Pharmacologically relevant intake during chronic, free-choice drinking rhythms in selectively bred high alcohol-preferring mice

Abstract

Multiple lines of High Alcohol Preferring (HAP) mice were selectively bred for their intake of 10% ethanol (v/v) during 24-h daily access over a four-week period, with the highest drinking lines exhibiting intakes in excess of 20 g/kg/day. We observed circadian drinking patterns and resulting blood ethanol concentrations in the HAP lines. We also compared the drinking rhythms and corresponding blood ethanol concentrations (BEC) of the highest drinking HAP lines to those of the C57BL/6J (B6) inbred strain. Adult male and female crossed HAP (cHAP), HAP replicate lines 1, 2, 3, and B6 mice had free-choice access to 10% ethanol and water for 3 weeks prior to bi-hourly assessments of intake throughout the dark portion of the light-dark cycle. All HAP lines reached and maintained a rate of alcohol intake above the rate at which HAP1 mice metabolize alcohol, and BECs were consistent with this finding. Further, cHAP and HAP1 mice maintained an excessive level of intake throughout the dark portion of the cycle, accumulating mean BEC levels of 261.5 ± 18.09 and 217.9 ± 25.02 mg/dl, respectively. B6 mice drank comparatively modestly, and did not accumulate high BEC levels (53.63 + 8.15 mg/dl). Free-choice drinking demonstrated by the HAP1 and cHAP lines may provide a unique opportunity for modeling the excessive intake that often occurs in alcohol-dependent individuals, and allow for exploration of predisposing factors for excessive consumption, as well as the development of physiological, behavioral, and toxicological outcomes following alcohol exposure.

The effect of prior alcohol consumption on the ataxic response to alcohol in high-alcohol preferring mice

“…With repeated cycles of continuous-access 2-bottle choice drinking, HAP mice typically increase their ethanol intake and preference over days (Grahame et al, 1999; Matson & Grahame, 2011; Oberlin et al, 2011), and this was generally the case in the current study. Given our previous findings (Fritz et al, 2013), we hypothesized that a prior history of alcohol consumption may enhance the already substantial rapid AFT capacity of HAP2 mice.…”

“…Four weeks of 2-bottle choice access for 10% ethanol or water has been previously shown to produce metabolic tolerance in cHAP mice (Matson et al, 2013). HAP2 mice consume significantly less ethanol than cHAP mice in this paradigm (Matson & Grahame, 2011), and considering that their ethanol consumption duration was only 18 days in the current study, this evidence of metabolic tolerance is impressive and is also the first seen following free-choice drinking in any of the uncrossed HAP lines. Although the E group may have cleared ethanol more quickly than the W group, this has no bearing on the observed differences in sensitivity or the potential to observe differences in M-AFT or AFT.…”

“…Therefore, testing replicate 3 was deemed unnecessary. Furthermore, the ethanol intake of HAP2 mice is greater and more stable than HAP3 mice (Matson & Grahame, 2011; Oberlin et al, 2011), perhaps because the selection process is further advanced.…”

“…These lines typically demonstrate an increase in 10% ethanol intake/preference over days in a continuous-access 2-bottle choice paradigm (Grahame, Li, & Lumeng, 1999; Matson & Grahame, 2011; Oberlin, Best, Matson, Henderson, & Grahame, 2011). Given the already demonstrated impressive rapid AFT capacity in ethanol-naïve HAP mice (Fritz et al, 2013), their capacity to escalate ethanol consumption over days may also be reflective of an enhanced ability for alcohol exposure to positively influence this response.…”

Lithium, but not Valproate, Reduces Impulsive Choice in the Delay-Discounting Task in Mice

“…Approximately 45% of all bipolar patients have a comorbid alcohol addiction and display high levels of impulsivity (McElroy et al, 2001;Swann et al, 2003). HAP mice consistently consume excessive amounts of ethanol, reaching average blood ethanol levels of over 200 mg/dl on a daily basis (Matson and Grahame, 2011) and demonstrate higher levels of impulsivity than selectively bred Low-AlcoholPreferring (LAP) mice and their outbred progenitor line (Oberlin and Grahame, 2009). In these ways, they parallel the patients with bipolar disorder more closely than LAP mice, which are less impulsive and do not drink alcohol.…”