Investigating anti-neuroinflammatory therapeutics for polysubstance use disorders - The ongoing opioid crisis, exacerbated by synthetic opioids like fentanyl, has been further complicated by rising co-use of stimulants such as methamphetamine. Despite the increasing prevalence of polysubstance use, current research largely focuses on single-drug models, limiting understanding and treatment options for polysubstance use disorders. Methamphetamine and fentanyl both induce neuroinflammation, but the combined effects of these co-used drugs on neuroinflammation and related behaviors remain unexplored. This project aims to address this gap by investigating the functional significance and mechanism of polysubstance-induced neuroinflammation utilizing a novel rodent model of polysubstance dependence and withdrawal using co- administered fentanyl and methamphetamine, with particular focus on the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) and the neuropeptide hypocretin/orexin (HCRT). HCRT influences a wide array of physiological functions, including those relevant to drug dependence and neuroinflammation, although the function of HCRT in drug-induced neuroinflammation is not yet well-understood. The overarching hypothesis is that during polysubstance withdrawal, HCRT functions as a pro-inflammatory agent in withdrawal-sensitive brain regions of the extended amygdala and the dorsal hypothalamus, contributing to neuroinflammation (including increases in TNFα) associated with polysubstance dependence. Aim 1 will determine TNFα’s role in motivated polysubstance use and stress-induced reinstatement of drug-seeking using neuropharmacological techniques with a small-molecule TNFα-inhibitor. Aim 2 will define the role of HCRT signaling on polysubstance-induced neuroinflammation by measuring cytokine response to HCRT manipulations in polysubstance dependent rats. Findings from this research could significantly advance our understanding of the neuroimmune mechanisms driving polysubstance dependence and lead to the development of more effective treatments for addiction. Students will play an integral role in conducting hands-on, rigorous research as aligned with current NIH priorities and under the direct supervision of the PI and a team of collaborators.
