Alteration of ethanol drinking in mice via modulation of the GABA _A receptor with ganaxolone, finasteride, and gaboxadol

Background: Neurosteroids and other γ-aminobutyric acid _A (GABA _A) receptor-modulating compounds have been shown to affect ethanol intake, although their mechanism remains unclear. This study examined how patterns of 24-hour ethanol drinking in mice were altered with the synthetic GABAergic neurosteroid ganaxolone (GAN), with an inhibitor of neurosteroid synthesis (finasteride [FIN]), or a GABA _A receptor agonist with some selectivity at extrasynaptic receptors (gaboxadol HCL [THIP]). Methods: Male C57BL/6J mice had continuous access to a 10% v/v ethanol solution (10E) or water. Using lickometer chambers, drinking patterns were analyzed among mice treated in succession to GAN (0, 5, and 10mg/kg), FIN (0 or 100mg/kg), and THIP (0, 2, 4, 8, and 16mg/kg). Results: GAN shifted drinking in a similar but extended manner to previous reports using low doses of the neurosteroid allopregnanolone (ALLO); drinking was increased in hour 1, decreased in hours 2 and 3, and increased in hours 4 and 5 postinjection. THIP (8mg/kg) and FIN both decreased 10E drinking during the first 5hours postinjection by 30 and 53%, respectively, while having no effect on or increasing water drinking, respectively. All 3 drugs altered the initiation of drinking sessions in a dose-dependent fashion. FIN increased and GAN decreased time to first lick and first bout. THIP (8mg/kg) decreased time to first lick but increased time to first bout and attenuated first bout size. Conclusions: The present findings support a role for the modulation of ethanol intake by neurosteroids and GABA _A receptor-acting compounds and provide hints as to how drinking patterns are shifted. The ability of THIP to alter 10E drinking suggests that extrasynaptic GABA _A receptors may be involved in the modulation of ethanol intake. Further, the consistent results with THIP to that seen previously with high doses of ALLO suggest that future studies should further examine the relationship between neurosteroids and extrasynaptic GABA _A receptors, which could provide a better understanding of the mechanism by which neurosteroids influence ethanol intake.