Alcohol Sensitivity as an Endophenotype of Alcohol Use Disorder: Exploring Its Translational Utility between Rodents and Humans

Abstract

Alcohol use disorder (AUD) is a complex, chronic, relapsing disorder with multiple interacting genetic and environmental influences. Numerous studies have verified the influence of genetics on AUD, yet the underlying biological pathways remain unknown. One strategy to interrogate complex diseases is the use of endophenotypes, which deconstruct current diagnostic categories into component traits that may be more amenable to genetic research. In this review, we explore how an endophenotype such as sensitivity to alcohol can be used in conjunction with rodent models to provide mechanistic insights into AUD. We evaluate three alcohol sensitivity endophenotypes (stimulation, intoxication, and aversion) for their translatability across human and rodent research by examining the underlying neurobiology and its relationship to consumption and AUD. We show examples in which results gleaned from rodents are successfully integrated with information from human studies to gain insight in the genetic underpinnings of AUD and AUD-related endophenotypes. Finally, we identify areas for future translational research that could greatly expand our knowledge of the biological and molecular aspects of the transition to AUD with the broad hope of finding better ways to treat this devastating disorder.

Ethanol-Related Behaviors in Mouse Lines Selectively Bred for Drinking to Intoxication

“…The genetic contribution to AUD is well known yet identifying important mechanisms remain challenging. A major barrier in this pursuit is the complexity of AUD, which includes a web of factors, such as complex genetic, environmental, and gene-by-environment interactions, that increase risk for developing an AUD [ 15 ]. Although the use of human genome-wide association studies (GWAS) have proven beneficial for the alcohol field—as well as many other mental health fields—they remain challenged by the need for large sample sizes and the difficulty in fully estimating trait heritability [ 35 , 36 , 37 ].…”

“…Testing and modeling endophenotypes remains a critical tool in understanding the genetic basis of complex behaviors, such as binge-like ethanol drinking and AUDs [ 15 ]. Ethanol sensitivity, loss of control (binge drinking), tolerance, and relapse have been identified as important factors in evaluating endophenotypes throughout the stages of the AUD diagnosis [ 15 ]. Each stage of AUD progression is likely influenced by unique gene networks, which should be systematically considered in preclinical alcohol research [ 15 ].…”

“…Ethanol sensitivity, loss of control (binge drinking), tolerance, and relapse have been identified as important factors in evaluating endophenotypes throughout the stages of the AUD diagnosis [ 15 ]. Each stage of AUD progression is likely influenced by unique gene networks, which should be systematically considered in preclinical alcohol research [ 15 ]. The HDID lines represent genetic models of high risk for binge-like ethanol drinking.…”

“…Sensitivity to the intoxicating effects of ethanol, or the subjective response in humans, is a critical predictor of risk for AUD development, the genetic contributions to relative sensitivity have been widely tested through endophenotypes of ethanol-induced locomotor activity, ataxia, hypothermia, and LORR [ 15 , 23 , 24 , 25 , 26 , 27 ]. There exists a negative genetic correlation between LORR and voluntary ethanol consumption [ 28 , 29 ], i.e., some genes or gene networks predisposing low sensitivity also predispose high risk for AUD, and vice versa.…”

Distinct and Overlapping Patterns of Acute Ethanol-Induced C-Fos Activation in Two Inbred Replicate Lines of Mice Selected for Drinking to High Blood Ethanol Concentrations

“…HDID2 animals tend to consume high levels of ethanol through a larger number of similarly sized bouts relative to HS or HDID1 animals for both ethanol and water, suggesting that they may show a generalized increase in intake [ 5 ]. They further display a more generalized reduction in CTA behavior, showing less CTA to both 2 g/kg ethanol and lithium chloride exposure [ 10 , 12 ]. Similar to the iHDID1 line the iHDID2 strain possess a similar level of ethanol CPP and anxiolysis following ethanol exposure as HS animals, suggesting that this line may also have little relative change in processing the reinforcing effects of ethanol versus the parent HS line.…”