Null mutation of 5α-reductase type I gene alters ethanol consumption patterns in a sex-dependent manner

Abstract

The neuroactive steroid allopregnanolone (ALLO) is a positive modulator of GABAA receptors, and manipulation of neuroactive steroid levels via injection of ALLO or the 5α-reductase inhibitor finasteride alters ethanol self-administration patterns in male, but not female, mice. The Srd5a1 gene encodes the enzyme 5α-reductase-1, which is required for the synthesis of ALLO. The current studies investigated the influence of Srd5a1 deletion on voluntary ethanol consumption in male and female wildtype (WT) and knockout (KO) mice. Under a continuous access condition, 6 and 10 % ethanol intake was significantly greater in KO versus WT females, but significantly lower in KO versus WT males. In 2-h limited access sessions, Srd5a1 deletion retarded acquisition of 10 % ethanol intake in female mice, but facilitated it in males, versus respective WT mice. The present findings demonstrate that the Srd5a1 gene modulates ethanol consumption in a sex-dependent manner that is also contingent upon ethanol access condition and concentration.

Fig. 1

Consumption of and preference for ethanol solutions under a continuous access condition in male (M) and female (F) Srd5a1 knockout (KO) and wildtype (WT) mice. Values for g/kg ethanol intake and ethanol preference ratio represent the 4-day mean ± SEM during serial presentation of 3 % v/v ethanol (3E), 6E, 10E and 20E solutions. Ethanol concentrations were first presented unsweetened (panels A–B) and then in combination with 0.2 % w/v saccharin (+S) (panels C–D). Sample sizes per group are shown in panel A. *p<0.05 and **p<0.01 versus same-sex WT; ^#p < 0.05, ^##p < 0.01 and ^###p < 0.001 versus respective genotype of opposite sex. Post-hoc pair-wise comparisons were conducted via the Fisher LSD method

Fig. 2

Acquisition of ethanol self-administration during limited access sessions in male (M) and female (F) Srd5a1 knockout (KO) and wildtype (WT) mice. Daily mean ± SEM values for g/kg ethanol intake (panel A) and ethanol preference ratio (panel B) are depicted following 2-h/day access to a 10 % v/v ethanol solution. Sample size per group was n = 11, except n = 13 for F WT mice. *p < 0.05 and **p < 0.01 versus respective session 1 value; #p < 0.05 and p < 0.01 versus M WT group. Post-hoc pair-wise comparisons were conducted via the Fisher LSD method

Fig. 3

Blood ethanol concentrations (BECs) following 2-h ethanol intake in male (M) and female (F) Srd5a1 knockout (KO) and wildtype (WT) mice. The mean ± SEM values for BEC sampled immediately following session 5 are depicted in panel A. The corresponding mean ± SEM g/kg consumed during the same 2-h session is reported in parentheses above each bar. Sample sizes per group are the same as stated in Fig. 2. In panel B, the solid line depicts the linear regression of data points representing the g/kg ethanol intake and BEC for individual mice (r = 0.81, p < 0.001, n = 46)

Fig. 4

Temporal distribution of ethanol licks upon acquisition of limited access ethanol intake in male (M) and female (F) Srd5a1 knockout (KO) and wildtype (WT) mice. Values depict the mean ± SEM of licks on the ethanol sipper within each 20-min interval throughout session 4 (i.e., asymptote reached in Fig. 2a). Sample sizes per group are the same as reported in Fig. 2. *p < 0.05 and **p < 0.01 versus same-sex WT; ^#p < 0.05 versus M WT group. Post-hoc pair-wise comparisons were conducted via the Fisher LSD method