Effects of orchiectomy on binge-like and inflexible alcohol consumption in mice

Introduction Alcohol use disorders (AUDs) and excessive alcohol use are a growing public health burden across the world, with sex differences in their presentation. Rodent models of drinking have revealed consistent sex differences in ethanol consumption, preference, and compulsive-like intake. Previous studies have found that ovariectomy reduces ethanol drinking. Increased consumption has also been observed in male, but not female, mice with XY sex chromosome complement. These results and others suggest an interaction between gonadal and genetic sex, but the influence of circulating gonadal hormones has not been assessed. Methods Three experiments used removal of the gonads and the Four Core Genotypes (FCG) mouse line to further investigate interactions between gonadal hormones and sex chromosome complement on alcohol drinking. Experiment 1: ovariectomy (OVX) was conducted before the onset of drinking in XX/ Sry - and XY/ Sry - FCG females. Experiment 2: orchiectomy (ORX) was performed in C57BL/6J male mice. Experiment 3: ORX was conducted in XX/ Sry + and XY/ Sry + FCG males. Voluntary, binge-like intake of 15% ethanol was measured in a 4-h, two-bottle choice drinking-in-the-dark (DiD) paradigm followed by tests of quinine-resistant drinking (0-500 µM) and, in Experiments 2 and 3 only, ethanol vs. sucrose (1.5-12%) choice. Results Removal of the testes increased 15% ethanol consumption and preference in male C57BL/6J mice and consumption in FCG mice. Conversely, there was evidence suggesting that ORX reduced quinine-resistance and ethanol vs. sucrose choice in C57BL/6J, but not FCG, males. Previously observed increases in binge-like consumption following OVX were not replicated in FCG female mice. Sex chromosome complement did not interact with gonadal status for any measure. Discussion These studies demonstrate that testicular hormones suppress voluntary binge-like ethanol consumption in male mice and provide some evidence for facilitatory effects on two measures of inflexible drinking – quinine resistance and ethanol vs. sucrose choice. These findings are interesting to consider alongside clinical data demonstrating positive associations between testosterone and alcohol drinking in men. There was no evidence for interactions between circulating gonadal hormones and sex chromosome complement, which may suggest gonadal sex-dependent effects of sex chromosome complement on drinking rely on organizational changes earlier in development.