Effect of a brain‐penetrant selective estrogen receptor degrader (SERD) on binge drinking in female mice

Abstract

Background Greater circulating levels of the steroid hormone 17β‐estradiol (E2) are associated with higher levels of binge drinking in women. In female mice, estrogen receptors in the ventral tegmental area, a dopaminergic region of the brain involved in the motivation to consume ethanol, regulate binge‐like ethanol intake. We recently developed a brain‐penetrant selective estrogen receptor degrader (SERD), YL3‐122, that could be used to test the behavioral role of brain estrogen receptors. We hypothesized that treating female mice with this compound would reduce binge‐like ethanol drinking. Methods Female C57BL/6J mice were treated systemically with YL3‐122 and a related SERD with low brain penetrance, XR5‐27, and tested for binge‐like ethanol consumption in the drinking in the dark (DID) test. Mice were also tested for sucrose and water consumption and blood ethanol clearance after treatment with the SERDs. Finally, the effect of ethanol exposure on Esr1 gene expression was measured in the ventral tegmental area (VTA), prefrontal cortex (PFC), and ventral hippocampus (vHPC) of male and female mice by quantitative real‐time PCR after 4 DID sessions. Results YL3‐122 reduced ethanol consumption when mice were in diestrus but not estrus. YL3‐122 also decreased sucrose consumption but did not alter water intake or blood ethanol clearance. XR5‐27 did not affect any of these measures. Binge‐like ethanol drinking resulted in increased Esr1 transcript in the VTA of both sexes, male vHPC, and female PFC. Conclusions These results indicate that SERD treatment can decrease binge‐like ethanol drinking in female mice. Thus, it could be a novel strategy to reduce binge drinking in women, with the caveat that effectiveness may depend on menstrual cycle phase. In addition, Esr1 transcript is increased by binge ethanol exposure in both sexes but in a brain region‐specific manner.

Sex differences in heart rate variability measures that predict alcohol drinking in rats

“…Also, estrous cycle sometimes has limited influence on level of intake once rodent addictive behaviours are established 9 . Even so, inhibiting oestrogen receptors decreases alcohol drinking in mice during higher but not lower estrous stages 66 . Thus, different underlying mechanisms could promote behaviour at different cycle stages, even if the level of behaviour does not differ 66,67 .…”

“… 9 Even so, inhibiting oestrogen receptors decreases alcohol drinking in mice during higher but not lower estrous stages. 66 Thus, different underlying mechanisms could promote behaviour at different cycle stages, even if the level of behaviour does not differ. 66 , 67 It will be critical in future studies to address potential differences across the estrous cycle in autonomic mechanisms that underly drinking.…”

Gonadal Sex and Sex-Chromosome Complement Interact to Affect Ethanol Consumption in Adolescent Four Core Genotypes Mice

“…In a study of ethanol consumption using the 1-bottle DID procedure in C57BL/6J mice, differences in ethanol consumption between estrus cycle phases were not detected (nor did DID cause changes in the estrous cycle), even though ovariectomy decreased ethanol consumption and injections of 17β-estradiol benzoate in those ovariectomized increase ethanol consumption [135]. However, in another 1-bottle DID study using C57BL/6J mice, Chen et al compared systemic treatments with selective estrogen receptor degraders that were either high or low in brain penetrance [143]. The high-penetrant compound reduced ethanol consumption in diestrus, but not in estrus (no effects of the low-penetrant compound detected).…”

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

“…There is significant evidence that E2 may be a key neuromodulator driving alcohol and drug-related behaviors 8,[32][33][34] , including excessive alcohol consumption 9,35,36 , which is a primary risk factor for numerous disease states including alcohol use disorder (AUD) and anxiety disorders [37][38][39][40][41] . Women exhibit an accelerated onset of, and a higher probability for developing, AUD with the same history of alcohol use as their male counterparts in a phenomenon known as the telescoping effect; further, binge-like patterns of alcohol consumption are increasingly prevalent 39,[42][43][44] .…”

“…It is well-established in preclinical rodent models that females consume more alcohol than their male counterparts [49][50][51][52][53] , and ovarian hormones likely contribute to this phenomenon. Both removal of the ovaries and degradation of estrogen receptors (ERs) in the brain reduce alcohol drinking 9,35 , and chronic E2 administration in ovariectomized females can restore high alcohol drinking in some cases 9,[54][55][56][57] . However, a specific role for fluctuating E2 across the estrous cycle in intact female alcohol drinking behavior has not been established, nor mechanistic insight into its role.…”