Anjali Rajadhyaksha, Ph.D., professor of neuroscience in pediatrics, has been awarded an NIH R01 grant for her study, “Investigating the mechanistic contribution of Cav1.2 channels in extinction of cocaine-associated memories.” The study will examine Cav1.2 L-type Ca2+ channels and its interacting signaling molecules within defined neuronal cell types in extinction of cocaine contextual memories.
Cocaine addiction exerts a high cost on society and individuals and to date no pharmacotherapies exist. Studies have shown that behavioral therapies are not effective at preventing relapse as 70-80% of cocaine users will experience relapse following therapy. Preventing relapse is the primary challenge 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. Therefore, understanding the neural mechanisms that are responsible for these drug-context associations 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, a major cause of relapse in patients. Despite this knowledge, the role of this brain region in cocaine addiction remains understudied. Previously, Dr. Rajadhyaksha and her research team identified a novel role for the Cav1.2 calcium channel, a key protein in neurons that allows entry of calcium and activates calcium signaling within neurons required for overriding cocaine memories. This led them to speculate that the Cav1.2 channels are a promising target for addiction therapies. Dr. Rajadhyaksha’s team used a preclinical addiction animal model and found that overriding cocaine memories involves increases in Cav1.2 protein and its phosphorylated form in the dHPC within a subset of neurons that express dopamine D1 receptors. This work is of particular importance given the finding that the gene for Cav1.2, CACNA1C has emerged as a top candidate risk gene for drug dependence and associate neuropsychiatric conditions.
For this study, Dr. Rajadhyaksha will capitalize on this knowledge to further explore dHPC Cav1.2 channel mechanisms in cocaine-associated memories. The team will test the central hypothesis that context extinction learning - a form of learning that is capable of overriding negative original memories - recruits Cav1.2 channel mechanisms at dHPC synapses via recruiting dopamine D1R signaling, and will use a combination of genetic, pharmacological, electrophysiological, and in vivo calcium imaging techniques with behavioral testing for the proposed studies. The findings of this study will have the potential to form the basis for developing novel treatment approaches to benefit cocaine dependent individuals.
Collaborators:
Dr. Natalia DeMarco Garcia, Ph.D., associate professor of neuroscience and Dr. Teresa Milner, Ph.D., professor of neuroscience at the Brain and Mind Research Institute, and Dr. Conor Liston, M.D., Ph.D., associate professor of neuroscience and psychiatry, Weill Cornell Medicine.
Dr. Mark Dell’Acqua, Ph.D., professor and Vice Chair of Pharmacology, University of Colorado.
Dr. Richard Huganir, Ph.D., Director, Department of Neuroscience and Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences, Johns Hopkins School of Medicine.