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 #
4R01DA035008-04
Application #
9000140
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
2016-01-01
Budget End
2016-12-31
Support Year
4
Fiscal Year
2016
Total Cost
$453,194
Indirect Cost
$151,044
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Hedges, Valerie L; Chen, Gang; Yu, Lei et al. (2018) Local Estrogen Synthesis Regulates Parallel Fiber-Purkinje Cell Neurotransmission Within the Cerebellar Cortex. Endocrinology 159:1328-1338
Tonn Eisinger, Katherine R; Woolfrey, Kevin M; Swanson, Samuel P et al. (2018) Palmitoylation of caveolin-1 is regulated by the same DHHC acyltransferases that modify steroid hormone receptors. J Biol Chem 293:15901-15911
Tonn Eisinger, Katherine R; Gross, Kellie S; Head, Brian P et al. (2018) Interactions between estrogen receptors and metabotropic glutamate receptors and their impact on drug addiction in females. Horm Behav :
Tonn Eisinger, Katherine R; Larson, Erin B; Boulware, Marissa I et al. (2018) Membrane estrogen receptor signaling impacts the reward circuitry of the female brain to influence motivated behaviors. Steroids 133:53-59
Gross, Kellie S; Moore, Kelsey M; Meisel, Robert L et al. (2018) mGluR5 Mediates Dihydrotestosterone-Induced Nucleus Accumbens Structural Plasticity, but Not Conditioned Reward. Front Neurosci 12:855
Meitzen, John; Britson, Kyla A; Tuomela, Krista et al. (2017) The expression of select genes necessary for membrane-associated estrogen receptor signaling differ by sex in adult rat hippocampus. Steroids :
Micevych, Paul E; Mermelstein, Paul G; Sinchak, Kevin (2017) Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction. Trends Neurosci 40:654-666
Peterson, Brittni M; Martinez, Luis A; Meisel, Robert L et al. (2016) Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine. Neuropharmacology 110:118-124
Gross, Kellie S; Brandner, Dieter D; Martinez, Luis A et al. (2016) Opposite Effects of mGluR1a and mGluR5 Activation on Nucleus Accumbens Medium Spiny Neuron Dendritic Spine Density. PLoS One 11:e0162755

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