Biology Ph.D. Dissertations

Title

Drosophila as a Model Organism to Study Opioid Use Disorder

Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Biological Sciences

First Advisor

Robert Huber (Committee Chair)

Second Advisor

Jessica Kiss (Other)

Third Advisor

Raymond Larsen (Committee Member)

Fourth Advisor

Jon Sprague (Committee Member)

Fifth Advisor

Moira Van Staaden (Committee Member)

Abstract

Substance use disorder (SUD) is a debilitating chronic disorder with enormous social and economic impact. According to the brain disease model of addiction (BDMA), this affliction progresses following three recurring stages: binge and intoxication, withdrawal and negative affect, and preoccupation. Each stage is hallmarked by changes in particular brain circuits, mediated by specific molecular effectors, and results in distinct behavioral characteristics. The opioid epidemic is a global health concern and opioid use disorder (OUD) leads all other types of SUD in drug overdose deaths. Human imaging studies in patients with OUD, along with preclinical research in animal models, continue to expand our understanding of the pathophysiology and etiology of this disorder. While treatments are available, their efficacy and availability are limited. Most addictive drugs are plant secondary metabolites (PSM) that evolved as chemical defenses against insect herbivory. PSMs interfere with reward, learning, and feeding mechanisms in insects, the same mechanisms hijacked in humans with SUD. In this study, we examine Drosophila’s sensitivity to morphine, in efforts to establish this valuable model organism for the study of OUD. Indeed, flies show a dose-dependent behavioral sensitivity to morphine, measured by feeding, activity, and choice assays. In this study, we highlight the sequence similarities between two related families of receptors - human somatostatin/opioid receptors and Allatostatin C (AstC) receptors in Drosophila.s. Using the Gal4/UAS system, we show that neuronal knockdown of AstC receptors modulates the behavioral sensitivities of flies to morphine. This study demonstrates proof-of-concept evidence on the importance of taking a phylogenetic approach in SUD research. Our results suggest that Drosophila offers a useful model for the study of OUD, and that allatostatin C receptors, as their phylogenetic ancestral forms, play a key role in a flies’ sensitivity to opioids.

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