Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice

Okuro, Masashi; Fujiki, Nobuhiro; Kotorii, Nozomu; Ishimaru, Yuji; Sokoloff, Pierre; Nishino, Seiji

doi:10.1093/sleep/33.7.930

Cited by 58 publications

(49 citation statements)

References 21 publications

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“…Nonetheless, 42% of our non-low consumer group had detectable levels of caffeine 372 and/or paraxanthine in their saliva. (Paraxanthine is the major metabolite of caffeine in 373 humans and is also psychoactive (Okuro et al 2010).) Perhaps at least some of theseindividuals were in fact consuming sufficient caffeine in their diet to cause them to 375 experience significant adverse effects when caffeine was withdrawn.…”

mentioning

confidence: 99%

Faster but not smarter: effects of caffeine and caffeine withdrawal on alertness and performance

et al. 2012

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms these measures in medium-high-high consumers, but, apart from decreasing sleepiness, had 40 little effect on them in non-low consumers. The failure of caffeine to increase mental 41 alertness and improve mental performance in non-low consumers was related to a substantial 42 caffeine-induced increase in anxiety/jitteriness that offset the benefit of decreased sleepiness. 43Caffeine enhanced physical performance (faster tapping speed and faster simple and choice 44 reaction times) in both medium-high and non-low consumers. Conclusions While caffeine 45 benefits motor performance and tolerance develops to its tendency to increase 46 anxiety/jitteriness, tolerance to its effects on sleepiness means that frequent consumption fails 47 to enhance mental alertness and mental performance. 48 49

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confidence: 99%

Faster but not smarter: effects of caffeine and caffeine withdrawal on alertness and performance

et al. 2012

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“…Paraxanthine has also less anxiogenic activity and toxicity in rodents than caffeine. [39][40][41] In a recent study, we demonstrated that, in rats, paraxanthine produces a much stronger locomotor-activating effect than caffeine, theophylline or theobromine. The order of efficacies being paraxanthine > caffeine = theophylline > theobromine.…”

Section: Ferré Et Almentioning

confidence: 96%

Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission

Ferré

Orrù

Guitart

2013

Journal of Caffeine Research

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Recent results obtained in our laboratory indicate that paraxanthine, the main metabolite of caffeine in humans, produces a significantly stronger locomotor activation in rats than caffeine. Furthermore, paraxanthine also produced a very significant increase in striatal extracellular concentrations of dopamine. Searching for an additional mechanism other than adenosine antagonism responsible for these psychostimulant-like effects, it was found that paraxanthine, but not caffeine, inhibited cGMP-preferring phosphodiesterases. Furthermore, interrupting nitric oxide neurotransmision (inhibiting nitric oxide synthase) significantly decreased both the locomotor-activating and the dopamine-releasing effects of paraxanthine. These results open up some obvious questions about the role of paraxanthine in the pharmacological effects of caffeine. Nitric Oxide Neurotransmission S ince nitric oxide (NO) was first identified as an endothelial-derived relaxation factor in peripheral blood vessels, 1 its role as a biological messenger, and particularly as a neurotransmitter has been well established. Thus, NO fits within the broad definition of neurotransmitter coined by Snyder and Ferris 2-that is, ''a molecule, released by neu-rons or glia, which physiologically influences the electro-chemical state of adjacent cells''. Because NO cannot be stored in cells, it depends on new synthesis to exert its functional properties. NO is produced by NO synthase (NOS), which generates NO from the amino acid L-arginine. NOS is a complex heterodimeric protein that is found constitu-tively in two isoforms, neuronal, and endothelial NO (nNOS and eNOS, respectively). A third inducible form (iNOS) can be expressed by macrophages and microglia upon immunological challenge. 3 nNOS is the most abundant isoform found in the brain and the one responsible for NO production in neurons and its enzyme activity is regulated by Ca 2+ and calmodulin. 4 The subcellular localization of nNOS is mediated by its ability to bind to adapter proteins. For instance, through its PDZ domain it binds to PSD95 (post-synaptic density protein 95), which links nNOS to the N-methyl-D-aspartate (NMDA) receptor and accounts for the efficient activation of nNOS by NMDA receptor stimulation. 5 In the central nervous system, nNOS is synthesized by specific populations of neurons (NO neurons). In the cerebellum, nNOS is expressed by local stellate, basket and granule, but not Purkinje cells, although Purkinje are abundant in NO receptors. 6 In the brainstem, nNOS is produced by cholinergic neurons of the ascending reticular activating system. 6 These cells originate in the latero-dorsal and pedunculo-pontine nu-clei (LDT and PPT nuclei), which through a dorsal tegmental pathway project heavily to the thalamus, to the midline-intralaminar and reticular nuclei, which transmit the activity of the ascending reticular activating system to extensive areas of the cerebral cortex (for a recent review see ref. 7). Through a ventral tegmental pathway the cholinergic cells of the LDT and P...

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“…Moreover, administration of caffeine and other stimulants in orexin/ataxin-3 transgenic narcoleptic mice induced an increase in motor activity but the effects on neuropathology remain to be investigated (Okuro et al, 2010) and should be further investigated in MJD models.…”

Section: Neuroprotectionmentioning

confidence: 99%

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

Nóbrega¹,

Almeida²

2012

Spinocerebellar Ataxia

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Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice

Abstract: Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.

Cited by 58 publications

References 21 publications

Faster but not smarter: effects of caffeine and caffeine withdrawal on alertness and performance

Faster but not smarter: effects of caffeine and caffeine withdrawal on alertness and performance

Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

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