Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

Abstract

Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual’s risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes’ roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction.

The Neurotransmitters Involved in Drosophila Alcohol-Induced Behaviors

“…Many of the genes implicated in mammalian alcohol reactions and human AUD have conserved functions in Drosophila (Grotewiel and Bettinger, 2015;Lathen et al, 2020). Some of these involve common molecular pathways for alcohol response, such as cyclic adenosine monophosphate (cAMP) (Moore et al, 1998) and neuropeptide Y (neuropeptide F in flies) (Wen et al, 2005).…”

Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man

“…Here, it is worth noting that NPY is of major interest to substance misuse disorders and has been implicated in human alcohol use disorder[ 137 - 139 ] as well as in rodent models[ 140 - 142 ]. Since genetic vulnerability remains the core disease-causing factor for humans, and given that unbiased genetic screening, QTL analyses or GWAS studies are easily paired with functional studies in D. melanogaster [ 143 , 144 ], the latter presents as a viable alternative organism to study gene-environment interactions and the triggers that drive alcoholism, with perhaps the next step being a pursuit of the epigenetic mechanisms underlying those pathologies.…”

The Use of Drosophila to Understand Psychostimulant Responses

“…Additionally, Drosophila is a valuable model for studying complex addictive disorders such as alcoholism [ 26 ]. Studies over the last 25 years have shown that flies express a range of alcohol-induced behaviors similar to those observed in intoxicated humans [ 27 ], and numerous genes isolated based on their involvement in Drosophila alcohol responses have helped identify corresponding genes that contribute to alcohol use disorder (AUD) in humans [ 28 ]. Additionally, the neurotransmitters important for mammalian alcohol-induced behaviors are also involved in Drosophila alcohol responses [ 29 ], including dopamine, which is required for reward in flies [ 26 ] and in humans [ 30 ].…”