In comparison to men, women are at an increased risk to abuse drugs. Across the spectrum of addiction, women show heightened intake of addictive substances, with greater craving, leading to an increased likelihood of addiction and relapse. These responses peak during the follicular phase of the menstrual cycle when estrogen levels are at their highest. These findings have been recapitulated in the female laboratory rat, where estradiol heightens multiple measures of drug responsiveness and abuse. Remarkably, the mechanisms by which estradiol mediates enhanced vulnerability to drug addiction are completely unknown. We propose a novel molecular mechanism mediating the actions of estradiol on nucleus accumbens neurons. Specifically we hypothesize that estradiol stimulation of estrogen receptor ? (ER?) localized to the surface membrane of nucleus accumbens neurons activates metabotropic glutamate receptor 5 (mGluR5) signaling. Activation of ER?/mGluR5 signaling by estradiol, in turn, affects nucleus accumbens spine structure, nucleus accumbens glutamatergic neurotransmission and ultimately responsiveness to drugs of abuse. Collectively, these studies will provide a foundation for developing novel therapeutic approaches targeted to treating drug addiction in women.

Public Health Relevance

The goal of this proposal is to understand the mechanism that underlies females being more at risk for addiction then men. We hypothesize that estrogen receptor ? (ER?) activates metabotropic glutamate receptor 5 (mGluR5) signaling in female nucleus accumbens neurons to cause structural, physiological and behavioral changes that impact the effects of psychostimulants. We propose to test this hypothesis and provide a novel means to disrupt ER?/mGluR5 signaling, thereby eliminating sex differences in the vulnerability to addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Pilotte, Nancy S
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Meitzen, John; Meisel, Robert L; Mermelstein, Paul G (2018) Sex Differences and the Effects of Estradiol on Striatal Function. Curr Opin Behav Sci 23:42-48
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Micevych, Paul E; Mermelstein, Paul G; Sinchak, Kevin (2017) Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction. Trends Neurosci 40:654-666
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