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The Influence of Menstrual Cycle Phase on Sensitivity to Ethanol-Like Discriminative Stimulus Effects of GABAA-Positive Modulators

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Abstract

Previous studies showed that sensitivity to the ethanol-like discriminative stimulus effects of allopregnanolone and ethanol are enhanced during the luteal phase of the menstrual cycle when progesterone levels peak in monkeys trained to discriminate 1.0 g/kg ethanol. The present study further explored the influence of the menstrual cycle phase on the discriminative stimulus effects of ethanol, allopregnanolone, and midazolam. Female adult cynomolgus monkeys (Macaca fascicularis) were trained to discriminate 1.0 g/kg ethanol (n = 3) or 2.0 g/kg ethanol (n = 4) (20% w/v; IG) from water (IG). A cumulative dosing procedure was used to test discriminative stimulus effects of ethanol (0.5–2.5 g/kg; IG) and the ethanol-like discriminative stimulus effects of allopregnanolone (0.1–1.0 mg/kg; IV) or midazolam (1.0–17 mg/kg; IG) during the follicular vs. luteal phase of the menstrual cycle. In the 2.0-g/kg group, sensitivity to the ethanol- like effects of allopregnanolone was increased during the luteal vs. follicular phase in two of three monkeys. In contrast, average sensitivity to ethanol was not different in the luteal compared to the follicular phase in the 2.0-g/kg group. Finally, there was no difference in sensitivity to midazolam between the follicular and luteal phases in monkeys trained with either 2.0 g/kg or 1.0 g/kg ethanol. Overall, the ethanol-like discriminative stimulus effects of midazolam are not sensitive to the menstrual cycle phase. In addition, there was less influence of the menstrual cycle phase on allopregnanolone and ethanol sensitivity in a 2.0-g/kg compared to a 1.0-g/kg ethanol training dose.

Section snippets

Method

Adult female cynomolgus monkeys were trained to discriminate either 1.0 g/kg (n = 3) or 2.0 g/kg (n = 4) ethanol from water in a two-lever operant procedure with food reinforcement. The details of this training are described in an earlier publication (8), but it should be noted that the monkeys were trained 5 days per week, regardless of menstrual cycle phase. Briefly, ethanol (1.0 or 2.0 g/kg) or a comparable volume of water was administered by intragastric intubation (IG) 30 min prior to the

Results

Over the 36 months the menstrual cycles were monitored; the average length of the cycle did not differ between monkeys trained to discriminate 1.0 g/kg (range 27–31 days) and 2.0 g/kg (range 28–34 days) ethanol. For purposes of the present study design, the follicular phase encompassed reverse cycle days 18–33 and the luteal phase encompassed reverse cycle days 7–13. Serum progesterone concentrations (ng/ml) were indicative of the menstrual cycle phase, with 10- to 50-fold higher levels in the

Discussion

The results show that substitution of allopregnanolone for the discriminative stimulus effects of ethanol varies with menstrual cycle phase in two of three monkeys trained to discriminate 2.0 g/kg ethanol. Allopregnanolone was more potent and efficacious when tested during the luteal phase of the menstrual cycle. These results replicate previous findings with a 1.0-g/kg ethanol training dose (9). When the present data are combined with prior data (9), five of six monkeys tested to date are more

Acknowledgements

Care and treatment of the subjects used in this study were in accord with state and federal guidelines. The experimental protocol was approved by the Wake Forest University Animal Care and Use Committee. This research was supported in part by grants from the National Institute on Alcohol Abuse and Alcoholism RO1 AA10009, T32 AA07565, and P5O AA06420. Midazolam was provided by Dr. P. Weber of Hoffmann–LaRoche Ltd. (Basel, France). Serum progesterone levels were determined at the Assay Services

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