Delta Opioid Receptor Regulation of Parvalbumin Interneuron Transmission and Oxycodone-Related Behavior

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Project Summary/Abstract Opioid use disorder (OUD) is a chronic and relapsing brain disorder that is characterized by an inability to control drug use and an intense withdrawal syndrome upon cessation. In addition to flu-like somatic symptoms, opioid withdrawal is plagued by motivational and affective disturbances that are powerful drivers of relapse. While Mu opioid receptor (MOR)-based therapies alleviate somatic discomfort and attenuate craving in OUD, these treatments are less effective at addressing long-lasting psychological symptoms that maintain drug use. The delta opioid receptor (DOR) system has been consistently linked to hedonic deficits in rodent models of affective and reward behavior, supporting a role for dysregulated DOR signaling in these symptoms of OUD. The prefrontal cortex (PFC) is heavily implicated in OUD, and a substantial preclinical literature has linked PFC function with affective and motivational behavior. The PFC expresses a rich endogenous opioid system that is strongly localized to GABAergic interneurons (INs). Parvalbumin (PV) INs, a key subpopulation involved in regulating PFC circuitry and affective behavior, express high levels of MOR and DOR and exhibit opioid- mediated plasticity in several brain structures. My preliminary data shows a striking dichotomy in PFC PV-IN opioid sensitivity, demonstrating that optically-evoked PV-IN transmission is strongly suppressed by DOR activation but not MOR. Furthermore, I’ve shown that oxycodone dependence increases the efficacy of DOR agonists for suppressing spontaneous inhibitory transmission, suggesting that repeated opioid use initiates DOR- induced adaptations to PFC PV-IN transmission. This proposal will test the hypothesis that opioid dependence induces aberrant DOR signaling in PFC PV-INs to mediate opioid-related behaviors in abstinence. Aim 1.1 and Aim 1.2 of this study use whole-cell patch-clamp electrophysiology, cell type-specific optogenetics, and selective pharmacology to determine how opioid dependence alters PV-IN intrinsic and synaptic physiology and opioid receptor regulation of PV-IN transmission. Aim 1.3 uses immunohistochemistry to measure changes to DOR expression in PV-INs following dependence. Aim 2 uses Cre-inducible RNA interference in genetically engineered PV-Cre mice to reduce DOR signaling in PFC PV-INs and test the role of PV-IN DOR in a behavioral battery assessing affective and motivational phenotypes during withdrawal. These Specific Aims will improve our understanding of cell type-specific DOR regulation of PFC function and provide insight into how DOR-mediated changes in inhibitory transmission impact opioid-related behaviors following dependence. I will bring my skills in electrophysiology and slice optogenetics to proficiency and expand my technical repertoire to include key molecular tools such as RNA interference for powerful causal interventions, building a strong skillset for a successful career as an independent investigator.