Elsevier

Neuropharmacology

Volume 122, 1 August 2017, Pages 201-243
Neuropharmacology

Invited review
Rat animal models for screening medications to treat alcohol use disorders

https://doi.org/10.1016/j.neuropharm.2017.02.004Get rights and content

Highlights

  • Several selectively bred rat lines serve as valid animal models of alcoholism.

  • Selectively bred rat lines serve as animal models of adolescent binge drinking.

  • Treatments for multiple stages of the addiction cycle have been tested in these rats.

  • The role of pharmacogenetics can be evaluated in these selectively bred rat lines.

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.

This article is part of the Special Issue entitled “Alcoholism”.

Section snippets

Societal burden of alcohol abuse and dependence

Approximately half of all Americans have at least one relative with an alcohol use disorders (AUD), with some of these individuals having this trait across multiple generations (Research Society on Alcoholism, 2011, Research Society on Alcoholism, 2015). Half of individuals meeting a life-time diagnosis for an AUD do so by age 21 with two-thirds doing so by age 25 (Hingson et al., 2006). This is especially troubling given between 15% and 25% of individuals in the military have AUDs (Bray and

Pros and cons of animal model research

While drug development relies heavily on in vitro assays early in the process, subsequent studies in vivo are required in the pathway to FDA regulation and clinical use (Blass, 2015). In vivo assays are required to evaluate a compound in a highly complex biological system as opposed to in vitro assays, which are constrained by their limited macromolecular environment (Blass, 2015). Essentially, the outcome measures of an in vivo assay are greater than the sum of its multiple constituent

Selective breeding

Bi-directional selective breeding is a powerful genetic tool that has been employed to study the genetics of many ethanol-associated phenotypes (Crabbe, 2010, Crabbe et al., 2010). Compared to pure association studies such as genome-wide association studies (GWAS) and studies using recombinant inbred lines (RILs) panels, selective breeding from a heterogeneous outbred stock can make low frequency/rare alleles more common. Selective breeding involves establishing a distribution of scores for the

The home-cage and operant environments

Home-cage drinking is relatively self-explanatory, such that the rat has access to ethanol in its home-cage environment. There are pros and cons to this test environment and there continues to be a debate as to its face validity with the clinical condition. However, home-cage drinking is positively associated with both the reinforcing and rewarding aspects of ethanol (e.g., Green and Grahame, 2008). On the other hand, operant self-administration requires removing the rat from its home-cage and

Caveats, challenges, and conclusions

A few caveats need to be mentioned before summarizing this review. First, the mouse ethanol research literature was not discussed. This was done due to space limitations and in no way minimizes the substantial literature that is associated with it. Second, transgenic ethanol research was not discussed. Similar to the first caveat, especially since most of the transgenic work has involved mice, this was done due to space limitations. For excellent discussions on both of these subjects see

Statement of conflict

All authors declare they have no perceived or real conflicts of interest associated with any part of this work.

Acknowledgements

The present work was supported in part by NIAAA grants AA07611, AA013522 and AA015512.

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