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.
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.
|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|
|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 110:118-24|
|Peterson, Brittni M; Mermelstein, Paul G; Meisel, Robert L (2015) Impact of immersion oils and mounting media on the confocal imaging of dendritic spines. J Neurosci Methods 242:106-11|
|Peterson, Brittni M; Mermelstein, Paul G; Meisel, Robert L (2015) Estradiol mediates dendritic spine plasticity in the nucleus accumbens core through activation of mGluR5. Brain Struct Funct 220:2415-22|
|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|