Selection for high alcohol preference drinking in mice results in heightened sensitivity and rapid development of acute functional tolerance to alcohol's ataxic effects

Abstract

Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of the current study was to assess this potential correlated response between alcohol preference and AFT in second and third replicate lines of mice selectively bred for high (HAP2&3) and low (LAP2&3) alcohol preference drinking. Male and female mice were tested for development of AFT on a static dowel task which requires that animals maintain balance on a wooden dowel in order to prevent falling. On test day, each mouse received one (1.75g/kg; Experiment 1) or two (1.75g/kg and 2.0g/kg; Experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in Experiment 2, an additional administration after the first regain of balance on the dowel. Blood samples were taken immediately after loss of balance (when BECs were rising) and at recovery (during falling BECs) in Experiment 1, and after first and second recovery in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BECs than LAP mice following the initial injection of ethanol and were therefore more sensitive to its early effects. Furthermore, Experiment 1 detected significantly greater AFT development (BECfalling - BECrising) in HAP mice as compared to LAP mice which occurred within ~30 min, supporting our hypothesis. However, AFT was not different between lines in Experiment 2, indicating that ~30–60 min following alcohol administration, AFT development was similar in both lines. These data show that high alcohol drinking genetically associates with both high initial sensitivity and very early tolerance to the ataxic effects of ethanol.

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

“…Similar to the human literature, studies have shown that these opposite genetic predispositions can associate with highly different responses to alcohol in these lines of rodents (Chester, Lumeng, Li, & Grahame, 2003; Crabbe, Colville, et al, 2012; Crabbe, Kruse, et al, 2012; Fritz et al, 2014; Fritz, Grahame, & Boehm, 2013; Grahame, Rodd-Henricks, Li, & Lumeng, 2000; Waller, McBride, Lumeng, & Li, 1983), suggesting that these responses ‘genetically correlate’ with the alcohol consumption phenotype. In other words, these associations can be indicative of common underlying genes for the response(s) of interest and form of alcohol consumption.…”

“…Three replicates of the HAP/LAP lines now exist and there are extreme differences in alcohol intake and preference with the replicate HAP lines consuming high, intoxicating amounts of alcohol, and replicate LAP lines demonstrating relative avoidance (Oberlin et al, 2011). Only HAP2 mice were used as we previously demonstrated that the genetic differences in ataxic ethanol sensitivity and AFT were present in both replicates 2 and 3 (Fritz et al, 2013). Therefore, testing replicate 3 was deemed unnecessary.…”

“…HAP mice are particularly sensitive to these effects on the ascending limb of the blood ethanol concentration (BEC) curve, as ethanol is being absorbed (Fritz et al, 2013). Furthermore, HAP mice have a significantly greater AFT capacity than do LAP mice.…”

“…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. This notion is supported by a previous study demonstrating that the AFT capacity of a mouse line selectively bred to develop a high degree of AFT (HAFT) following acute ethanol administration was augmented by alcohol pre-exposure (Wu, Tabakoff, Szabó, & Hoffman, 2001).…”

The Genetics of Alcohol Responses of Invertebrate Model Systems

“…However, identifying a simple relationship between tolerance and drinking in model systems has been difficult. The relationship between tolerance and drinking appears to depend on how tolerance was induced and how it was measured (Crabbe et al, 2012;Fritz, Grahame, & Boehm, 2013). Acute tolerance has been described in worms and mammals, but not in flies.…”