Estradiol enhances ethanol reward in female mice through activation of ERα and ERβ - PubMed (original) (raw)

Estradiol enhances ethanol reward in female mice through activation of ERα and ERβ

Elisa R Hilderbrand et al. Horm Behav. 2018 Feb.

Abstract

Alcohol use disorder (AUD) manifests differently in men and women, but little is known about sex differences in the brain's response to ethanol. It is known that the steroid hormone 17β-estradiol (E2) regulates voluntary ethanol consumption in female rodents. However, the role of E2 as a regulator of ethanol reward has not been investigated. In this study, we tested for the effects of E2 and agonists selective for the classical estrogen receptors, ERα and ERβ, on ethanol reward in ovariectomized (OVX) mice using the conditioned place preference (CPP) test. E2 enhanced ethanol CPP and, while specific activation of either receptor alone had no effect, co-activation of ERα and ERβ also enhanced ethanol CPP, suggesting that E2 enhances ethanol reward in female mice through actions at both ERα and ERβ. These results have implications for sex differences in the development of AUD, suggesting that women may find ethanol more rewarding than men because of higher circulating E2 levels.

Keywords: Addiction; Alcohol; Estrogen; Female; Reward.

PubMed Disclaimer

Figures

Fig. 1

17β-Estradiol-3-benzoate (EB) enhances ethanol conditioned place preference (CPP) in ovariectomized (OVX) C57BL/6J mice. Mice were OVX bilaterally and allowed to recover for 12–15 days before the start of behavioral procedures. (A) Timeline and design of the ethanol CPP experiment. (B) Graph shows time spent on the ethanol-paired side (in seconds) before conditioning (Test 1) and after conditioning (Test 2) in VEH- and EB-treated mice (n = 18 per group). Two-way repeated measures ANOVA revealed a significant main effect of time (****p < 0.0001) and a significant time-by-treatment interaction (#p < 0.086, by post hoc Sidak’s tests comparing EB- to VEH-treated within Test 2). (C) Graph shows percent change in preference for the ethanol-paired side in VEH- and EB-treated mice. Student’s t-test revealed a significant increase in preference for the ethanol-paired compartment in EB-treated mice (*p < 0.05). Data are presented as means ± SEM.

Fig. 2

EB does not alter the rate of ethanol metabolism in OVX C57BL/6J mice. OVX mice were treated with either VEH or EB (n = 5 per group). Four hours later, 2.0 g/kg ethanol was administered by IP injection. Blood was collected at seven time points post-injection. Graph shows blood ethanol concentration (BEC) in milligrams per 100 milliliters (mg%) over 180 minutes. Two-way ANOVA found no difference in BEC between VEH- and EB-treated animals at any of the seven time points measured. Data are presented as means ± SEM.

Fig. 3

Neither PPT (ERα agonist) nor DPN (ERβ agonist) treatment alone is sufficient to enhance ethanol CPP, but combined treatment with both agonists enhances ethanol CPP. Mice were OVX bilaterally and allowed to recover for 12–15 days before the start of behavioral procedures. (A) Timeline and design of the CPP experiments. (B) Graph showing the time spent on the ethanol-paired side (in seconds) before conditioning (Test 1) and after conditioning (Test 2) of vehicle (VEH)-, 4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT)-, and diarylpropionitrile (DPN)-treated mice (n = 27–32 per group). Two-way repeated measures ANOVA revealed a significant main effect of time (****p < 0.0001). (C) Percent change in preference for the ethanol-paired side in VEH-, PPT-, and DPN-treated mice. A one-way ANOVA found no significant difference between treatment groups. (D) Graph shows time spent on the ethanol-paired side before and after conditioning by mice treated with either VEH or a combined treatment of PPT plus DPN (n = 16 per group). Two-way repeated measures ANOVA revealed a significant main effect of time (****p < 0.0001) and a significant time-by-treatment interaction (#p < 0.061, post-hoc Sidak’s test comparing VEH- to PPT+DPN-treated within Test 2). (E) Percent change in preference for the ethanol-paired side in mice treated with either VEH or a combined treatment of PPT plus DPN. Student’s t-test revealed a significant increase in preference for the ethanol-paired compartment in mice treated with PPT plus DPN vs. VEH (*p < 0.05). Data are presented as means ± SEM.

References

1. Almeida OF, Shoaib M, Deicke J, Fischer D, Darwish MH, Patchev VK. Gender differences in ethanol preference and ingestion in rats. The role of the gonadal steroid environment. J Clin Invest. 1998;101:2677–2685. - PMC - PubMed
1. Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol. 2009;30:1–9. - PMC - PubMed
1. Barker JM, Torregrossa MM, Arnold AP, Taylor JR. Dissociation of genetic and hormonal influences on sex differences in alcoholism-related behaviors. J Neurosci. 2010;30:9140–9144. - PMC - PubMed
1. Becker HC, Anton RF, De Trana C, Randall CL. Sensitivity to ethanol in female mice: effects of ovariectomy and strain. Life Sci. 1985;37:1293–1300. - PubMed
1. Becker JB. Sex differences in addiction. Dialogues in clinical neuroscience. 2016;18:395–402. - PMC - PubMed

Estradiol enhances ethanol reward in female mice through activation of ERα and ERβ - PubMed (original) (raw)