Alteration of ethanol drinking in mice via modulation of the GABA(A) receptor with ganaxolone, finasteride, and gaboxadol - PubMed (original) (raw)

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

Marcia J Ramaker et al. Alcohol Clin Exp Res. 2011 Nov.

Abstract

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 10 mg/kg), FIN (0 or 100 mg/kg), and THIP (0, 2, 4, 8, and 16 mg/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 (8 mg/kg) and FIN both decreased 10E drinking during the first 5 hours 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 (8 mg/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.

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Figures

Figure 1

Positive correlation between 24-hour 10E intake (g/kg) and licks on the 10E bottle. Data points show the average 10E licks and 10E g/kg consumed for each mouse (n=24) for the five baseline days preceding the first drug treatment. Solid line represents linear regression of the data. p < 0.001 as determined by a Pearson bivariate correlation analysis. 10E = 10% (v/v) ethanol solution

Figure 2

Effects of GAN on the first 6 hours of ethanol access. The number of licks of 10E with each dose of GAN are shown for hour 1 (A), hour 2 (B), hour 3 (C), hour 4 (D), hour 5 (E), and hour 6 (F). A collapsed mean of the baseline days immediately preceding a drug day are shown for non-statistical comparative purposes. One animal’s data was removed from all 10E lick analysis due to a discordance between licks and g/kg consumed. Vertical bars represent the mean ± SEM for 23 mice. +p ≤ 0.10, *p ≤ 0.05, **p ≤ 0.01 versus within subjects vehicle (0 mg/kg). 10E=10% (v/v) ethanol solution

Figure 3

Effects of FIN on the first 6 hours of ethanol access. Total 10E licks during each phase of FIN (100 mg/kg) treatment are shown for hour 1 (A), hour 2 (B), hour 3 (C), hour 4 (D), hour 5 (E), and hour 6 (F). A collapsed mean of the last three 10E-access days before FIN treatment are shown as baseline. Vehicle treated animals’ data were collapsed across treatment phase and are graphed for non-statistical comparative purposes. Vertical bars represent the mean ± SEM for 14 mice (FIN) or 10 mice (vehicle). +p ≤ 0.10, *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 versus within subjects baseline. FIN=finasteride; 10E = 10% (v/v) ethanol solution

Figure 4

Effects of THIP on the first 6 hours of ethanol access. The number of licks of 10E with each dose of THIP are shown for hour 1 (A), hour 2 (B), hour 3 (C), hour 4 (D), hour 5 (E), and hour 6 (F). A collapsed mean of the vehicle days immediately preceding a drug day are shown as 0 mg/kg. Four animals were removed from all 10E lick analysis due to discordance between licks and g/kg 10E consumed on a drug or baseline day. Vertical bars represent the mean ± SEM for 19 mice. +p ≤ 0.10, *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 versus 0 mg/kg. THIP = gaboxadol HCl; 10E = 10% (v/v) ethanol solution

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Alteration of ethanol drinking in mice via modulation of the GABA(A) receptor with ganaxolone, finasteride, and gaboxadol - PubMed (original) (raw)