The Stage-Based Model of Addiction-Using Drosophila to Investigate Alcohol and Psychostimulant Responses

Abstract

Addiction is a progressive and complex disease that encompasses a wide range of disorders and symptoms, including substance use disorder (SUD), for which there are few therapeutic treatments. SUD is the uncontrolled and chronic use of substances despite the negative consequences resulting from this use. The progressive nature of addiction is organized into a testable framework, the neurobiological stage-based model, that includes three behavioral stages: (1) binge/intoxication, (2) withdrawal/negative affect, and (3) preoccupation/anticipation. Human studies offer limited opportunities for mechanistic insights into these; therefore, model organisms, like Drosophila melanogaster, are necessary for understanding SUD. Drosophila is a powerful model organism that displays a variety of SUD-like behaviors consistent with human and mammalian substance use, making flies a great candidate to study mechanisms of behavior. Additionally, there are an abundance of genetic tools like the GAL4/UAS and CRISPR/Cas9 systems that can be used to gain insight into the molecular mechanisms underlying the endophenotypes of the three-stage model. This review uses the three-stage framework and discusses how easily testable endophenotypes have been examined with experiments using Drosophila, and it outlines their potential for investigating other endophenotypes.

Keywords: Drosophila; addiction; anhedonia; assays; substance use disorder.

Figure 1

The cycle of addiction as explained with the neurobiological stage-based model in humans is characterized by proposed endophenotypes within each stage. The ventral tegmental area, substantia nigra, dorsal striatum, ventral and dorsal globus pallidus, and thalamus (pink) are involved in the binge/intoxication stage, while the extended amygdala and hypothalamus (green) are involved in the withdrawal/negative affect stage and the prefrontal cortex, hippocampus, insula, and basolateral amygdala (blue) are involved in the preoccupation/anticipation stage. The list (right) and text below each stage indicate the proposed behavioral characteristics of that stage. These endophenotypes are not necessarily stage-specific and some occur in multiple stages. This schematic is adapted from the Substance Abuse and Mental Health Services Administration [39].

Figure 2

Drosophila offer opportunities for insights into the neurobiological stage-based model of addiction. (a) How the proposed three-stage model of addiction maps onto the fly brain. Each stage is labeled with numbers that correspond to the endophenotypes listed on the right. These endophenotypes are not necessarily stage-specific and some occur in multiple stages. The fly brain schematic shows the mushroom body and the PAM neuronal DA cluster (pink), which are involved in the binge/intoxication stage, and the ellipsoid body and PPM neuronal DA cluster (green), which are involved in the withdrawal/negative affect stage. No brain regions are known to be involved in the preoccupation/anticipation stage. (b) The Fly Liquid–Food Interaction Counter (FLIC) assay can be used to study endophenotypes in the binge/intoxication stage (e.g., positive reinforcement and bingeing) in flies. The assay is assembled with an aluminum plate at the base, the reservoir base, and the printed circuit board (PCB). The reservoir base is where the solutions are stored, and the PCB contains the electrical circuitry needed to measure the time flies spend interacting with the solution. Flies are transferred to the behavior arenas where they have the choice between solutions in two food reservoir wells. The food wells are surrounded by a signal pad where flies close an electrical circuit upon interacting with the solution. Software measures the amount of interaction time that flies have with the solution. This schematic is adapted from Ro et al., 2014 [51].