Neural and psychological basis of compulsive drug seeking and relapse prevention in drug addiction.

Drug addiction is a major form of neuropsychiatric disorder that also places an enormous burden on society through its repercussions on crime-rate and health-care. As highlighted in the 2005 Technology Foresight project, ?Brain Science, Addiction and Drugs? (http://www.foresight.gov.uk/Brain_Science_Addiction_and_Drugs/index.html), there is a major need to develop new treatments for drug addiction. This requires a much better psychological and neural explanation, of the processes by which casual, or intermittent, 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 the transition from voluntary drug seeking through loss of control over this behaviour so that it becomes ultimately compulsive and persistent. We will investigate the neural basis of this transition, especially testing the hypothesis that it involves a loss of control by the prefrontal cortex, an area of the brain involved in ?executive function? that include inhibitory processes that would, for example, normally prevent the establishment of maladaptive habits, such as compulsive drug taking. Abstinence in human addicts 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 activation of drug memories by exposure to drug-associated stimuli and environments makes them vulnerable to disruption, since they undergo a process of ?reconsolidation? during which the memories are updated and re-engage neural mechanisms of plasticity. Thus we will study the molecular and neurochemical basis of drug memories and then investigate whether it is possible to diminish or block the pervasive impact of these memories on drug addiction and relapse. A longer term goal, therefore, is the development of novel neuropharmacological approaches to the treatment of drug addiction that will promote abstinence and prevent relapse in individuals trying to relinquish their compulsive, drug seeking habits.

The overarching hypothesis in the proposed research programme is that drug addiction can be understood as the maladaptive expression of normal learning and memory systems of the brain. Thus, we hypothesize that chronically self-administered drugs subvert the neural networks underlying these systems and, as a consequence, drug seeking and taking becomes established as a compulsive habit, elicited by drug-associated environmental stimuli. Memories evoked by drug-associated stimuli are potent precipitators of relapse, even after long periods of abstinence. We now seek to understand the ways in which these memories become labile when reactivated (memory reconsolidation) and whether this memory reactivation-dependent plasticity can be exploited therapeutically to promote abstinence. The proposed research will: (i) utilize models of habit learning and compulsion developed in this laboratory to test the hypothesis that drug seeking progresses from voluntary (response-outcome) to habit control (stimulus-response), thence to become compulsive, i.e. persistent in the face of adverse outcomes, such as the risk of punishment. (ii) Test the hypothesis that, at a neural systems level, this progression reflects a transition from prefrontal cortical to striatal control over drug seeking behaviour, as well as from ventral to more dorsal regions of the striatum, mediated by the unique, spiraling nature of its dopaminergic innervation. (iii) Investigate the relationship between impulsive behaviour and the vulnerability to escalate drug intake and to compulsively self-administer drugs. (iv) Investigate the neurochemical and molecular basis of drug memory reconsolidation and test the hypothesis that disrupting this process using neuropharmacological agents will diminish or abolish the capacity of drug-associated stimuli to evoke drug memories, craving and drug seeking, thereby promoting abstinence and preventing relapse. We propose a necessarily multidisciplinary and convergent neurobiological approach involving causal interventions in specific neural locations to investigate habit learning and the establishment of compulsive behaviour, genetic and proteomic profiling of drug memory reconsolidation, gene knockdown and neuropharmacological manipulations to investigate ways of diminishing the impact of drug-associated stimuli on relapse. We hypothesize that understanding the psychological and neural basis of compulsive drug seeking habits, as well as relapse in terms of aberrant learning and memory reconsolidation, will allow therapies to be targeted at these plastic processes to promote re-learning and hence rehabilitation.