A patch circuit dissection of opioid addiction

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PROJECT SUMMARY/ABSTRACT The opioid crisis remains a major health concern with millions of Americans addicted to opioid drugs and thousands of opioid related deaths per year. The sad reality is that while medication assisted therapies are highly effective, relapse rates remain high. More understanding is needed into the neurobiology and circuits of opioid addiction to identify new therapies. Opioids exert their rewarding and addictive effects through action at the mu opioid receptor (MOR). The MOR is expressed widely throughout the nervous system including regions associated with drug reward such as the nucleus accumbens. It is present in a peculiar neuroanatomic organization referred to as “patch” or “striosome,” with dense regional expression situated in a network of islands throughout dorsal striatum and nucleus accumbens. The region outside of these islands is referred to as matrix. The functional relevance of this level of neuroanatomic organization is mysterious and its consequence for opioid use disorders is almost completely unknown. While the direct and indirect pathway of striatal organization has revealed critical insights into motivated behavior and pathologic changes associated with substance use disorders, it remains incomplete especially in regions of the ventral striatum such as the nucleus accumbens. The neuroanatomy of “patch” vs “matrix,” and the cell types contained within each compartment, opens the possibility for a revived lens through which to look at the functional organization of the nucleus accumbens in motivated behavior and addiction. Recently, the power of mouse genetics revealed two separate populations of direct pathway medium spiny neurons housed within MOR positive patch networks. Further work has shown that while one population encodes positive valence and positive reinforcement, the other encodes negative valence and negative reinforcement, challenging the traditional dogma of the direct pathway. This proposal resubmission begins to define a role for these cell populations in preclinical models of opioid abuse, investigating the properties of patches in the valence of opioids and withdrawal, opioid consumption, maintenance, extinction and reinstatement. Input and output circuitry will be defined in each patch cell type within the nucleus accumbens. The work will combine opioid self-administration, behavioral economic analysis, viral neuroanatomic techniques, optogenetic and chemogenetic manipulations and cell type neuroimaging with fiber photometry. This work will be among the first to study MOR (+) patch circuits in the context of opioid use disorder. Through this new lens of functional organization, insights can be revealed that could lead to new therapies in treating the devastating health and societal impact of opioid use disorders.