Elsevier

Neuroscience

Volume 123, Issue 4, 2004, Pages 813-819
Neuroscience

Sex differences in the effect of ethanol injection and consumption on brain allopregnanolone levels in C57BL/6 mice

https://doi.org/10.1016/j.neuroscience.2003.11.017Get rights and content

Abstract

The pharmacological profile of allopregnanolone, a neuroactive steroid that is a potent positive modulator of γ-aminobutyric acidA (GABAA) receptors, is similar to that of ethanol. Recent findings indicate that acute injection of ethanol increased endogenous allopregnanolone to pharmacologically relevant concentrations in male rats. However, there are no comparable data in mice, nor has the effect of ethanol drinking on endogenous allopregnanolone levels been investigated. Therefore, the present studies measured the effect of ethanol drinking and injection on allopregnanolone levels in male and female C57BL/6 mice. One group was given 17 days of 2-h limited access to a 10% v/v ethanol solution in a preference-drinking paradigm, while another group had access to water only. The ethanol dose consumed in 2 h exceeded 2 g/kg. Then, separate groups of mice were injected with either 2 g/kg ethanol or saline. Mice were killed 30 min after the 2-h drinking session or injection. Blood ethanol concentration was significantly higher in the ethanol-injected versus ethanol-drinking groups, even though the dose was similar. Consumption of ethanol significantly increased brain allopregnanolone levels in male but not female mice, compared with animals drinking water, but did not alter plasma corticosterone levels. In contrast, injection of ethanol did not significantly alter brain allopregnanolone levels in male or female mice and only significantly increased plasma corticosterone levels in the male mice, when compared with saline-injected animals.

The sex differences in the effect of ethanol administration on endogenous allopregnanolone levels suggest that the hormonal milieu may impact ethanol's effect on GABAergic neurosteroids. Importantly, these data are the first to report the effect of ethanol drinking on allopregnanolone levels and indicate that ethanol consumption and ethanol injection can produce physiologically relevant allopregnanolone levels in male mice. These results have important implications for studies investigating the potential role of endogenous allopregnanolone levels in modulating susceptibility to ethanol abuse.

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Subjects

Male and female B6 mice (The Jackson Laboratory, Bar Harbor, ME, USA) were purchased at 5–6 weeks of age. For a minimum of 2 weeks, same-sex mice were housed four to a cage, and allowed to acclimate to the temperature- and humidity-controlled environment and to a 12-h reverse light/dark cycle (lights off 0900 h). The light cycle was reversed to allow collection of limited access EtOH consumption data during the animals' dark phase, when the majority of consummatory behavior occurs. Food and

EtOH dose and EtOH preference ratio

The 17-day average EtOH dose consumed by female B6 mice was significantly greater than that consumed by male B6 mice [F(1,46)=6.81, P≤0.05; Fig. 1A] during the daily 2-h limited access sessions. While the EtOH dose consumed by the female mice was 22% higher than that consumed by male B6 mice, both female and male B6 mice exhibited preference for the 10% EtOH solution (Fig. 1B), and no sex difference was observed for this measure.

BECs

The average dose of EtOH consumed on day 17 during the 2-h access

Discussion

The present study examined the effect of EtOH administration, either by voluntary consumption or by injection of a comparable dose, on endogenous ALLOP levels in male and female mice. Consumption of EtOH significantly increased brain ALLOP levels in male but not female B6 mice, compared with water-consuming controls. In contrast, injection of EtOH did not significantly increase brain ALLOP levels in male or female mice. These findings suggest that sex and mode of EtOH administration both can

Acknowledgements

This research was supported by USPHS grants AA12439, AA13478, AA10760 and the Department of Veterans Affairs. We thank Stacy Matthews and Tho Truong for excellent technical assistance.

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    Present address: CROET (L-606), Oregon Health & Science University, Portland, OR 97239, USA.

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