Fluctuating estrogen levels may make alcohol more rewarding to female mice, according to new research in Journal of Neuroscience.
Untangling the involved signaling pathways could unveil sex-based treatments for alcohol use disorders.
Recreational use of alcohol can escalate into something more dire such as excessive binge drinking or even an alcohol use disorder. Women are more susceptible than men to these negative effects of alcohol, potentially because of the sex hormone estrogen.
Vandegrift et al. activated estrogen receptors in mice and tracked how the activation influenced alcohol’s effects on the brain. The research team targeted two subtypes of estrogen receptors in the ventral tegmental area (VTA), a brain region involved in drug reward and reinforcement.
Activating the α estrogen receptor subtype caused neurons to fire even more than normal in response to alcohol. Increased neuron firing releases more dopamine and could translate to a greater feeling of reward when drinking, making abuse more likely when estrogen levels rise.
The scientists then reduced the number of estrogen receptors in the VTA of both male and female mice. This decreased binge drinking behavior in female mice but had no effect on male mice — even though they have estrogen in their brains, too.
Elevations in estrogen (17β-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 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 neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of estrogen receptor subtypes (ERα and ERβ) in regulating the ethanol sensitivity of VTA neurons in female mice and found that ERα promotes the enhanced ethanol response of VTA neurons.
We also demonstrated that enhancement of ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERα at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus expressing short hairpin RNAs targeting either ERα or ERβ 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 ERα in the VTA had a more dramatic effect on binge-like drinking than reducing ERβ, consistent with the ability of ERα to alter ethanol sensitivity of VTA neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking.
SIGNIFICANCE STATEMENT
Estrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances such as alcohol. We investigated the mechanisms by which estrogen increases the response of neurons in the ventral tegmental area (VTA) to ethanol. We found that activation of the estrogen receptor, ERα, increased the ethanol-induced excitation of VTA neurons. E2-mediated enhancement of ethanol-induced excitation required the metabotropic glutamate receptor mGluR1.
We also demonstrated that estrogen receptors in the VTA 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.
Footnotes
This work was supported by the National Institute on Alcohol Abuse and Alcoholism (Grant P50 AA022538 to AWL and MSB and grant U01 AA020912 to AWL), the National Institute on Drug Abuse (Grant R01 DA033429 to AWL), and the National Center for Advancing Translational Sciences (Grant UL1TR002003). The authors thank Lucas Ibrahimi for mouse breeding and genotyping.
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