The use of Drosophila to study sleep impairments in stimulant use disorder

Stimulant drugs like cocaine and methamphetamine acutely enhance the release of monoamine neurotransmitters, particularly dopamine, to induce euphoria, motivation, hyperlocomotion, and strong sleep suppression. Chronic stimulant use can lead to the development of stimulant use disorder (SUD), which is characterized by risky, excessive, or uncontrolled drug intake and an inability to cease use. At time of writing, there is no FDA-approved pharmacological treatment for SUD. Though symptoms and comorbidities of SUD vary, studies on abstinent stimulant-users repeatedly identify sleep disorder as a symptom that persists long into abstinence and drives relapse to stimulant use. This review discusses the use of the vinegar fly Drosophila melanogaster to identify the neural and genetic pathways mediating this sleep disorder. The fly has a long history of use in neurogenetics research, boasting efficient and low-cost husbandry, an extremely well-studied genome, widely available tools for manipulating neurons and genes with high spatiotemporal specificity, and a connectome cataloguing each neuron and synapse in the fly brain. Additionally, the fly rest state is a face-valid model of sleep in mammals, as it shares key features and is regulated by conserved neurotransmitter systems; flies also respond similarly to stimulant drugs, again mediated by common monoamine signals. As such, flies represent an excellent and under-utilized invertebrate model for studying sleep deficits in stimulant abstinence. This review describes methods available for studying sleep and stimulant use in Drosophila, highlighting key findings in the existing literature relevant to this phenotype while indicating where the literature is lacking. Identification of the genetic and neural pathways mediating stimulant-induced sleep disorder in flies will shed light on the critical role of dopamine systems in sleep regulation, facilitating the development of more efficacious treatments for SUD.