Sunday, May 18, 2025
5/18/2025
Impact of Opioid Withdrawal on SNl-TS Dopamine and Glutamate in Threat Learning - PROJECT SUMMARY The opioid epidemic remains a critical public health crisis, marked by high rates of addiction, overdose, and mortality. Opioid addiction is a chronic, relapsing disorder with withdrawal often triggering anxiety and avoidance, leading to subsequent drug-seeking and taking behavior. This proposal aims to investigate the neural mechanisms underlying opioid withdrawal-induced anxiety using a combination of behavioral animal models and advanced neurotechnological techniques. Our experimental approach involves a model in which mice self- administer oral oxycodone and display somatic withdrawal symptoms when oxycodone availability is removed. My preliminary data show that mice will self-administer oral oxycodone and display withdrawal signs when oxycodone availability is removed. Further, exposure to an innately threatening visual looming stimulus prompts mice to engage in defensive behaviors, including avoidance. However, my recent work indicates that repeated exposures to this looming stimulus leads to decreased avoidance behaviors, demonstrating that these defensive behaviors are adaptive. Integrating these two models, my preliminary data show that mice undergoing opioid forced abstinence exhibit impaired adaptive defensive responses, as evidenced by their persistent avoidance behaviors toward the looming stimulus. The midbrain-striatal pathway utilizes dopamine and glutamate for learning of rewarding and threatening stimuli and reinforces avoidance behaviors. The midbrain region, substantial nigra pars lateralis (SNl) sends dopaminergic and glutamatergic projections to the tail of the striatum (TS). Preliminary data indicate that dopamine and glutamate respond to threatening stimuli. Additionally, dopamine release in the tail of the striatum (TS) initially responds to the visual looming stimulus and attenuates with repeated exposures. During opioid abstinence, dopamine and glutamate response to threatening stimuli is exaggerated, therefore, I hypothesize in opioid-abstinence disrupts dopamine and glutamate functioning in the TS, leading to sustained avoidance behavior to the looming stimulus. A combination of fiber photometry, optogenetics, and behavioral analyses of oxycodone intake and defensive behaviors will be used to target and investigate the SNl-TS pathway. In Aim 1, we will evaluate opioid withdrawal-induced changes in dopamine and glutamate release from SNl neurons to the TS. In Aim 2, we will manipulate dopamine, glutamate, and co- transmission of dopamine-glutamate from the SNl to the TS during VLS presentations and identify changes in defensive behaviors. The data generated from this project may identify novel mechanisms of neurotransmitter transmissions that may reduce opioid withdrawal-induced anxiety.
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