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.