Tuesday, April 23, 2024
4/23/2024
Project Summary/Abstract Opioid side effects including euphoria, tolerance and dependence limit clinical applications and have increasingly contributed to fatal misuse. Opioid analgesia, reinforcement, and withdrawal are mediated by the µ-opioid receptor, that is expressed throughout the reward circuit of the brain. Our long-term goal is to identify mechanisms underlying and regulating µ-opioid receptor coupling to downstream pathways, and how these respective pathways contribute to cellular and synaptic plasticity that promote addiction and dependence. In addition to its acute neuromodulatory effects, cyclic AMP (cAMP) signaling is intimately involved in modulating cellular, structural and synaptic plasticity from repeated opioid administration. Unlike the µ-opioid effectors Gai and Gß¿, our understanding of the mechanistic role of Gao in transducing MOR signals is limited. Our lab and others have supported a role of Gao in coupling µ-opioid receptor activation to cAMP signaling using knockdown approaches or by manipulating specific Regulators of G-Protein Signaling proteins. More recently, we have identified changes in cAMP levels, opioid reinforcement behavior, and withdrawal phenotypes resulting from striatal conditional Gao knockout. We propose that these effects of Gao deletion result from impaired MOR coupling to AC, via modulation of Gß¿ availability. In Aim 1, I will determine the contribution of Gao to opioid- evoked cAMP response dynamics of cultured striatal neurons using a genetically encoded optical cAMP biosensor pioneered by our lab. This approach will be further applied in combination with optogenetic stimulation of striatal inputs in brain slices to investigate how Gao contributes to opioid induced adaptations of striatal dopamine signal integration in an intact mesolimbic circuit. In Aim 2, I will use electrophysiology to determine how Gao contributes to opioid-induced adaptations that regulate striatal physiology and synaptic plasticity. In Aim 3, I will determine the specific striatal circuits in which Gao influences opioid reinforcement behaviors. These studies will identify mechanistic contributions of Gao to µ-opioid receptor signaling, subsequent adaptations that modify striatal physiology, and how these effects ultimately influence opioid reinforcement behavior within discrete striatal circuits. This research has the potential to identify new strategies for manipulating opioid reinforcement for therapeutic applications, to address the ongoing epidemic of opioid abuse.
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