Female Rats Display Enhanced Rewarding Effects of Ethanol That Are Hormone Dependent

Abstract

Background Ethanol abuse is a major health and economic concern, particularly for females who appear to be more sensitive to the rewarding effects of ethanol. This study compared sex differences to the rewarding and aversive effects of ethanol using place-conditioning procedures in rats. Methods Separate groups of adult (male, female, ovariectomized [OVX] female) and adolescent (male and female) rats received ethanol (0, 0.5, 1.0, 2.0 or 2.5 g/kg; ip) and were confined to their initially non-preferred side of our conditioning apparatus for 30 minutes. On alternate days, they received saline and were confined to the other side. Following 5 drug pairings, the rats were re-tested for preference behavior. Separate cohorts of the same groups of rats were injected with a similar dose range of ethanol and blood ethanol levels (BELs) were compared 30 minutes later. Results Ethanol produced rewarding or aversive effects in a dose-dependent manner. An intermediate dose of ethanol (1.0 g/kg) produced rewarding effects in adult female but not male or OVX female rats, suggesting that ovarian hormones facilitate the rewarding effects of ethanol. Similarly, this intermediate dose of ethanol produced rewarding effects in adolescent female but not male rats. The highest dose of ethanol (2.5 g/kg) produced aversive effects that were similar across all adult groups. However, the aversive effects of ethanol were lower in adolescents than adults, suggesting that adolescents are less sensitive to the aversive effects of ethanol. The aversive effects of ethanol did not vary across the estrous cycle in intact adult females. There were also no group differences in BELs, suggesting that our results are not related to ethanol metabolism. Conclusion Our results in rats suggest that human females may be more vulnerable to ethanol abuse due to enhanced rewarding effects of this drug that are mediated by the presence of ovarian hormones.

Sex Differences in Animal Models: Focus on Addiction

“…In these rats, females exhibited greater intake than males during the first 10 days, but after that time, total intake was not different between males and females (Moore and Lynch, 2015). In the Wistar rat, there are also sex differences in the rewarding versus aversive properties of ethanol that are dose dependent, with females displaying enhanced sensitivity to the rewarding effects of ethanol relative to males (Torres et al, 2014).…”

Effects of Ovariectomy and 17<i>β</i>-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

“…These observations suggested that women should be more vulnerable to ethanol abuse which rewarding effects were enhanced by ovarian hormones [75]. Furthermore, bromocriptine efficiently inhibited alcohol consumption regardless of 17β-estradiol.…”

Sex hormones in alcohol consumption: a systematic review of evidence

“…However, a study in female rats showed increased ethanol consumption during diestrus (when estrogen levels are low) than both proestrus (when estrogen levels are high) and estrus (when estrogen levels are lowest; Roberts et al 1998). Moreover, findings indicate that the effects of estrogen on ethanol consumption in female rodents may depend on the dose of estradiol, as well as the presence or absence of gonads (Forger & Morin 1982;Sandberg & Stewart 1982;Hilakivi-Clarke 1996;Almeida et al 1998;Ford et al 2002a;Ford, Eldridge, & Samson 2004;Sherrill et al 2011;Torres et al 2014). On the contrary, in male rodents, estradiol was shown both to stimulate ethanol intake (Lakoza & Barkov 1980;Hilakivi-Clarke 1996) and to reduce voluntary alcohol consumption (Juarez, De Tomasi, & Virgen 2002).…”

“…The majority of animal studies also found positive associations between estrogen levels and alcohol intake in females (Forger & Morin 1982;Mello, Bree, & Mendelson 1986;Reid et al 2002;Ford, Eldridge, & Samson 2002a;Marinelli, Quirion, & Gianoulakis 2003;Reid, Hubbell, & Reid 2003;Quirarte et al 2007;Rajasingh et al 2007;Sherrill et al 2011;Torres et al 2014). For example, an experimental study in female monkeys found decreased ethanol intake during menstrual phase (when estrogen levels are low) compared with mid-cycle or the late luteal phase (Mello et al 1986).…”