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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice</title>
<author><name sortKey="Okuro, Masashi" sort="Okuro, Masashi" uniqKey="Okuro M" first="Masashi" last="Okuro">Masashi Okuro</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fujiki, Nobuhiro" sort="Fujiki, Nobuhiro" uniqKey="Fujiki N" first="Nobuhiro" last="Fujiki">Nobuhiro Fujiki</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kotorii, Nozomu" sort="Kotorii, Nozomu" uniqKey="Kotorii N" first="Nozomu" last="Kotorii">Nozomu Kotorii</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ishimaru, Yuji" sort="Ishimaru, Yuji" uniqKey="Ishimaru Y" first="Yuji" last="Ishimaru">Yuji Ishimaru</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sokoloff, Pierre" sort="Sokoloff, Pierre" uniqKey="Sokoloff P" first="Pierre" last="Sokoloff">Pierre Sokoloff</name>
<affiliation><nlm:aff id="aff2">Pierre Fabre Research Institute, Neurology-Psychiatry Department, Castres, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nishino, Seiji" sort="Nishino, Seiji" uniqKey="Nishino S" first="Seiji" last="Nishino">Seiji Nishino</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">20614853</idno>
<idno type="pmc">2894435</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894435</idno>
<idno type="RBID">PMC:2894435</idno>
<date when="2010">2010</date>
<idno type="wicri:Area/Pmc/Corpus">000557</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000557</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice</title>
<author><name sortKey="Okuro, Masashi" sort="Okuro, Masashi" uniqKey="Okuro M" first="Masashi" last="Okuro">Masashi Okuro</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fujiki, Nobuhiro" sort="Fujiki, Nobuhiro" uniqKey="Fujiki N" first="Nobuhiro" last="Fujiki">Nobuhiro Fujiki</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kotorii, Nozomu" sort="Kotorii, Nozomu" uniqKey="Kotorii N" first="Nozomu" last="Kotorii">Nozomu Kotorii</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ishimaru, Yuji" sort="Ishimaru, Yuji" uniqKey="Ishimaru Y" first="Yuji" last="Ishimaru">Yuji Ishimaru</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sokoloff, Pierre" sort="Sokoloff, Pierre" uniqKey="Sokoloff P" first="Pierre" last="Sokoloff">Pierre Sokoloff</name>
<affiliation><nlm:aff id="aff2">Pierre Fabre Research Institute, Neurology-Psychiatry Department, Castres, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nishino, Seiji" sort="Nishino, Seiji" uniqKey="Nishino S" first="Seiji" last="Nishino">Seiji Nishino</name>
<affiliation><nlm:aff id="aff1">Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Sleep</title>
<idno type="ISSN">0161-8105</idno>
<idno type="eISSN">1550-9109</idno>
<imprint><date when="2010">2010</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Study Objective:</title>
<p>Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine.</p>
</sec>
<sec><title>Design:</title>
<p>We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle.</p>
</sec>
<sec><title>Results:</title>
<p>Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did.</p>
</sec>
<sec><title>Conclusions:</title>
<p>Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.</p>
</sec>
<sec><title>Citation:</title>
<p>Okuro M; Fujiki N; Kotorii N; Ishimaru Y; Sokoloff P; Nishino S. Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice. <italic>SLEEP</italic>
2010;33(7):930-942.</p>
</sec>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Sleep</journal-id>
<journal-id journal-id-type="publisher-id">Sleep</journal-id>
<journal-title-group><journal-title>Sleep</journal-title>
</journal-title-group>
<issn pub-type="ppub">0161-8105</issn>
<issn pub-type="epub">1550-9109</issn>
<publisher><publisher-name>Associated Professional Sleep Societies, LLC</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">20614853</article-id>
<article-id pub-id-type="pmc">2894435</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Effects of Stimulants on Narcoleptic Mice</subject>
</subj-group>
</article-categories>
<title-group><article-title>Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Okuro</surname>
<given-names>Masashi</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fujiki</surname>
<given-names>Nobuhiro</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kotorii</surname>
<given-names>Nozomu</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ishimaru</surname>
<given-names>Yuji</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sokoloff</surname>
<given-names>Pierre</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nishino</surname>
<given-names>Seiji</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"></xref>
</contrib>
<aff id="aff1"><label>1</label>
Sleep and Circadian Neurobiology Laboratory, Stanford University, Stanford University Center for Narcolepsy, Palo Alto, CA</aff>
<aff id="aff2"><label>2</label>
Pierre Fabre Research Institute, Neurology-Psychiatry Department, Castres, France</aff>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to: Seiji Nishino MD, PhD,
<addr-line>Sleep and Circadian Neurobiology Laboratory, Stanford University, MSLS Bldg Room P213, 1201 Welch Road, Palo Alto, CA 94304</addr-line>
<phone>(650) 723-3724</phone>
<fax>(650) 723-5873</fax>
<email>nishino@stanford.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>1</day>
<month>7</month>
<year>2010</year>
</pub-date>
<volume>33</volume>
<issue>7</issue>
<fpage>930</fpage>
<lpage>942</lpage>
<history><date date-type="received"><month>9</month>
<year>2009</year>
</date>
<date date-type="rev-recd"><month>2</month>
<year>2010</year>
</date>
<date date-type="accepted"><month>2</month>
<year>2010</year>
</date>
</history>
<permissions><copyright-statement>© 2010 Associated Professional Sleep Societies, LLC.</copyright-statement>
</permissions>
<abstract><sec><title>Study Objective:</title>
<p>Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine.</p>
</sec>
<sec><title>Design:</title>
<p>We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle.</p>
</sec>
<sec><title>Results:</title>
<p>Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did.</p>
</sec>
<sec><title>Conclusions:</title>
<p>Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.</p>
</sec>
<sec><title>Citation:</title>
<p>Okuro M; Fujiki N; Kotorii N; Ishimaru Y; Sokoloff P; Nishino S. Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice. <italic>SLEEP</italic>
2010;33(7):930-942.</p>
</sec>
</abstract>
<kwd-group><kwd>Narcolepsy</kwd>
<kwd>caffeine</kwd>
<kwd>paraxanthine</kwd>
<kwd>cataplexy</kwd>
<kwd>modafinil</kwd>
<kwd>mice</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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