Mechanisms Regulating Cocaine Memory Strength

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Abstract Drug addiction is a serious disorder that affects millions of people and produces a large burden on society. Many individuals try to abstain from use, but at least 60% of people relapse within one year. Thus, relapse prevention remains an important goal for addiction treatment research. One of the primary causes of relapse is exposure to the environmental cues (people, places, and things) that remind individuals of drug use and initiate craving. One potential treatment strategy is to reduce the strength of these drug-cue memories so that they are less able to cause renewed drug use. Clinically, this can be accomplished using exposure therapy, which is based on extinction learning and involves multiple presentations of drug-associated cues until the craving response is reduced. Unfortunately, this approach is only mildly effective. Thus, we have investigated the neurobiological mechanisms underlying the maintenance and extinction of cocaine memories, in order to identify potential strategies for improving the ability of cue exposure therapy to reduce relapse. We identified both neural circuit and molecular mechanisms that underlie cocaine memory formation and extinction. Specifically, we found that plasticity at synapses in the lateral amygdala (LA) that receive inputs from the medial geniculate nucleus of the thalamus (MGN) are strengthened after cocaine self-administration and that this plasticity is reversed by cue extinction training. We further found that we could induce long-term depression (LTD) at MGN-LA synapses to reduce relapse-like behavior in a manner that mimicked cue extinction training. Additionally, we found that modulating the activity of kinases and phosphatases in this region could either promote extinction learning or disrupt memory reconsolidation to reduce relapse and the strength of MGN-LA synapses. Thus, in this administrative supplement to support a NIDA Summer Research Intern, we aim to train the student in how to perform experiments investigating the regulation of cocaine- associated memories. The intern will be trained to perform IV drug self-administration experiments, including being given the opportunity to perform surgical procedures. The intern will be trained in proper care and handling of rodents and in the common behavioral methods used in the substance use disorder field. The intern will be assigned a specific experiment to investigate the role of GABAB receptors as a potential target for cocaine memory manipulation. The intern will test whether GABAB receptor agonists could be useful adjuncts to exposure therapy. We will determine if GABAB agonists enhance extinction, prevent reconsolidation, and if pharmacologically assisted exposure therapy is associated with changes in cue-associated neural activity across contexts. We will test if GABAB agonists are effective when infused directly into the LA, and if they are effective when given systemically. Overall, the proposed studies are designed to provide a rich training experience for an undergraduate fellow interested in substance use research.