Impact of stress on heroin seeking and ventral pallidal synapse function

PROJECT SUMMARY: Deaths related to opioid use disorders (OUD) have sky-rocketed in recent years, leading to a widespread public health crisis. This opioid endemic is worsened by a lack of effective therapeutic intervention strategies that directly target or reverse the opioid induced neuroadaptations driving drug use and relapse. Prior research

indicates that experiencing a major stressful event in life is the greatest risk factor for exacerbated opioid use and relapse among adults. Congruent with clinical data, preclinical work indicates that acute stress in adulthood increases psychostimulant seeking in intravenous drug self-administration rodent models, but the effects of acute

stress on opioid seeking remain unknown. Further, the neurobiological mechanisms by which stress confers OUD susceptibility are unclear. Emerging literature shows that ventral pallidal glutamate neurons (VPGlu) are key regulators of drug seeking behavior and aversive states, which suggests that this neuronal subpopulation may

be a strong candidate for mediating the effects of stress on OUD-relevant circuit function that exacerbates OUD pathology. My preliminary data sought to begin addressing these gaps in the OUD literature by examining how acute stress impacts heroin sensitization and VPGlu activity using in vivo miniscope Ca2+ imaging in non-head

fixed male and female mice. To the best of my knowledge, this preliminary work represents the first in vivo characterization of VPGlu activity during intense acute stress, and I am the first to report that VPGlu are responsive to both stress and heroin. Furthermore, my sensitization data demonstrate that stress produces sexually

dimorphic changes in the psychomotor effects of heroin. Taken together, these preliminary data show that adult acute stress alters the psychomotor properties of heroin and highlight VPGlu as promising mediators of stress and OUD-relevant behaviors. My data warrant further investigation into the impact of stress on clinically relevant

opioid behaviors such as motivation and relapse to heroin seeking, and the systematic characterization of how stress, opioids, and their intersection regulate the activity of VPGlu by altering synaptic inputs onto these cells. Together, my preliminary data informed my main hypothesis that acute stress will enhance heroin

motivation and relapse to heroin seeking and that stress and opioids interact to alter VPGlu synaptic function. The goals of this proposal are to interrogate 1) how stress impacts the motivation and relapse to heroin seeking using an intravenous self-administration model and 2) assess the effect of stress, opioids, and their

interaction on synaptic function of VPGlu using ex vivo whole cell patch clamp electrophysiology. The outcomes of this proposal will determine the consequences of acute stress on clinically relevant behavioral responses to heroin and systematically characterize alterations in synaptic function of a newly established stress-reactive

neuronal subpopulation. Completing this proposal will be invaluable to my development into a successful physician-scientist by providing the necessary skills to perform high-impact, rigorous substance use disorder research while gaining essential clinical proficiencies to treat patients affected by these disorders.