Oral Self‐Administration of EtOH: Sex‐Dependent Modulation by Running Wheel Access in C57BL/6J Mice

Abstract

Background The effects of stress, including neuroendocrine and behavioral sequelae aimed at maintaining homeostasis, are associated with increased alcohol consumption. Because both stress and drinking are multifactorial, the mechanisms underlying the relationship are difficult to elucidate. We therefore employed an animal model investigating the influence of blocked access to a running wheel on drinking in C57BL/6J (B6) mice. Methods In the first experiment, naïve, adult male and female subjects were individually housed for 2 weeks with 24hr access to a running wheel and 12% EtOH in a 2-bottle, free choice paradigm. After determining baseline consumption and preference, experimental subjects had the running wheel placed in a locked position for 6hr, and the EtOH bottle was removed during the first half of this period. Two subsequent experiments, again in adult, naïve B6 mice, examined the influence of locked running wheels on self-administration of 20% EtOH in a limited access paradigm, and blood EtOH concentrations (BECs) were determined. Results In all three studies, using both between and within subject analyses, females showed transient yet reliable increases in alcohol drinking during blocked access to a rotating activity, while drinking in male mice was largely insensitive to this manipulation, though both sexes showed appreciable BECs (>130 mg/dL in females, and 80 mg/dL in males) following a 2hr EtOH access period. Conclusions These data add to a burgeoning literature suggesting that the factors contributing to excessive alcohol use differ between males and females, and that females may be especially sensitive to the influence of wheel manipulation. Elucidating the sex-dependent mechanisms mediating differences in alcohol sensitivity and response is critical to understanding the causes of alcoholism and in developing effective treatments and interventions.

β-endorphin regulates alcohol consumption induced by exercise restriction in female mice

“…Our previous investigation of the effect of restricted wheel access on drinking (Piza-Palma et al, 2014) showed that female but not male B6 mice increased alcohol consumption in response to the stressor, and therefore we did not include males in the present study. However, it remains possible that low β-endorphin would also shift the reward sensitivity curve in male mice in this experimental context.…”

“…Attempts to better understand the complex interactions between stress and ethanol have frequently employed animal models (Crabbe, 2014), and these strategies have helped to identify some of the specific mechanisms contributing to aspects of the paradoxical relationship, especially as they pertain to the dependent state (Becker, Lopez, & Doremus-Fitzwater, 2011; Crabbe, Phillips, & Belknap, 2010). Our lab has employed intermittent interruptions of access to a running wheel as a model of stress (Ehringer, Hoft, & Zunhammer, 2009; Piza-Palma et al, 2014). We have argued that blocking access to a running wheel in the home cage induces frustration stress, and that this manipulation may be relevant to the human condition where stressors often involve loss of something desired, such as a loved one, health, or job (Thoits, 2010).…”

“…These factors include environmental challenges, genetic background, family history, and gender. Restricting rotations of an appetitive running wheel results in significant increases in voluntary ethanol consumption in female, but not male, C57BL/6J mice (Piza-Palma et al, 2014). Because women are generally more sensitive to stress (Burk et al, 2011; Randall et al, 1999; Young-Wolff, Kendler, & Prescott, 2012) and prone to disproportionately escalating their use and abuse of the drug compared to men (Becker et al, 2005; Greenfield, Back, Lawson, & Brady, 2010; Keyes, Grant, & Hasin, 2008), this sex-dependent effect may be a useful tool in addressing the general shortage of research on sex-dependent factors (Beery & Zucker, 2011) and may help shed light on the general relationship between stress and alcohol in non-dependent subjects.…”

“…In order to begin exploring the effects of constitutive β-endorphin deficiency on endocrine responses to stress, we also evaluated plasma ACTH, corticosterone (CORT), and mRNA for the CRH peptide and its type 1 receptor (CRH-R1) in brain areas implicated in the stress response, including the ventral hippocampus (VH), amygdala and bed nucleus stria terminalis (BNST), and dorsomedial prefrontal cortex (dmPFC) (Silberman & Winder, 2013; Stamatakis et al, 2014). A modified drinking-in-the-dark paradigm was employed with locked running wheels acting as an external stressor in female C57BL/6J, βE-HT, and βE-KO mice (Ehringer et al, 2009; Piza-Palma et al, 2014). We hypothesized the finding of increased drinking in β-endorphin-deficient mice in response to stress, and speculated that the differences in behavioral sensitivity to stress would be reflected in heightened ACTH and/or CORT levels and alterations in Crh and/or Crh-R1 .…”

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

“…Numerous studies in rodents have provided evidence for an interaction between voluntary wheel running and alcohol consumption . In a recent review, Hallgreen et al pointed out that, “physical exercise is widely regarded as “medicine” for the prevention and treatment of myriad somatic health conditions.” However, the effectiveness of physical activity to treat AUDs remains understudied.…”