Neurosteroid Modulators of GABAA Receptors Differentially Modulate Ethanol Intake Patterns in Male C57BL/6J Mice

Abstract

Background-Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of 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.

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

“…The effects of intracranial ALLO on drinking patterns closely resemble the previously reported influence of systemically-administered neurosteroid assessed within a 2-bottle choice procedure in mice (see [14]). The 50 ng (ICV) and 10 mg/kg (intraperitoneally; IP) doses similarly augmented both the mean and first bout sizes.…”

“…The 50 ng (ICV) and 10 mg/kg (intraperitoneally; IP) doses similarly augmented both the mean and first bout sizes. Furthermore, a low systemic dose of ALLO (3.2 mg/kg, IP) significantly elevated the maintenance of ethanol licks, whereas higher doses (17 and 24 mg/kg, IP) suppressed licks [14]. This cumulative lick profile mirrored the current finding that 50 ng ALLO enhanced licks during the initial 10-min of the selfadministration session whereas 400 ng led to a significant attenuation in licks.…”

“…A 3 mg/kg ALLO dose, but not 1 or 10 mg/kg, significantly enhanced ethanolreinforced responding in rats [21]. Similarly, our laboratory previously reported a significant enhancement in ethanol intake following systemic pre-treatment with 3.2 mg/kg ALLO, no change with a 10 mg/kg dose, and a significant decrease with 24 mg/kg [14]. Intra-accumbal infusion of 0.55 and 1.0 ng ALLO (~1.5 and 3 pmol) partially substituted for a systemic ethanol injection in a drug discrimination procedure, whereas lower and higher doses were without effect [19].…”

“…Appetitive and consummatory measures were derived from these cumulative records. Based on previous experience [12,13,14], an ethanol bout was defined as ≥ 20 licks separated by less than a 60-sec pause between successive licks. Mice were required to meet two performance-based criteria to be included in the analysis: 1) completion of the RR8 for at least three of the four ALLO doses examined (including the test session and preceding VEH treatment sessions), and 2) consistent demonstration of a 100-lick minimum (approximately 0.25 g/kg ethanol).…”

“…Furthermore, a subsequent study using lickometer circuits to assess ethanol consumption patterns of B6 mice revealed that ALLO dose-dependently altered ethanol intake patterns by promoting the onset of ethanol drinking (increased first bout size) and blunting the maintenance of consumption during the later half of a 2-hr session [14]. In contrast, acute treatment with the 5α-reductase enzyme inhibitor finasteride, which blocks the biosynthesis of endogenous ALLO, suppressed the onset of ethanol self-administration [13].…”