Determination of an Estradiol Dose-Response Relationship in the Modulation of Ethanol Intake

Background: Estradiol (E₂) potentiates the self-administration of numerous psychoactive drugs in female rodents. An analogous modulatory role of E₂ on ethanol consumption remains unresolved because of examination of limited doses. The purpose of this study was to delineate a dose-response relationship for E₂ on ethanol intake with an extended range and number of E₂ doses. Methods: Female Long-Evans rats had continuous access (22 hr/day) to both 10% ethanol (10E) solution and water. After the establishment of stable 10E intake baselines, rats were assigned to one of seven dose groups balanced for 10E intake [sham-operated (Shm) or ovariectomized (Ovx) plus E₂ (μg/ kg)]: Shm + 0, Ovx + 0, Ovx + 0.05, Ovx + 0.15, Ovx + 0.5, Ovx + 1.5, and Ovx + 5. Ethanol preference drinking was evaluated during 25 consecutive days of E₂ replacement treatment, and trunk blood was collected for the determination of plasma E ₂ and progesterone concentrations. Results: Chronic E₂ replacement regimens (0.05-1.5 μg/kg) dose-dependently augmented 10E intakes and ethanol preference ratios without concomitantly altering water consumption. Despite the maintenance of 2- to 3-fold greater plasma E₂ levels, a supraphysiologic E₂ dose (5 μg/kg) failed to precipitate ethanol intakes in excess of levels observed after treatment with a high physiologic E₂ dose (1.5 μg/kg). Plasma progesterone concentrations were significantly increased in treatment groups (1.5 and 5 μg/kg E₂) that exhibited corresponding significant increases in ethanol consumption. Conclusions: A positive dose-response relationship between E₂ and ethanol intake (incremental increases in E₂ dose corresponded to incremental increases in intake) was apparently limited to a physiologic concentration range, because a supraphysiologic dose failed to elicit an additional stepwise increase in ethanol intake. These findings stipulate a modulatory role for E₂ in the regulation of moderate ethanol intake and suggest that endogenous fluctuations of E₂ may alter the propensity toward consumption in women and in female animal models of ethanol self-administration.