Rat animal models for screening medications to treat alcohol use disorders

Abstract

The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence. The focus will be on rats and in particular selectively bred rats. Brief introductions discuss various aspects of the clinical picture, which provide characteristics of individuals with alcohol use disorders (AUDs) to model in animals. Following this, multiple selectively bred rat lines will be described and evaluated in the context of animal models used to screen medications to treat AUDs. Next, common behavioral tests for drug efficacy will be discussed particularly as they relate to stages in the addiction cycle. Tables highlighting studies that have tested the effects of compounds using the respective techniques are included. Wherever possible the Tables are organized chronologically in ascending order to describe changes in the focus of research on AUDs over time. In general, high ethanol-consuming selectively bred rats have been used to test a wide range of compounds. Older studies usually followed neurobiological findings in the selected lines that supported an association with a propensity for high ethanol intake. Most of these tests evaluated the compound's effects on the maintenance of ethanol drinking. Very few compounds have been tested during ethanol-seeking and/or relapse and fewer still have assessed their effects during the acquisition of AUDs. Overall, while a substantial number of neurotransmitter and neuromodulatory system targets have been assessed; the roles of sex- and age-of-animal, as well as the acquisition of AUDs, ethanol-seeking and relapse continue to be factors and behaviors needing further study.

High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking

“…Various studies with rats, mostly employing chronic choice drinking paradigms [e.g. 36;37;28 ] showing positive effects of acamprosate on alcohol drinking have been reviewed 2 .…”

“…In a 1 hr single bottle test, one injection of 10 mg/kg baclofen (but not higher or lower doses from 5–20 mg/kg) increased drinking and the resulting BAL 39 . However, multiple studies with different test parameters and subject populations including both mice and rats have shown that baclofen could either increase or decrease ethanol intake [for reviews, see 2;40 ]. Reasoning that enantiomer-specific effects could have contributed to this variability, Steve Boehm’s group showed that a peripheral injection of 10 mg/kg of the R(+) enantiomer deceased DID drinking and BAL in C57BL/6J male mice while the same dose of the S(-) enantiomer modestly increased ethanol intake without affecting BAL.…”

“…Perhaps the most surprising of our results was the lack of any effect of naltrexone at doses up to 10 mg/kg (Figures 1 & 5). Several rat papers reporting naltrexone effects over the years have found reduced drinking using operant and choice drinking procedures using various rat genotypes [reviewed in 2 ]. A recent study reported reduced ethanol intake in the DID procedure with male C57BL/6J mice after single injections of 3 or 10 mg/kg naltrexone, but not doses of 0.3 or 1 mg/kg.…”

“…In such studies, solutions of 10–20% alcohol in tap water are typically offered as a choice versus plain tap water, with access offered 24 hours a day. Using the existing rodent models based on preference drinking, many drugs reduce drinking 2 . One limitation of these studies is that many compounds initially shown to be effective in rodent preference models have not proven to be effective in subsequent human clinical trials 3 .…”

“…Comprehensive reviews of studies attempting to reduce rat preference drinking in the several selectively-bred, high-preferring rat lines describe results for many compounds 2;4 . Reviews of studies with the DID limited access drinking model have also shown that many peripherally administered drugs can reduce drinking 15;16 .…”