Optogenetic and Chemogenetic Investigation of the Projection Inputs to the Mpfc Involved in Cb1-Mediated Cocaine-Associated Memory

The greatest challenge for cocaine addiction remedy is the neural plasticity change associated with its chronic use, which renders persistence of psychological craving for cocaine even after prolonged abstinence. Cannabinoid CB1 receptors are implicated in neural plasticity and various forms of learning and memory, including acquisition and reinstatement of cocaine-associated memory. Our previous findings indicate that blockade of the medial prefrontal CB1 receptors by rimonabant bidirectionally modulates the consolidation of cocaine-induced conditioned place preference (CPP) memory, depending on the low- vs. high-dose cocaine. While the mechanism underlying this bidirectional modulation of cocaine memory by rimonabant remains elusive, it is speculated that activity-dependent plasticity of CB1 receptors may be involved. Likewise, dopamine, probably via its interaction with other glutamatergic inputs or GABA interneurons, often exerts the bidirectional effect on PFC cells. Indeed, our preliminary data shows the involvement of the medial prefrontal D1 and D2 receptors in rimonabant's effect on cocaine CPP memory. Therefore, this research aims to investigate the role of the projection-specific and dopamine-specific pathways to the mPFC in CB1-mediated cocaine-associated memory via chemogenetics and optogenetics. First and Second, we will target the vHPC-to-mPFC and the BLA-to-mPFC pathways to examine their roles in rimonabant's effect in wild-type mice, including utilizing in situ hybridization. Third, by using the TH-Cre mice, we will target the VTA-to-mPFC dopaminergic inputs and test its role in rimonabant's effect on cocaine-associated memory. We propose to depict the roles of these inputs and their possible interaction with the dopaminergic inputs to the mPFC in rimonabant's effect on cocaine memory. By getting insight into the circuit mechanism of medial prefrontal CB1-mediated cocaine-associated memory, we can explore possible application in treating cocaine addiction.