Neurosteroid modulators of GABA(A) receptors differentially modulate Ethanol intake patterns in male C57BL/6J mice

Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of gamma-aminobutyric acid A (GABA(A)) receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns.

Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10 E) by a saccharin fading procedure during daily 2-hr limited-access sessions beginning 1-hr after dark-phase onset. Cumulative lick responses were recorded for 10 E and water by lickometer circuits. After establishing 10 E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v beta-cyclodextrin ip), and then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design.

The GABA(A) receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked alterations in intake corresponded to significant, dose-dependent alterations in bout frequency and interbout interval. ALLO also elicited robust, dose-dependent elevations in 10 E licks during the initial 5 min of access but subsequently produced in a dose-dependent suppression of 10 E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated.

The present findings suggest that GABA(A) receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABA-ergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA(A) receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.