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.

Keywords: SERD; binge drinking; estrogen; estrogen receptor; sex differences.

Figure 1

Mice in diestrus treated with a brain‐penetrant selective estrogen receptor degrader (SERD) drink less EtOH in the drinking in the dark (DID) test. (A) Chemical structures for YL3‐122 and XR5‐27. (B) Mice (18 per group) underwent the DID test with 20% EtOH. Mice were treated with vehicle or the SERDs YL3‐122 or XR5‐27 on days 2 to 4 (indicated by arrows), 5 h prior to the drinking session. Graph shows g EtOH/kg body weight consumed during 2 h on days 1 to 4. *p < 0.05, comparing YL3‐122 to vehicle and XR5‐27 by post hoc Tukey's test after two‐way ANOVA. (C) EtOH consumption on days 2 to 4 separated by diestrus or estrus. **p < 0.01, comparing YL3‐122 to vehicle in diestrus, #p < 0.05, comparing YL3‐122 and XR5‐27 in diestrus. Data are shown as the mean ± SEM

Figure 2

Female mice treated with a brain‐penetrant selective estrogen receptor degrader (SERD) drink less sucrose in the drinking in the dark (DID) test. (A) Mice (12 per group) underwent the DID test with 2% sucrose for 2 h on days 1 to 4. Mice were treated with vehicle or the SERDs YL3‐122 or XR5‐27 on days 2 to 4, 5 h prior to the drinking sessions as indicated by the arrows. Graph shows ml sucrose consumed/kg body weight each day. **p < 0.01, comparing YL3‐122 to vehicle by post hoc Tukey's test after two‐way ANOVA. (B) Sucrose consumption data separated by diestrus and estrus on days 2 to 4 in a cohort of 6 mice from panel (a). (C) Mice (6 per group) underwent the DID test with water for 2 h on days 1 to 4. Mice were treated with vehicle or the SERDs as in panel (a). Graph shows ml water consumed/kg body weight each day. Data are shown as the mean ± SEM

Figure 3

Selective estrogen receptor degraders (SERDs) do not affect blood EtOH clearance. Mice (5 per group) were treated with SERDs (YL3‐122, XR5‐27) or vehicle 5 h prior to injection with 2 g/kg EtOH i.p. at the indicated times after EtOH injection, blood was collected from the tail vein for measurement of blood EtOH concentration (BEC). Data are shown as the mean ± SEM

Figure 4

Esr1 gene expression is altered in a sex‐ and brain region‐dependent manner after drinking in the dark (DID). Mice underwent the 4‐day DID procedure with 20% EtOH or water as a control. Mice were euthanized immediately after the last drinking session and the (a) ventral tegmental area (VTA, 6 female water, 7 male water, 4 female EtOH, 6 male EtOH), (B) ventral hippocampus (vHPC, 9 per sex per group) and (C) prefrontal cortex (PFC, 9 per sex per group) were dissected and RNA isolated for measurement of Esr1 expression by quantitative real‐time PCR. *p < 0.05, main effect of EtOH by two‐way ANOVA. **p < 0.01 by Tukey's post hoc test after two‐way ANOVA, comparing water vs. EtOH within sex. Data are shown as the mean ± SEM