Neuron Subtype Translatomics in Opiate Abuse

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Project Summary: Opiate use, dependence, and addiction have dramatically increased to epidemic proportions in recent years, leading to substantial financial and societal health burdens, as well as an increasing number of overdoses. Thus, there is a crucial need for novel therapies to treat opiate dependence and cravings occurring with abstinence, which lead to relapse. Many studies indicate dysfunctional brain circuits in opiate use and abstinence, while other studies have identified distinct molecular adaptations underlying opiate-induced behaviors. Such studies emphasize a need to approach opiate use from a combined circuit and molecular perspective to link candidate opiate use and abstinence molecules to dysfunctional neuronal subtypes. This could uncover molecules in disease vulnerable neuron subtypes that can be pharmacologically targeted for opiate use therapeutics. The neuronal subtypes in the nucleus accumbens (NAc) deserve considerable attention in opiate abuse. The NAc is a critical brain hub for altered molecular processes that mediate behavioral responses to opiates and other drugs of abuse. Further, we previously demonstrated distinct roles of the two NAc projection medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor 1 vs. 2 (D1-MSNs vs. D2-MSNs), in opiate induced behaviors. However, there is little information into the molecular adaptations, and corresponding neuronal adaptations occurring in specific NAc neuron subtypes in opiate use and abstinence. To provide insight into this we will perform translatome profiling, using RiboTag, in the two MSN subtypes after opiate use. Since cellular and behavioral plasticity associated with opiate exposure occurs along a continuum we will perform this translatome profiling in D1-MSNs vs. D2-MSNs following abstinence from heroin self-administration at early and prolonged time periods. The studies proposed in this grant application will, for the first time, identify the distinct translatome adaptations occurring temporally following discontinuance of heroin in a cell-type-specific manner. Such studies are essential for uncovering molecules underlying cellular and circuit dysfunction in opiate use and abstinence, thus providing multiple avenues of investigation into the subtype-specific neurobiological underpinnings of opiate abuse.