The reconsolidation of instrumental cocaine-seeking memories

Addiction to illicit drugs, such as cocaine, has important socio-economic and health consequences, causing an estimated total cost of £12 billion in the UK in 2000. Therefore, strategies to improve abstinence from drug taking are highly desired. Addictive drugs are powerful rewards, acting in much the same way as natural rewards such as food. As such, addiction is characterised by strong memories that link the drug to both drug-related cues and to the instrumental responses in drug seeking behaviour. Both of these memoryies are important in perpetuating drug-seeking behaviour. Therefore strategies to diminish these drug-associated memories would be potentially useful as a pro-abstinence/anti-relapse treatment.

The phenomenon of memory reconsolidation provides a potential opportunity to disrupt existing memories, including cue-drug and response-drug memories. When a memory is retrieved, it sometimes enters into a process termed "reconsolidation", which is necessary for the memory to persist thereafter. If the reconsolidation process is disrupted, the memory is disrupted. We have previously demonstrated in a rat model that cue-food and cue-cocaine memories can be disrupted in this manner, leading to a partial reduction in cue-induced food- and cocaine-seeking. Moreover, we have recent evidence that response-food memories also undergo reconsolidation. Importantly, reconsolidation-based treatments are already being translated to human post-traumatic stress disorder patients, and so there is a real possibility of beneficial effects in drug addiction. However, it remains to be demonstrated that the reconsolidation of instrumental response-cocaine memories can be disrupted to reduce cocaine seeking in translationally-relevant rodent models.

There are three main causes of relapse in addiction. These are exposure to the drug-associated cues, exposure to the drug itself, and exposure to stress. Most previous studies of memory reconsolidation in addictive drug settings have focussed on cue-induced relapse by targeting cue-drug memories. However, there is little evidence that drug-induced and stress-induced relapse can be reduced by cue-drug memory reconsolidation-based treatments. Given the fundamental dependence of drug seeking upon the memory that the instrumental response gives access to the drug, it would be expected that an impairment in response-drug memory reconsolidation will reduce all manners of relapse. Therefore, the current project is focussed upon the potential application of instrumental reconsolidation-based treatments for relapse to drug seeking, and will ask 2 main questions:

1. Can the reconsolidation of instrumental response-cocaine memories be disrupted?

2. Is the disruption of instrumental response-cocaine memory reconsolidation effective at reducing cue-induced, drug-induced and stress-induced relapse?

In order to answer these questions, and test our specific hypotheses, we will primarily use behavioural testing (behavioural pharmacological analyses in freely behaving rats), with the addition of analyses of molecular changes that are associated with memory reconsolidation. The nature of the hypotheses and the approaches needed to test them require the use of experimental animals. Rats are the least sentient species that retain a level of biological similarity to humans such that our conclusions can reasonably be applied to the understanding of human learning and memory.

Memories can be destabilised by their retrieval. This allows those memories to be diminished by disrupting the reconsolidation process that restabilises the memory. We have previously demonstrated that the reconsolidation of pavlovian cue-reward memories can be disrupted by systemic NMDA receptor antagonism in both sucrose- and cocaine-seeking settings. More recently, we have shown that instrumental lever press-food memories can be diminished by disrupting memory reconsolidation, similarly by systemic NMDA receptor antagonism.

In this project, we will test the hypothesis that disruption of instrumental memory reconsolidation (through both NMDA receptor antagonism) is an effective method of reducing relapse to cocaine-seeking behaviour. In rats self-administering cocaine intravenously, we will destabilise the instrumental cocaine memory in conjunction with either systemic injections of MK-801 or local intracerebral infusions of protein synthesis inhibitors, and test the impact of these treatments upon subsequent cue-induced, stress-induced and cocaine-induced cocaine seeking. We will test the hypothesis that disrupting instrumental memory reconsolidation is more effective than impairing pavlovian memory reconsolidation for reducing stress-induced and cocaine-induced relapse. Moreover, combined targeting of both instrumental and pavlovian memories is hypothesised to be most effective at reducing cue-induced cocaine seeking.

The expected results will greatly inform our understanding of the basic mechanisms of instrumental memory reconsolidation. As experimental impairment of appetitive memory reconsolidation is suggested to be a potential therapeutic strategy for maladaptive cue-induced reward seeking in drug addiction and some forms of obesity, such basic scientific understanding is an essential prerequisite for any future translational application.

We are committed to the dissemination of our research to a wide audience. Our work has been reported previously in popular magazines and we have contacts within the excellent Birmingham University Public Relations Office. We will work with them to communicate our results via diverse media such as newspaper, magazines, and TV and radio. The PI and existing members of the lab are involved in the activities of Understanding Animal Research, promoting the value of animal-based research (within the context of the importance of our own research) to school-age children. We would anticipate making two such visits per year. Moreover, the University of Birmingham is making increasing efforts to engage the public during the Dana Foundation-associated Brain Awareness Week, through which our findings will also be publicised.

The results of this research will have implications for the application of reconsolidation-based treatment strategies for maladaptive reward-seeking conditions. The direct context is cocaine-seeking, but the results will also have relevance to addictions to other drugs and potentially non-homeostatic forms of obesity. In particular, we will gain an understanding of the relative efficacy of targeting pavlovian and instrumental memories for different triggers of relapse.

Within the University of Birmingham, we are involved in discussion groups and collaborations, both within the School of Psychology and also in the Medical School. The School of Psychology has a strong Clinical Psychology group with expertise in Cognitive Behavioural Therapy, to which the behavioural element of this work may become relevant. Our links to the Clinical and Experimental Medicine group in the medical school enables our work to be disseminated effectively towards translationally-relevant clinical settings. The close relationship between the Medical School and the local NHS Trust, as well as the Royal Centre for Defence Medicine, is a particular advantage in ensuring that the results of our work are made known to relevant clinical researchers and practitioners.

Finally, it should be noted that the application of reconsolidation-based treatments, while promising, is in its early stages, with a single open-label trial using beta blockers in relation to PTSD the only clinical application of which we are aware (7 years after the initial published preclinical study). Given that beta blockers are unlikely to be of benefit in a reward-seeking setting, the timeframe for the potential translational impact of the current project will be more extended. If the outcomes of the grant are compelling, we would collaborate with the Behavioural Medicine Group at the University of Birmingham to translate the approach to human subjects, seeking further funding from MRC, NIHR or the Wellcome Trust.