Interactions between estrogen receptors and metabotropic glutamate receptors and their impact on drug addiction in females

Eisinger, Katherine R. Tonn; Gross, Kellie S.; Head, Brian P.; Mermelstein, P.

doi:10.1016/j.yhbeh.2018.03.001

Cited by 47 publications

(50 citation statements)

References 139 publications

(161 reference statements)

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“…Note: AR, androgen receptor; BNST, bed nucleus of the stria terminalis; ER-alpha, estrogen receptoralpha; ER-beta, estrogen receptor-beta; GABA, gamma-aminobutyric acid; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; mPFC, medial prefrontal cortex; MR, mineralocorticoid receptor; PR, progesterone receptor (both isoforms); PVN, paraventricular nucleus; VTA, ventral tegmental area. Source: Circuitry 13,24 and steroid receptor distribution 13,15,21,[33][34][35][36] are modified from other sources.…”

Section: Steroid Hormone Receptors and Circuitry Important For Stressmentioning

confidence: 99%

“…For instance, estradiol and progesterone can rapidly affect dopamine signaling via actions at their respective steroid receptors, functional coupling between estrogen receptors (both alpha and beta) and metabotropic glutamate receptors (Group I or Group II) can activate distinct signaling pathways, and neurosteroids can rapidly increase GABA A receptor-mediated signaling. 21,23,24,[33][34][35][36] Thus, rapid steroid actions at associated receptors and neurosteroid actions at GABA A receptors are other mechanisms for fine-tuning central nervous system excitability.…”

Section: Steroid Hormone Receptors and Circuitry Important For Stressmentioning

confidence: 99%

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The Endocrine System and Alcohol Drinking in Females

Finn

2020

ARCR

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Sexually dimorphic effects of alcohol exposure throughout life have been documented in clinical and preclinical studies. In the past, rates of alcohol use disorder (AUD) were higher in men than in women, but over the past 10 years, the difference between sexes in prevalence of AUD and binge drinking has narrowed. Recent evidence adds to historical data regarding the influence of sex steroids on alcohol drinking and the interaction with stress-related steroids. This review considers the contribution of the endocrine system to alcohol drinking in females, with a focus on the hypothalamic pituitary gonadal axis and the hypothalamic pituitary adrenal axis and their reciprocal interactions. Emphasis is given to preclinical studies that examined genomic and rapid membrane effects of estrogen, progesterone, glucocorticoids, and GABAergic neurosteroids for their effects on alcohol drinking and models of relapse. Pertinent comparisons to data in males highlight divergent effects of sex and stress steroids on alcohol drinking and emphasize the importance of considering sex in the development of novel pharmacotherapeutic targets for the treatment of AUD. For instance, pharmacological strategies targeting the corticotropin releasing factor and glucocorticoid receptor systems may be differentially effective in males and females, whereas strategies to enhance GABAergic neurosteroids may represent a biomarker of treatment efficacy in both sexes.

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Section: Steroid Hormone Receptors and Circuitry Important For Stressmentioning

confidence: 99%

Section: Steroid Hormone Receptors and Circuitry Important For Stressmentioning

confidence: 99%

The Endocrine System and Alcohol Drinking in Females

Finn

2020

ARCR

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“…We used selective agonists and antagonists to ERa and ERb combined with extracellular recordings of VTA DA neurons. Because membrane-bound estrogen receptors can rapidly activate cell signaling pathways through interactions with metabotropic glutamate receptors (mGluRs) and affect neurotransmission and behavior (Tonn Eisinger et al, 2018), the second goal of this study was to determine if the enhancement of ethanol-stimulated VTA DA neuron firing by E2 is dependent on mGluR1 activity.…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice

Vandegrift

Hilderbrand

Satta

et al. 2019

Preprint

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Elevations in estrogen (17b-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the ventral tegmental area (VTA) and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that during high E2 states, VTA dopamine neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA dopamine neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of estrogen receptor subtypes (ERa and ERb) in regulating the ethanol sensitivity of VTA dopamine neurons and found that ERa promotes the enhanced ethanol response of VTA dopamine neurons. We also demonstrated that the E2-induced increase in ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERa at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus expressing short hairpin RNAs targeting either ERa or ERb into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERa in the VTA had a more dramatic effect on binge-like drinking than reducing ERb, consistent with the ability of ERa to alter ethanol sensitivity of dopamine neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking. Significance StatementEstrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances such as cocaine and alcohol. We investigated the mechanisms by which estrogen increases the response of dopamine neurons in the ventral tegmental area to ethanol. We found that activation of the estrogen receptor, ERa, increased the ethanol-induced excitation of dopamine neurons and that this required the metabotropic glutamate receptor mGluR1. We also demonstrated that estrogen receptors in the ventral tegmental area regulate binge-like alcohol drinking by female, but not male, mice. The influence of estrogen receptors on binge drinking in female mice suggests that treatments for alcohol use disorder in women may need to account for this sex difference.

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“…Estrogen, progestin, and androgen signaling in the brain is involved in the display of motivated behaviors such as copulation, aggression, and physical activity (Beatty, 1979). Moreover, gonadal hormones have been shown to influence the susceptibility to addiction-like behavior (Tonn Eisinger et al, 2018a). In order to understand how hormones affect behavior, it is important to study the underlying neurobiological mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…Previous research has shown that spine density, spine morphology, and dendrite length can be impacted by gonadal hormones in multiple brain regions involved in motivation (Calizo and Flanagan-Cato, 2002;Cooke and Woolley, 2005;Cunningham et al, 2007;Peterson et al, 2015). These hormone-induced structural reorganizations are both sexually dimorphic and strikingly different between brain regions, and have been linked to motivated behavior, learning, memory, and addiction (Frankfurt and Luine, 2015;McEwen and Milner, 2017;Tobiansky et al, 2018;Tonn Eisinger et al, 2018a).…”

Section: Introductionmentioning

confidence: 99%

Effects of gonadectomy and androgen on neuronal plasticity in motivation and reward related brain regions in the male rat

Huijgens

Snoeren

Meisel

et al. 2020

Preprint

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Gonadal hormones affect neuronal morphology to ultimately regulate behavior. Here, we investigated the effect of both castration and androgen replacement on spine plasticity in the nucleus accumbens shell and core (NAcSh and NAcC), caudate putamen (CPu), medial amygdala (MeA), and medial preoptic nucleus (MPN). Intact and castrated (GDX) male rats were treated with dihydrotestosterone (DHT, 1.5mg) or vehicle (oil) in 3 experimental groups: intact-oil, GDX-oil and GDX-DHT. Spine density and morphology, measured 24 hours after injection, were determined through 3D reconstruction of DiI-labeled dendritic segments. GDX decreased spine density in the MPN, which was rescued by DHT treatment. MeA spine density increased in GDX-DHT animals compared to intact-oil animals. In the NAcSh, DHT decreased spine density, and also rapidly increased the number of pCREB+ cell bodies.These findings indicate that androgen signaling plays a role in the regulation of spine plasticity within neurocircuits involved in motivated behaviors.

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Interactions between estrogen receptors and metabotropic glutamate receptors and their impact on drug addiction in females

Cited by 47 publications

References 139 publications

The Endocrine System and Alcohol Drinking in Females

The Endocrine System and Alcohol Drinking in Females

Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice

Effects of gonadectomy and androgen on neuronal plasticity in motivation and reward related brain regions in the male rat

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