Biological Sex And Ovarian Hormones Matter In Addiction

Females have been underrepresented in clinical and preclinical research of addictive drugs and substance use disorders (SUD), which has led to huge gaps in our knowledge regarding the disease process in females and sex-informed treatment strategies. The goal of this dissertation was to investigate sex differences in development, neurobiological basis, and treatment of SUDs with a focus on cocaine and opioids. In Chapter I, I discuss the evidence for and against one of the most widely cited gender/sex differences in SUD research, the telescoping effect. Chapter II and III show original research that firmly establishes the biological basis of the telescoping effect using a rat model of cocaine use disorder (CUD). Chapter IV contributes additional evidence for the possibility that the neuroadaptations underlying addiction maybe sex-dependent. Chapter V evaluates the efficacy of the patented nutritional supplement SMAASH-C at reducing cue-induced relapse vulnerability and cocaine-induced toxicity in males and females and finds the beneficial effects to be sex-specific highlighting the importance of considering biological sex when evaluating candidate treatments for CUD. In Chapters VI to VIII, I pivot to sex differences in opioid use disorder (OUD) using a rat model with fentanyl. More specifically in Chapter VI, I show original research that evaluates sex differences across a broad range of fentanyl doses, including low (0.25 and 0.75 ug/kg/infusion) and high (1.5 and 3.0 ug/kg/infusion) doses expected to minimized and maximize the expression of addiction-like features (e.g., vulnerability to relapse and physical dependence), respectively. Chapter VII demonstrates that the role of estradiol in vulnerability to opioid addiction in females is similar to that of psychostimulants and alcohol. Chapter VIII evaluates sex differences in time-course for the incubation of fentanyl-craving and the efficacy of R-ketamine as an anti-craving treatment for OUD. Notably, we show that the beneficial effects of R-ketamine are also sex-specific thereby highlighting the importance of considering biological sex when evaluating candidate treatments for OUD as well. Finally, Chapter IX highlights some of the most exciting findings presented in this dissertation and provides preliminary data on the directions we are taking to follow up on these exciting advances in addiction research. Together, I hope this dissertation will encourage clinical and preclinical researchers in the field to consider biological sex as an important risk factor in addiction as I strongly believe a better understanding of the disease process in females is necessary for continuing to move the science forward and producing a more representative and translationally relevant body of knowledge on addiction.