparing three addictive drug classes, we seek to define commonalities and differences in the underlying psychological mechanisms and neural circuitry, involving the amygdala, ventral and dorsal striatum, prefrontal and insula cortex. In (iii) we will use longitudinal MRI, combined with in vivo electrophysiology and 'hotspot' molecular imaging to identify the neural correlates of behavioural traits associated with addiction (e.g. impulsivity, locomotor reactivity to novelty, anxiety, novelty preference, sign/goal tracking, decision-making, response learning) and then investigate the degree to which they predict the development of compulsive drug seeking. Thus, we seek to define 'addiction neurobehavioural endophenotypes' across three major addictive drug classes.
In (iv) we will use our established behavioural approaches to define the molecular and neural systems basis of drug memory destabilisation, restabilisation (reconsolidation), extinction and 'super-extinction' and the degree to which the impact of drug-cue elicited memories can be diminished to reduce the propensity to relapse, including in animals that compulsively seek drugs. This approach has significant potential for translation to the clinic.

Drug addiction is a devastating neuropsychiatric disorder that places an enormous financial burden on society, estimated to cost the country more than £40 billion pounds each year (The Centre for Social Justice: Sept 2013 "No quick fix: exposing the depth of Britain's drugs and alcohol problem"). Addiction leads to poverty, family breakdown, crime, debt, homelessness, and long-term unemployment. However, despite intensive research we are only at the beginning of understanding the neural and psychological mechanisms of addiction, an even more limited understanding of major vulnerability traits, and no truly effective treatments for drug addiction. Addressing this urgent unmet need requires a much greater understanding of the psychological and brain-based processes by which social and recreational drug use can progress to a compulsive drug-seeking habit. The proposed research will focus on the psychological transitions between initial 'recreational' drug use, through habitual use to compulsive use and investigate the underlying neural circuitry. This animal experimental approach sits well with both the Research Domain Criteria (RDoc) approach of NIH to psychiatric disorders as well as the more symptom-based approach of DSM5. This enables our findings to impact clinicians through a better understanding of addiction mechanisms.
The research will also focus on individuals, which by virtue of their predisposing behavioural traits more readily abuse drugs by identifying risk markers in the brain long before the manifestation of addiction, at a point when early intervention may be more efficacious. Here we extend our previously successful research on cocaine to heroin and alcohol, where there is astonishingly little understanding of key vulnerability traits. The impact of our work would extend beyond the large number of preclinical neuroscientists around the world presently working on specific behavioural traits in addiction to clinicians. Specifically, a tangible impact of our work is to establish the proof-of-concept principle that diagnostic behavioural and neural pre-symptomatic markers can be detected in individuals destined to develop compulsive drug use. Our work therefore has the potential to have broader impacts for other complex neuropsychiatric disorders characterised by compusivity (e.g. OCD, gambling and binge-eating disorder) where beneficiaries would be those trying to develop new preventive therapies. Our strategy to simultaneously acquire behavioural and functional neuroimaging data provides an additional level of specification and precision to more accurately draw predictive inferences, thereby increasing the impact and relevance of our work for research in humans.
The research on memory plasticity will have impact not only on academic research groups interested in memory reconsolidation, extinction and 'superextinction', but also on experimental and clinical scientists interested in extending this research to human populations, including those in treatment. Already, reconsolidation blockade has been used successfully to treat PTSD and phobic anxiety and, in a single study, superextinction has been shown to reduce the propensity of relapse in heroin addicts. Our experiments designed to understand these phenomena and explore their potential from translation to addiction, especially alcohol addiction, will therefore be of considerable potential impact on clinicians seeking psychological relapse prevention treatments.
The immediate impacts of our work would be realised through publications and conference presentations. By continuing to participate in public engagement events we expect additional immediate impacts through education and scientific dialogue with various interested groups. Longer term impacts (5-10 years) may be realised through influencing public and clinical policy makers to adopt new intervention strategies to personalise treatments in addiction-prone individuals.