Caffeine promotes wakefulness via dopamine signaling in Drosophila

Nall, Aleksandra H.; Shakhmantsir, Iryna; Cichewicz, Karol; Birman, Serge; Hirsh, Jay; Sehgal, Amita

doi:10.1038/srep20938

Cited by 70 publications

(77 citation statements)

References 59 publications

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“…This is relevant when considering the recent findings showing that caffeine also stimulates dopaminergic neurons in a direct and dose-dependent manner [30]. On the other hand, microdialysis studies showed that dopamine levels rise in the brains of rats after an acute caffeine administration, suggesting a direct effect of the ergogenic compound on dopamine synthesis.…”

mentioning

confidence: 84%

Potential pitfalls when investigating the ergogenic effects of caffeine in mice

Solano¹,

Scheffer²,

Alves³

et al. 2017

J Syst Integr Neurosci

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Caffeine (1,3,7-trimethylxantine) is the most commonly consumed social drug in western society for increased physical and cognitive performance [1][2][3][4][5], and it is the main ergogenic resource used by athletes [6]. Initially controversial, caffeine was banned by the International Olympic Committee from 1980-2003 [1,6,7], but then in 2004 its use was approved by the World Anti-doping Agency (WADA), and later this year by the U.S. Anti-doping Agency (USADA; 2016). However, caffeine has remained on the lists of monitored substances of these anti-doping agencies. Caffeine is rapidly and completely absorbed by the gastrointestinal tract and is readily distributed throughout all tissues of the body, including muscles and the central nervous system (CNS), which are believed to be the main recipients of caffeine's ergogenic effects [2,14]. Ergogenic doses of caffeine ranging from 3 to 9 mg/kg body mass [6] appear to have no adverse effects. A moderate oral dose of 6 mg/ kg body mass, which elicits peak plasma levels of about 60 µmol/L concentrations after 30 to 60 min, with half-life for elimination range between 2.5-10 h, is known to enhance physical and cognitive performance [5,6,10,14,15]. Blood levels of 1 -2 mmol/L are known to be toxic and even lethal [14], and have been associated with suicides [16]. Caffeine's molecular mechanisms for increasing physical performance are still virtually undefined. However, due to its ability to cross the blood-brain barrier at blood concentrations generated by a moderate ergogenic dose, and because of its properties as a stimulant psychotropic drug [15,17], mechanisms involving metabolic and central effects have been proposed.Metabolic effects of caffeine have been mainly related to the enhancement of lipolysis, fatty acid oxidation and energy expenditure via the stimulation of the sympathetic nervous system [18,19] and a sequential sparing of muscle glycogen [20]. However, the main pharmacological effects of caffeine appear to be mediated via the CNS where caffeine counterbalances the inhibitory neuromodulation of adenosine in order to induce effects on both the CNS and peripheral nervous system to reduce pain and exertion perception [21], to improve motor recruitment [22] and to increase excitation-contraction coupling [23,24].Caffeine is a non-selective competitive adenosine receptor antagonist (A 1 R and A 2 AR subtypes) that increases neurotransmission via dopamine D 2 receptors (D 2 R) [25,26]. The striatum expresses high levels of A 2 AR where they are co-expressed with postsynaptic D 2 R, forming A 2 AR-D 2 R heterodimers [25]. In this scenario, caffeine fails to be ergogenic in the mouse lacking A 2 AR [27], or in wild type rats treated with the selective A 2 AR agonist 5'-N-ethylcarboxamidoadenosine (NECA) [26], which denotes the participation of these receptors in caffeine's central-mediated ergogenic effects.When designing experimental models to better define the molecular mechanisms involved in the enhanced capacity of caffeine to positively modulate physical ...

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mentioning

confidence: 84%

Potential pitfalls when investigating the ergogenic effects of caffeine in mice

Solano¹,

Scheffer²,

Alves³

et al. 2017

J Syst Integr Neurosci

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“…Moreover, other targets of caffeine action have probably not been accorded the attention they deserve. Caffeine has very robust wake-promoting effects in Drosophila, and these are not mediated by the only known adenosine receptor in flies but rather by dopamine signaling (Andretic et al 2008b;Wu et al 2009;Nall et al 2016).…”

Section: Sleep and Cellular Metabolismmentioning

confidence: 99%

Molecular Mechanisms of Sleep Homeostasis in Flies and Mammals

Allada¹,

Cirelli

Sehgal

2017

Cold Spring Harb Perspect Biol

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136

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“…Dopamine (DA) is a conserved neurotransmitter responsible for controlling voluntary movement (Riemensperger et al 2011), arousal (Friggi-Grelin, Coulom, et al 2003; Lebestky et al 2009), sleep (Nall et al 2016; Ueno et al 2012), male courtship behaviors (Liu et al 2008), learning and reward in Drosophila (Owald & Waddell 2015; Swinderen & Andretic 2011) and vertebrates (reviewed in (Iversen & Iversen 2007)). Its importance for humans is manifested in pathological conditions such as Parkinson’s disease (PD), caused by death of DA neurons via only partly understood mechanisms (Brichta & Greengard 2014; Kalia & Lang 2015).…”

Section: Introductionmentioning

confidence: 99%

A new brain dopamine‐deficient Drosophila and its pharmacological and genetic rescue

Cichewicz

Garren

Adiele

et al. 2016

Genes Brain and Behavior

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Dopamine (DA) is a neurotransmitter with conserved behavioral roles between invertebrate and vertebrate animals. In addition to its neural functions, in insects DA is a critical substrate for cuticle pigmentation and hardening. Drosophila tyrosine hydroxylase (DTH) is the rate limiting enzyme for DA biosynthesis. Viable brain DA deficient flies were previously generated using tissue selective GAL4-UAS binary expression rescue of a DTH null mutation and these flies show specific behavioral impairments. To circumvent the limitations of rescue via binary expression, here we achieve rescue utilizing genomically integrated mutant DTH. As expected, our DA deficient flies have no detectable DTH or DA in the brain, and show reduced locomotor activity. This deficit can be rescued by L-DOPA/carbidopa feeding, similar to human Parkinson’s disease treatment. Genetic rescue via GAL4/UAS-DTH was also successful, although this required the generation of a new UAS-DTH1 transgene devoid of most untranslated regions, since existing UAS-DTH transgenes express in the brain without a Gal4 driver via endogenous regulatory elements. A surprising finding of our newly constructed UAS-DTH1m is that it expresses DTH at an undetectable level when regulated by dopaminergic GAL4 drivers even when fully rescuing DA, indicating that DTH immunostaining is not necessarily a valid marker for DA expression. This finding necessitated optimizing DA immunohistochemistry, revealing details of DA innervation to the mushroom body and the central complex. When DA rescue is limited to specific DA neurons, DA does not diffuse beyond the DTH-expressing terminals, such that DA signaling can be limited to very specific brain regions.

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Caffeine promotes wakefulness via dopamine signaling in Drosophila

Cited by 70 publications

References 59 publications

Potential pitfalls when investigating the ergogenic effects of caffeine in mice

Potential pitfalls when investigating the ergogenic effects of caffeine in mice

Molecular Mechanisms of Sleep Homeostasis in Flies and Mammals

A new brain dopamine‐deficient Drosophila and its pharmacological and genetic rescue

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