1Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.
In addition to excessive drinking, alcohol seeking is the key feature of alcohol addiction leading to relapse and for which, unlike the former, there are few effective treatments. In particular, drug seeking behaviour is triggered and maintained by drug-associated environmental and conditioned stimuli, which are also known to influence appetitive and consummatory behaviours. Moreover, when the control over drug seeking and taking despite negative physical and social consequences is lost, drug seeking is defined as compulsive. Here we first established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which alcohol preferring (P) rats have the opportunity to drink alcohol. Then we further adapted a seeking-taking chained schedule of alcohol reinforcement in P rats in which instrumental seeking responses resulted either in the opportunity to respond on a second lever that resulted in the opportunity to drink alcohol, or in unpredictable mild foot-shock punishment (i.e. probabilistic seeking punishment). In a subgroup of animals trained under this task, alcohol seeking persisted despite the unpredictable, intermittent delivery of 0.45 mA foot shock punishment, thereby resulting in compulsive alcohol seeking behaviour. Seeking behaviour under both tasks was then challenged by treatment with the novel selective µ-opioid receptor antagonist GSK1521498, which significantly reduced both compulsive and non-compulsive alcohol-seeking, as well as alcohol drinking. Taken together with our data showing that GSK1521498 also prevented cue-maintained cocaine and heroin seeking, these data indicate the great potential for selective µ-opioid receptor antagonism in relapse prevention and abstinence promotion across addictive drug classes.