Cell-Types Specific Neuroadaptations in the Nucleus Accumbens Shell Associated with Individual Differences in Cocaine-Seeking

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Project Summary/Abstract Although cocaine is powerfully rewarding, not all people who are exposed to this drug are equally prone to abusing it. The reasons for these differences remain unknown but may involve predisposing factors whose elucidation could lead to therapies that, in the future, may prevent cocaine addiction. One such predisposing factor is behavioral sensitivity to the aversive attributes of cocaine, which overlap with the rewarding effects to protect against cocaine-seeking. Preliminary data in this proposal suggest that the aversive effect of cocaine may be much stronger in some individuals than others and potentially a determinant for cocaine addiction vulnerability. The underlying cellular mechanism of this variability remains unknown. However, our preliminary data revealed that higher RhoA activity and D2-MSN excitability in the mNACshell correlate with rats displaying higher aversive effects of cocaine (and consequently lower drive to seek cocaine). Nevertheless, it is unknown if these cellular and molecular adaptations in the mNACshell are involved in the aversive attributes of cocaine. Accordingly, to address this gap in knowledge, I’m proposing two aims. In aim 1, I will determine the roles of D2MSN on cocaine avoidance behavior, and for this, I will be trained in fiber photometric and optogenetic methods. I hypothesize that D2- but not D1-MSNs are activated during cocaine’s aversive phase, and that D2 activity in turn drives conditioned negative attributes of cocaine. In aim 2, I will examine the roles of RhoA and related genes on neural excitability and cocaine avoidance in a cell-specific manner. First, I will use mRNA TRAP methods to analyze cell-specific gene translation associated with RhoA signaling or excitability linked to cocaine avoidance phenotypes. In addition, to test the causal role of RhoA in excitability and cocaine avoidance behavior, I will decrease or increase RhoA activity in a cell-specific manner using an adeno-associated gene manipulation strategy. I hypothesize that increases in RhoA activity in D2-MSN but not D1-MSN enhances excitability in the mNACshell confer protection against the acquisition of cocaine-seeking. An intense and comprehensive training, mentoring, and research plan has been developed to achieve these goals. This plan will be guided by a powerful team of mentors and collaborators that will help blend my current skill set with new conceptual and technical frameworks as I continue to establish my own unique and innovative research program in addiction neuroscience.