Influence of opioid and estrogen systems on cocaine withdrawal in females
Recent interest has focused on elucidating sex differences in cocaine addiction, a major public health concern worldwide. Anxiety, a hallmark of cocaine withdrawal, is mediated by both estrogen and δ-opioid receptor (DOR) systems. The overall aim of this thesis project was to evaluate the contribution of circulating estrogen and the DOR system on cocaine withdrawal-induced anxiety in females. In humans, retrospective analysis of treatment-seeking females supports a potential link between menstrual cycle, anxiety, intake urinalysis and treatment outcome. Preclinical studies were conducted using ovariectomized (OVX) and intact female rats to directly test the role of estrogen on cocaine-withdrawal induced anxiety using the elevated-plus and elevated-zero mazes. A direct correlation between blood estrogen level and anxiety-like behavior was not evident; however, these data point to the potential role of circulating hormones on all phases of addiction and warrant further analysis. Moreover, the DOR agonist SNC-80 was shown to be anxiolytic in females highlighting a potential role for DOR in the modulation of cocaine withdrawal-induced anxiety. Electron microscopic (EM) analysis in the nucleus accumbens (NAcb), a major target of cocaine's action, revealed cocaine-induced sex-dependent DOR trafficking and co-existence of DOR and Dopamine-D1 Receptor (D1R) providing an anatomical substrate for dopamine-opioid receptor interaction. Finally, preliminary evidence using immunofluorescence microscopy supports the co-existence of estrogen receptor β (ERβ) and DOR which may facilitate potential co-mediation of anxiety by these systems. In summary, our results demonstrate cocaine withdrawal-induced changes in DOR and the anxioytic properties of DOR agonists in female rodent models. Future studies are needed to gain a greater understanding of how circulating hormones contribute to sex differences in cocaine addiction. This project corroborates the need for development of individualized treatment and implementation of pharmacotherapy targeting opioid and estrogen systems to improve current cocaine addiction treatments.
Ambrose-Lanci, Lisa M, "Influence of opioid and estrogen systems on cocaine withdrawal in females" (2009). ETD Collection for Thomas Jefferson University. AAI3390415.