Neural mechanisms and treatment of compulsive drug seeking habits and relapse in cocaine and alcohol addiction

Drug addiction is a major form of psychiatric disorder that also places an enormous burden on society through its repercussions on crime and health care provision. There is a major need to develop new treatments for drug addiction and to identify who may be at risk of addiction following exposure to drugs (as was highlighted in the Academy of Medical Sciences 2008 report ?Brain Science, addiction and drugs?). Addressing these questions requires an improved psychological and brain-based explanation of the processes by which casual or controlled drug use can progress to a compulsive drug seeking 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. In the proposed research, we aim to model and investigate in rats the neural basis of the transition from voluntary drug seeking through loss of control over this behaviour so that it becomes ultimately compulsive and persistent. We will continue our studies with cocaine, which along with other stimulant drugs such as methamphetamine presents a serious problem in the UK. But we will also introduce a new aspect to our research by studying compulsive alcohol seeking and drinking. Alcoholism and binge drinking are a major and growing problem,
bringing with them extreme personal and societal costs ? alcohol misuse alone is estimated to cost the UK #25.1 billion every year (http://www.nao.org.uk/publications/0708/reducing_alcohol_harm.aspx). Abstinence in addictive drug-dependent individuals is especially difficult to maintain and relapse, often triggered by drug-associated stimuli in the environment, is a characteristic of drug addiction. We now know that retrieval of positive memories of earlier drug taking by exposure to drug-associated stimuli and environments makes these memories vulnerable to disruption, since they undergo a process of ?reconsolidation? during which the memories are updated by re-engaging plastic brain processes. Therefore, we will continue to study the molecular and neurochemical basis of cocaine and alcohol memories and then investigate whether it is possible to diminish or block their pervasive impact on relapse to drug taking and addiction. A longer-term goal, therefore, is the development of novel medications for the treatment of drug addiction that will promote abstinence and prevent relapse in individuals trying to relinquish their compulsive drug seeking and taking habits.

Several inter-related themes in the proposed research programme test hypotheses concerning: (i) Extending our actions-to-habits-to-compulsive drug-seeking hypothesis from stimulant drugs to alcohol. (ii) Investigating the neural mechanisms underlying alcohol seeking habits and the transition to alcohol seeking. This extension is in part motivated by the burgeoning problem of alcohol abuse and will specifically test hypotheses that the acquisition of alcohol seeking habits and compulsion as well as the vulnerability to lose control over alcohol seeking, share common, or depend upon different, neural mechanisms to those engaged during transitions to compulsive cocaine seeking. (iii) Examining serotonergic and limbic-cortical-striatal mechanisms implicated in compulsive cocaine-seeking, including experiments on microPET imaging of a presynaptic 5-HT marker. (iv) Analysing further the limbic cortical control over the functional links between the ventral and dorsal striatum, via serial dopaminergic connectivity with the midbrain, in the establishment of drug seeking habits. (v) Investigating whether individual differences in prefrontal cortical function, as well as impulsivity and anxiety, are vulnerability characteristics (possibly endophenotypes) for loss of control over different addictive drugs. (vi) Investigating potential novel treatments of addiction based on existing drugs used in the treatment of other disorders, but translated to our enhanced understanding of the neural mechanisms of drug seeking, compulsion and relapse. These potential treatments test hypotheses that different treatments may be effective at different stages of the addiction cycle and also whether the same drugs are effective in decreasing drug seeking and relapse across different drug classes. (vii) Continuing our research on drug memory reconsolidation, testing hypotheses concerning fundamental neural mechanisms underlying the destabilisation and restablisation of retrieved memories and the potential for disrupting them. The case has been made for disruption of memory reconsolidation as a treatment for drug addiction and other neuropsychiatric disorders characterised by aberrantly strong and intrusive memories, including post-traumatic stress disorder where there has already been treatment success. (viii) Finally, we propose an experimental medicine study with abstinence-seeking, alcohol-dependent volunteers to test the hypothesis based upon our experimental data that the ?-blocker propranolol, given at the retrieval of alcohol memories elicited by the presence of alcohol-associated stimuli and scripts, will subsequently reduce the impact of those stimuli on subjective craving and its physiological correlates, as well decrease relapse to drinking.