Abstract
Alcohol is a widely used and abused substance with numerous negative consequences for human health and safety. Historically, alcohol's widespread, non-specific neurobiological effects have made it a challenge to study in humans. Therefore, model organisms are a critical tool for unraveling the mechanisms of alcohol action and subsequent effects on behavior. Drosophila melanogaster is genetically tractable and displays a vast behavioral repertoire, making it a particularly good candidate for examining the neurobiology of alcohol responses. In addition to being experimentally amenable, Drosophila have high face and mechanistic validity: their alcohol-related behaviors are remarkably consistent with humans and other mammalian species, and they share numerous conserved neurotransmitters and signaling pathways. Flies have a long history in alcohol research, which has been enhanced in recent years by the development of tools that allow for manipulating individual Drosophila neurotransmitters. Through advancements such as the GAL4/UAS system and CRISPR/Cas9 mutagenesis, investigation of specific neurotransmitters in small subsets of neurons has become ever more achievable. In this review, we describe recent progress in understanding the contribution of seven neurotransmitters to fly behavior, focusing on their roles in alcohol response: dopamine, octopamine, tyramine, serotonin, glutamate, GABA, and acetylcholine. We chose these small-molecule neurotransmitters due to their conservation in mammals and their importance for behavior. While neurotransmitters like dopamine and octopamine have received significant research emphasis regarding their contributions to behavior, others, like glutamate, GABA, and acetylcholine, remain relatively unexplored. Here, we summarize recent genetic and behavioral findings concerning these seven neurotransmitters and their roles in the behavioral response to alcohol, highlighting the fitness of the fly as a model for human alcohol use.
Highlights
Alcohol is one of the most commonly used and abused psychoactive substances
We have identified that even though there are only about 250 DA neurons, many small subsets of these impact distinct behaviors (e.g., Kong et al, 2010), and DA is an area of high interest to researchers studying Drosophila behavior
These discoveries have been made possible through tools like split-GAL4 lines that enable overexpression or knockdown of genes in specific subsets of neurons, and CRISPR/Cas9 mutagenesis, which allows for the targeted investigation of a mutated gene
Summary
Alcohol is one of the most commonly used and abused psychoactive substances. Approximately 86% of American adults have reported drinking alcohol at some point in their lifetimes (Substance Abuse and Mental Health Services Administration, 2019), and, as of 2018, alcohol use disorder (AUD) affected over 14 million adults in the United States (Substance Abuse and Mental Health Services Administration, 2019). Locomotor activity begins to decline, and sedation takes effect, indicating that flies experience a biphasic ethanol response similar to mammals (Wolf et al, 2002). Like humans, flies can develop a learned preference for alcohol (see Figure 3). Like in mammalian neural circuits, inputs to these brain regions by specific neurotransmitters mediate various alcohol-induced behavioral responses.
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