The Role of the Dopamine Transporter in the Effects of Amphetamine on Sleep and Sleep Architecture in Drosophila

Karam, Caline S.; Williams, Brenna L; Jones, Sandra K.; Javitch, Jonathan A.

doi:10.1007/s11064-021-03275-4

Cited by 13 publications

(36 citation statements)

References 89 publications

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“…Dopamine generally inhibits sleep by stimulating locomotor activity, in flies as well as mammals [35][36][37]41 . For example, compounds like amphetamine increase synaptic dopamine levels, which enhance fly activity and inhibit sleep 42 . However, a specific sleep-promoting subpopulation of DN1ps uses this neurotransmitter for the opposite purpose, namely to promote sleep.…”

Section: Discussionmentioning

confidence: 99%

Dopamine and GPCR-mediated modulation of DN1 clock neurons gates the circadian timing of sleep

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Richhariya

Herndon

et al. 2021

Preprint

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The metronome-like circadian regulation of sleep timing must still adapt to an uncertain environment. Recent studies in Drosophila indicate that neuromodulation not only plays a key role in clock neuron synchronization but also affects interactions between the clock network and brain sleep centers. We show here that the targets of neuromodulators, G-Protein Coupled Receptors (GPCRs), are highly enriched in the fly brain circadian clock network. Single cell sequencing indicates that they are not only differentially expressed but also define clock neuron identity. We generated a comprehensive guide library to mutagenize individual GPCRs in specific neurons and verified the strategy with a targeted sequencing approach. Combined with a behavioral screen, the mutagenesis strategy revealed a novel role of dopamine in sleep regulation by identifying two dopamine receptors and a clock neuron subpopulation that gate the timing of sleep.

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Section: Discussionmentioning

confidence: 99%

Dopamine and GPCR-mediated modulation of DN1 clock neurons gates the circadian timing of sleep

Schlichting

Richhariya

Herndon

et al. 2021

Preprint

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“…Observation of DAT fmn flies using the DAM system showed hyperactivity and reduced sleep, with hyperactivity exacerbated in the absence of light, e.g., at night, but also during the subjective daytime when housed in dark:dark conditions. Feeding DAT fmn flies methylphenidate [ 105 ] or amphetamine [ 111 ] rescued hyperactivity and sleep loss. This study highlights how disruption of Drosophila DAT , the orthologue of a well-known ADHD risk gene highly represented in human GWAS studies, recapitulates two common symptoms of ADHD observed in humans that can be rescued by psychostimulant drugs used to treat the symptoms of human ADHD.…”

Section: Studying the Therapeutic Use Of Psychostimulants With Drosophilamentioning

confidence: 99%

“…Tyrosine hydroxylase influences coloration of the flies’ cuticle, and loss of function mutants were named pale because of their discoloration [ 153 ]. pale mutants have reduced brain dopamine, are hypoactive [ 154 , 155 ], and do not exhibit a reduction in sleep after treatment with amphetamines [ 111 ]. Reducing dopamine also impacts response to cocaine, and flies fed 3-iodotyrosine (3IY), a competitive inhibitor of tyrosine hydroxylase show a reduction in cocaine-induced locomotion [ 58 ].…”

Section: Studying Psychostimulant Abuse With Drosophilamentioning

confidence: 99%

The Use of Drosophila to Understand Psychostimulant Responses

2022

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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.

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“…Using a Drosophila behavioral assay, we previously showed that flies respond to AMPH by increasing their locomotor activity (27,28) and decreasing their sleep (27) in a dopamine-dependent manner. Flies that carry a loss-of-function mutation in the gene encoding the Drosophila DAT homolog (dDAT fmn , henceforth referred to as DAT mutants) display no detectable DAT in the brain and exhibit heightened activity levels at baseline, consistent with increased levels of extracellular dopamine caused by the impairment of reuptake (27,29). Critically, our data showed that DAT mutant flies failed to increase their activity in response to AMPH (27), consistent with DAT being the principal molecular target for AMPH (4, 5).…”

Section: Introductionmentioning

confidence: 99%

“…Flies that carry a loss-of-function mutation in the gene encoding the Drosophila DAT homolog (dDAT fmn , henceforth referred to as DAT mutants) display no detectable DAT in the brain and exhibit heightened activity levels at baseline, consistent with increased levels of extracellular dopamine caused by the impairment of reuptake (27,29). Critically, our data showed that DAT mutant flies failed to increase their activity in response to AMPH (27), consistent with DAT being the principal molecular target for AMPH (4, 5). Taken together, these data demonstrate that we have developed a robust tool to associate molecular perturbations with the actions of AMPH in vivo.…”

Section: Introductionmentioning

confidence: 99%

Functional Genomic Analysis of Amphetamine Sensitivity in Drosophila

et al. 2022

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Abuse of psychostimulants, including amphetamines (AMPHs), is a major public health problem with profound psychiatric, medical, and psychosocial complications. The actions of these drugs at the dopamine transporter (DAT) play a critical role in their therapeutic efficacy as well as their liability for abuse and dependence. To date, however, the mechanisms that mediate these actions are not well-understood, and therapeutic interventions for AMPH abuse have been limited. Drug exposure can induce broad changes in gene expression that can contribute to neuroplasticity and effect long-lasting changes in neuronal function. Identifying genes and gene pathways perturbed by drug exposure is essential to our understanding of the molecular basis of drug addiction. In this study, we used Drosophila as a model to examine AMPH-induced transcriptional changes that are DAT-dependent, as those would be the most relevant to the stimulatory effects of the drug. Using this approach, we found genes involved in the control of mRNA translation to be significantly upregulated in response to AMPH in a DAT-dependent manner. To further prioritize genes for validation, we explored functional convergence between these genes and genes we identified in a genome-wide association study of AMPH sensitivity using the Drosophila Genetic Reference Panel. We validated a number of these genes by showing that they act specifically in dopamine neurons to mediate the behavioral effects of AMPH. Taken together, our data establish Drosophila as a powerful model that enables the integration of behavioral, genomic and transcriptomic data, followed by rapid gene validation, to investigate the molecular underpinnings of psychostimulant action.

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The Role of the Dopamine Transporter in the Effects of Amphetamine on Sleep and Sleep Architecture in Drosophila

Cited by 13 publications

References 89 publications

Dopamine and GPCR-mediated modulation of DN1 clock neurons gates the circadian timing of sleep

Dopamine and GPCR-mediated modulation of DN1 clock neurons gates the circadian timing of sleep

The Use of Drosophila to Understand Psychostimulant Responses

Functional Genomic Analysis of Amphetamine Sensitivity in Drosophila

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