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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA035008-02
Application #
8601302
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Pilotte, Nancy S
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$365,207
Indirect Cost
$121,307
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Martinez, Luis A; Peterson, Brittni M; Meisel, Robert L et al. (2014) Estradiol facilitation of cocaine-induced locomotor sensitization in female rats requires activation of mGluR5. Behav Brain Res 271:39-42
Meitzen, John; Luoma, Jessie I; Boulware, Marissa I et al. (2013) Palmitoylation of estrogen receptors is essential for neuronal membrane signaling. Endocrinology 154:4293-304