Contribution of BLA-mPFC pathway to risky choice and compulsive cocaine seeking

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Project Summary/Abstract This is a resubmission of a renewal application for an AREA R15 grant to continue research funded in DA047610 (“Contribution of NMDA NR2B subunit to risky choice and economic demand for cocaine” now titled “Contribution of BLA-mPFC pathway to risky choice and compulsive cocaine seeking”). The purpose of the R15 grant is to stimulate research at primarily educational institutions like Northern Kentucky University (NKU) that support baccalaureate training but are not recipients of major NIH support. Risky choice is characteristic of several psychiatric conditions, including substance use disorders (SUDs). Substance misuse can be considered a risky behavior as individuals can become incarcerated for their drug use or can ultimately die from overdose. Understanding the neurobiology of risky choice is important for designing effective treatment interventions for individuals that are at risk for developing SUDs. During our current funding period, we have shown that the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor mediates risky choice as assessed in the risky decision task (RDT), and it mediates addiction-like behaviors as measured in cocaine self-administration and in methamphetamine conditioned place preference. Because the RDT uses foot shock as punishment, determining if a rat displays increased risky choice or insensitivity to shock is difficult. Thus, the first goal of the current proposal is to use a novel task to measure risky choice. To this end, rats will be tested in an equivalent expected value (EEV) task, in which reinforcer magnitude and reinforcement probability will be adjusted across concurrently available reinforcers such that the expected utility (value) of each alternative is equivalent. Because the expected value is equivalent across reinforcer alternatives, there is no suboptimal choice. However, risky choice can be measured by the percentage of responses for the lower probability/larger reward alternative. To further elucidate the neurocircuitry of risky choice, we will determine if chemogenetic inhibition of medial prefrontal cortex (mPFC)-projecting basolateral amygdala (BLA) neurons and/or BLA- projecting mPFC neurons decreases risky choice in the EEV task (Specific Aim 1). Specific Aims 2 and 3 will utilize the same chemogenetic approach from Specific Aim 1 to determine if the reciprocal connections between the BLA and the mPFC mediate compulsive cocaine seeking and resurgence of cocaine seeking (model of relapse-like behavior). Renewed funding will allow us to answer these critical questions and will allow undergraduate students to continue gaining research experience in behavioral neuroscience research at NKU.