Investigating the mechanistic contribution of Cav1.2 channels in extinction of cocaine-associated memories

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Project Summary Cocaine addiction exerts a high cost on society and individuals and to date no pharmacotherapies exist. Behavioral therapies are not effective at preventing relapse; indeed, 70-80% of cocaine users will experience relapse following therapy. Preventing relapse to cocaine use represents the primary challenge that exists for the treatment of cocaine dependent individuals. One of the many factors that contribute to relapse is the exceptionally strong associations that drugs of abuse, such as cocaine make between environmental contexts and the rewarding properties of the drug. Thus, understanding the neural mechanisms that are responsible for these drug-context associations and ways in which we can override them, is critical for the development of improved treatment options. The dorsal hippocampus (dHPC), well known for its role in learning and memory, is an important anatomical region involved in cocaine-context associations. Despite this knowledge, the role of this brain region in cocaine addiction remains understudied. Work from our laboratory has identified a novel role for the Cav1.2 L-type Ca2+ channel (LTCC) in the dHPC in extinction of cocaine-associated contextual memories, consistent with their well-known role in hippocampal-dependent synaptic plasticity underlying certain forms of learning/memory. Extinction learning involves a new form of learning that is capable of overriding original memories, particularly maladaptive memories. Thus Cav1.2 channels serve as a promising candidate for overriding drug-context associations. Using the cocaine conditioned place preference (CPP), a preclinical model used to study cocaine-associated contextual memories, we find that extinction of cocaine CPP increases synaptic levels of Cav1.2 and its phosphorylated form in the dorsal dentate gyrus (dDG), a hippocampal subregion, in a dopamine D1 receptor cell type-dependent manner. This is consistent with growing evidence for a role of dHPC dopamine for learning/memory mechanisms including cocaine contextual memories. Our molecular studies have identified that extinction increases key signaling molecules in the dDG. These include AKAP150 anchoring protein, PKA, NFATc3 and the GluA1 subunit of AMPA receptors. Thus, in this application we aim to capitalize on this knowledge to further explore dDG Cav1.2 channel mechanisms in extinction of cocaine-associated memories. We will test the central hypothesis that contextual extinction learning recruits Cav1.2 channel mechanisms at dDG synapses via recruiting dopamine D1R signaling. We will use a combination of genetic, pharmacological, electrophysiological, and in vivo calcium imaging techniques with behavioral testing for the proposed studies. Aim 1 will test the involvement of AKAP-PKA-Cav1.2 signaling. Aim 2 will address the involvement of AKAP-CaN-NFAT signaling and Aim 3 will examine the contribution of D1R signaling, in cocaine CPP extinction and dDG cell activity.