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The Role of Estrogen in Increased Alcohol Consumption in Women


By investigating the role of estrogen in the brain, researchers are advancing our understanding of the mechanisms that regulate complex behaviors, offering new insights into interventions for alcohol use disorders. This study demonstrated that estrogen can rapidly act through non-genomic mechanisms to regulate neuronal function and behavior, especially in the context of alcohol consumption in females with intact reproductive organs.


Biological sex is a crucial factor that regulates behavior across species, but the underlying neurobiological mechanisms that govern these differences are not yet fully understood.


One of the central players in modulating behavior is estrogen (17β-estradiol, E2), a sex steroid hormone produced primarily in the ovaries of females.


Estrogen plays key roles in a variety of adaptive behaviors, such as reproduction, learning, memory, and emotional responses.


However, it may also contribute to maladaptive behaviors associated with neuropsychiatric disorders.


Estrogen is traditionally understood to act through nuclear estrogen receptors (ERs) to promote extensive transcriptional changes via genomic mechanisms.


Recently, however, it has been discovered that estrogen can also rapidly act on membrane-associated ERs in several brain regions, such as the hippocampus, hypothalamus, striatum, nucleus accumbens, and amygdala.

These rapid actions are less well explored, but studies in ovariectomized (ovarian-deprived) rodents have shown that estrogen can rapidly promote memory consolidation.


These rapid effects have been investigated using modified forms of estrogen that do not cross the cell membrane, thus limiting their action to receptors on the cell surface.


Experimental research in rodents has shown that acute administration of estrogen or ER modulators can rapidly influence behaviors such as aggression and sexual behavior, as well as regulate learning, memory, and self-administration of psychostimulants.


In birds, for example, estrogen, produced from testosterone, rapidly regulates song and reproductive behavior.


However, the impact of endogenous E2 produced by the ovaries on the female brain and its role in regulating behavior in animals with intact reproductive organs has not yet been fully explored.


There is growing evidence that E2 plays an important role in alcohol and drug-related behaviors, such as binge drinking and anxiety, which are primary risk factors for psychiatric disorders, including alcohol use disorder (AUD).


Women are more likely to develop AUD than men with a similar history of alcohol use, a phenomenon known as the “telescoping effect.” In addition, binge drinking is increasingly common among women, especially during puberty when sex hormones begin to fluctuate.

Studies have shown that female rodents tend to consume more alcohol than males, and this difference is partly mediated by ovarian hormones.


Removal of the ovaries decreases alcohol consumption, while administration of E2 can restore elevated consumption. E2 signaling has been shown to promote alcohol consumption in intact females, and reducing estrogen receptor activity reduces consumption.


In a recent study conducted by researchers at Cornell University, alcohol consumption and avoidance behavior in female mice were shown to vary across the estrous cycle according to E2 levels.


Estrogen (E2) promoted increased alcohol consumption in female mice through rapid signaling at membrane-associated estrogen receptor alpha (ERα) located in the bed nucleus of the stria terminalis (BNST).


The BNST is a brain region known for presenting significant differences between the sexes, called sexual dimorphism, and for expressing high levels of estrogen receptors. The activation of these receptors by E2 signaling does not follow the traditional genomic pathway, but rather a fast-track pathway that directly influences communication between neurons.

Human anxiety and addiction circuits. The BNST is a central node in both the anxiety and addiction neurocircuitry. (left) The BNST is centrally located to influence human anxiety responses, with connections to multiple limbic and brainstem regions that mediate defensive response to threat, including the amygdala, anterior insula, hippocampus, hypothalamus, and periaqueductal gray (adapted from Grupe and Nitschke, 2013). (right) The BNST is engaged during the negative emotional stage of withdrawal and interacts with the amygdala and ventral striatum, including the nucleus accumbens shell and ventral tegmental area, to mediate negative reinforcement (adapted from Koob and Volkow, 2010). AI, anterior insula; Amyg, amygdala; BNST, bed nucleus of the stria terminalis; Hy, hypothalamus; PAG, periaqueductal gray; VS, ventral striatum. SOURCE: S N Avery, J A Clauss & J U Blackford. Neuropsychopharmacology, volume 41, pages 126–141 (2016).


Within the BNST are neurons that synthesize and release corticotropin-releasing factor (CRF), a neuropeptide involved in stress responses and strongly linked to alcohol- and anxiety-related behaviors.


The study showed that these neurons are critical to the effect of E2 on behavior, as rapid E2 signaling increases synaptic excitation, that is, communication between neurons, and enhances the activity of those BNST neurons that release CRF.


This increase in neuronal activity facilitates alcohol consumption behavior, suggesting a specific mechanism by which E2 regulates alcohol consumption in females.


This study demonstrated that estrogen can rapidly act through non-genomic mechanisms to regulate neuronal function and behavior, especially in the context of alcohol consumption in females with intact reproductive organs.


By investigating the role of estrogen in the brain, researchers are advancing our understanding of the mechanisms that regulate complex behaviors, offering new insights into interventions for alcohol use disorders.



READ MORE:


Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice

Lia J. Zallar, Jean K. Rivera-Irizarry, Peter U. Hamor, Irena Pigulevskiy, Ana-Sofia Rico Rozo, Hajar Mehanna, Dezhi Liu, Jacqueline P. Welday, Rebecca Bender, Joseph J. Asfouri, Olivia B. Levine, Mary Jane Skelly, Colleen K. Hadley, Kristopher M. Fecteau, Scottie Nelson, John Miller, Pasha Ghazal, Peter Bellotti, Ashna Singh, Lauren V. Hollmer, David W. Erikson, Jacob Geri & Kristen E. Pleil 

Nature Communications, volume 15, Article number: 10725 (2024) 


Abstract:


Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen occurred via rapid signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking. Thus, this study demonstrates a rapid, nongenomic signaling mechanism for ovarian-derived estrogen in the brain controlling behavior in gonadally intact females.

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© 2024 by Lidiane Garcia

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