Drug addiction is a widespread condition affecting 8-10% of the population nationwide. Although men and women are both affected by drug addiction, sex-differences in responsiveness to drugs of abuse are apparent, with women showing a greater sensitivity than men. For over 30 years, the ovarian hormone estradiol has been recognized as a key biological factor contributing to the development of drug addiction in females, with little understanding of the neurobiological underpinnings. Here we propose a neural mechanism through which estradiol primes females to respond more strongly to drugs of abuse. Estradiol can act at intracellular or membrane-localized estrogen receptors to influence cellular function. Exclusively in females, a subset of these membrane estrogen receptors are coupled to group I metabotropic glutamate receptors (mGluRs). We demonstrate that it is through group I mGluRs that estradiol structurally remodels reward circuits in the nucleus accumbens (NAc), an effect associated with heightened sensitivity to drugs of abuse in females. In the nervous system, both estradiol and group I mGluRs can influence the activity of the endogenous cannabinoid (endoCB) system, an emerging mediator of neural plasticity and behavioral responses to drugs of abuse. Interestingly, we find that estradiol enhances the activity of the endoCB system in the female NAc by rapidly altering concentrations of the two best known endoCBs and increasing cannabinoid receptor expression. Further we demonstrate that activation of the endoCB system is critical for estradiol to induce structural plasticity in the NAc and facilitate behavioral responses to repeated drug exposure. Collectively, our results suggest that estradiol, group I mGluRs and the endoCB system may be linked through a serial pathway that is principally important in female drug addiction. These findings begin to elucidate a neural mechanism underlying female vulnerability to addiction that contributes to sex differences in drug abuse and may actually provide putative therapeutic targets that are particularly effective in treating drug abuse in women.
University of Minnesota Ph.D. dissertation. July 2016. Major: Neuroscience. Advisors: Paul Mermelstein, Robert Meisel. 1 computer file (PDF); ix, 130 pages.
From Estradiol to the Endogenous Cannabinoid System: A Gateway to Drug Addiction in Females.
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