The Use of Drosophila to Understand Psychostimulant Responses

Abstract

The addictive properties of psychostimulants such as cocaine, amphetamine, methamphetamine, and methylphenidate are based on their ability to increase dopaminergic neurotransmission in the reward system. While cocaine and methamphetamine are predominately used recreationally, amphetamine and methylphenidate also work as effective therapeutics to treat symptoms of disorders including attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Although both the addictive properties of psychostimulant drugs and their therapeutic efficacy are influenced by genetic variation, very few genes that regulate these processes in humans have been identified. This is largely due to population heterogeneity which entails a requirement for large samples. Drosophila melanogaster exhibits similar psychostimulant responses to humans, a high degree of gene conservation, and allow performance of behavioral assays in a large population. Additionally, amphetamine and methylphenidate reduce impairments in fly models of ADHD-like behavior. Therefore, Drosophila represents an ideal translational model organism to tackle the genetic components underlying the effects of psychostimulants. Here, we break down the many assays that reliably quantify the effects of cocaine, amphetamine, methamphetamine, and methylphenidate in Drosophila. We also discuss how Drosophila is an efficient and cost-effective model organism for identifying novel candidate genes and molecular mechanisms involved in the behavioral responses to psychostimulant drugs.

Syntaxin 1 Ser 14 phosphorylation is required for nonvesicular dopamine release

“…Drosophila is a powerful model system to determine in vivo processes underlying altered DA function due to its conserved mechanisms of DA neurotransmission ( 51 , 52 ) and its genetic tractability. We used the fmn Drosophila (DAT fmn ) background, which lacks expression of full-length Drosophila DAT (dDAT) and serves as a functional knockout ( 53 ), in combination with phiC31-based integration, to insert an upstream activation sequence (UAS)-driven hDAT WT or hDAT SD to express these hDAT constructs specifically in DA neurons, as previously shown ( 8 , 9 , 54 ).…”

Influence of Redox and Dopamine Regulation in Cocaine-Induced Phenotypes Using Drosophila

“…Increased evidence about the importance of redox regulation, and the role that redox intermediates play in the regulation of neuronal plasticity prompted us to examine several redox parameters in Drosophila , a laboratory organism that over the last decades has significantly advanced our knowledge about the genetic mechanisms that underlie addiction related phenotypes [ 41 ]. We show that brief exposures to volatilized cocaine are sufficient to significantly change the amount of oxygen radicals and H 2 O 2 in D. melanogaster with accompanying activation of endogenous antioxidant enzymes CAT and SOD in the whole body homogenates.…”

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

“…These rewarding drug properties are key factors in what makes drugs addictive. Though the mechanisms of action are different for alcohol and psychostimulants, they all converge on the human reward system, where many neurotransmitters are conserved with flies [ 58 , 59 , 60 ]. Cocaine blocks DA reuptake into the presynaptic terminal, leaving large amounts of DA in the synapse.…”

“…The locomotor-activating phase of alcohol has been studied in flies [ 40 ] and it requires the activity of DAergic neurons projecting to the ellipsoid body pre-motor center [ 69 ]. Additionally, flies and rodents under the influence of psychostimulants, like cocaine or a methamphetamine, will experience enhanced acute locomotor activity [ 59 , 70 , 71 ]. Locomotor activity is a useful output metric of initial drug effects that can help us measure if and when the following endophenotypes occur.…”