Sex Differences in a Rat Model of Opioid Use disorder

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PROJECT SUMMARY Opioid use disorder (OUD) is a major epidemic in the United States, and women appear be more vulnerable than men to certain aspects of the disease. Specifically, women develop OUD more rapidly (i.e. the telescoping effect), experience higher levels of cue-induced drug craving, and suffer more serious drug-related health consequences as compared to men. Despite the severity of this problem in women, preclinical studies have historically focused on males only, resulting in a male-centric basis of OUD; therefore, the purpose of this application is to determine sex differences in the development, expression, and molecular mechanisms of OUD. Our extended access (24-hr/day) self-administration procedure readily induces an addiction-like phenotype in rats, including an enhanced motivation for the drug, compulsive use, and vulnerability to relapse, when examined following protracted withdrawal. We have also validated this animal model by showing that treatment during withdrawal with buprenorphine, an FDA-approved medication for OUD, greatly attenuated vulnerability to relapse in both males and females. Notably, in this animal model, we have established biological sex as an important vulnerability factor with females showing an enhanced vulnerability to relapse compared to males, which mirrors the sex differences observed in humans. We also have strong preliminary data indicating that, as with findings for stimulants, estradiol drives the enhanced vulnerability to OUD in females. Thus, an additional goal of this application is to evaluate the impact of ovarian hormones on the expression and molecular mechanisms of an opioid addiction-like phenotype in females. Sex and hormone-dependent differences in the molecular mechanisms underlying an addiction-like phenotype will be characterized using RNA sequencing. This will allow us to characterize the transcriptome profiles associated with addiction-like phenotype in females for the first time and to determine how these changes differ from those observed in males and in females as a function of hormonal status. We will focus on changes in the dorsal medial prefrontal cortex (dmPFC) given its critical role in OUD. Our overall hypothesis is that an addiction-like phenotype will develop sooner in females than males and that in females, estradiol will be critical for the expression of addiction-like phenotype and the corresponding transcriptional changes. To address this hypothesis, we will first determine whether the telescoping effect reported in women with an OUD is biologically based (Aim 1) and address the impact of ovarian hormones on the expression of this phenotype in females (Aim 2). We will then use RNA-seq to identify sex- and hormone-specific molecular changes associated with the development of an enhanced vulnerability to relapse (Aim 3). The findings from these studies will provide critical information on sex differences in the development and expression of key features of OUD and foundational molecular data on the underlying mechanisms of OUD in females, which can be used to guide the development of new sex-specific prevention and treatment strategies for OUD.