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

研究 Cav1.2 通道在可卡因相关记忆消退中的机制贡献

基本信息

批准号：
10366896
负责人：
Anjali M RAJADHYAKSHA
金额：
$ 53.17万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366896
关键词：
A kinase anchoring protein AMPA Receptors Address Affect Anatomy Behavior Behavior Therapy Binding Biochemical Brain Brain region C-terminal Calcineurin Cell Nucleus Cells Cocaine Cocaine Dependence Cocaine Users Complex Coupling Cues Cyclic AMP-Dependent Protein Kinases Development Dopamine Dopamine D1 Receptor Dorsal Electrophysiology (science)Event Extinction (Psychology)Fiber Gene Expression Genetic Genetic Transcription Heterodimerization Hippocampus (Brain)Human Image Imaging Techniques Impairment Individual Knock-out Knowledge Laboratories Learning Maintenance Maps Mediating Memory Modification Molecular Monitor Mus Mutant Strains Mice Neurons Nuclear Translocation Peptides Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Photometry Pre-Clinical Model Process Property Protein Biosynthesis Proteins Regulation Relapse Resistance Rewards Rodent Role Scaffolding Protein Signal Transduction Signaling Molecule Site Slice Societies Study models Surface Synapses Synaptic plasticity Techniques Testing Training Variant Viral Work addiction behavior test brain reward regions cell type cocaine relapse prevention cocaine use conditioned place preference cost dentate gyrus drug of abuse experience gain of function granule cell hippocampal subregions improved in vivo in vivo calcium imaging knock-down learning extinction mutant neuromechanism novel prevent protein protein interaction recruit sensor small hairpin RNA transcription factor transcription factor NF-AT c3

项目摘要

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.

项目总结