Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats
Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positi...
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| Veröffentlicht in: | Neuropsychopharmacology (New York, N.Y.) N.Y.), 2013-11, Vol.38 (12), p.2401-2408 |
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| creator | FOX, Steven V GOTTER, Anthony L LIHANG YAO BOWLBY, Mark R KUDUK, Scott D COLEMAN, Paul J HARGREAVES, Richard WINROW, Christopher J RENGER, John J TYE, Spencer J GARSON, Susan L SAVITZ, Alan T USLANER, Jason M BRUNNER, Joseph I TANNENBAUM, Pamela L MCDONALD, Terrence P HODGSON, Robert |
| description | Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague-Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep. |
| doi_str_mv | 10.1038/npp.2013.139 |
| format | Article |
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DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague-Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep.</description><identifier>ISSN: 0893-133X</identifier><identifier>EISSN: 1740-634X</identifier><identifier>DOI: 10.1038/npp.2013.139</identifier><identifier>PMID: 23722242</identifier><identifier>CODEN: NEROEW</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing Group</publisher><subject><![CDATA[Animals ; Azabicyclo Compounds - administration & dosage ; Azabicyclo Compounds - pharmacology ; Biological and medical sciences ; Brain - drug effects ; Brain - physiology ; Electroencephalography ; Eszopiclone ; Eye movements ; Foxes ; GABA-A Receptor Agonists - administration & dosage ; GABA-A Receptor Agonists - pharmacology ; Insomnia ; Laboratory animals ; Male ; Medical sciences ; Nervous system ; Neurosciences ; Orexin Receptor Antagonists ; Original ; Piperazines - administration & dosage ; Piperazines - pharmacology ; Piperidines - administration & dosage ; Piperidines - pharmacology ; Pyridines - administration & dosage ; Pyridines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Sleep ; Sleep Stages - drug effects ; Sleep Stages - physiology ; Triazoles - administration & dosage ; Triazoles - pharmacology]]></subject><ispartof>Neuropsychopharmacology (New York, N.Y.), 2013-11, Vol.38 (12), p.2401-2408</ispartof><rights>2014 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Nov 2013</rights><rights>Copyright © 2013 American College of Neuropsychopharmacology 2013 American College of Neuropsychopharmacology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3539-b648451edd66d01aabfff604af1954e8267bb6bd17f78fd29dd40e8964fffdbe3</citedby><cites>FETCH-LOGICAL-c3539-b648451edd66d01aabfff604af1954e8267bb6bd17f78fd29dd40e8964fffdbe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799059/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799059/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27868404$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23722242$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>FOX, Steven V</creatorcontrib><creatorcontrib>GOTTER, Anthony L</creatorcontrib><creatorcontrib>LIHANG YAO</creatorcontrib><creatorcontrib>BOWLBY, Mark R</creatorcontrib><creatorcontrib>KUDUK, Scott D</creatorcontrib><creatorcontrib>COLEMAN, Paul J</creatorcontrib><creatorcontrib>HARGREAVES, Richard</creatorcontrib><creatorcontrib>WINROW, Christopher J</creatorcontrib><creatorcontrib>RENGER, John J</creatorcontrib><creatorcontrib>TYE, Spencer J</creatorcontrib><creatorcontrib>GARSON, Susan L</creatorcontrib><creatorcontrib>SAVITZ, Alan T</creatorcontrib><creatorcontrib>USLANER, Jason M</creatorcontrib><creatorcontrib>BRUNNER, Joseph I</creatorcontrib><creatorcontrib>TANNENBAUM, Pamela L</creatorcontrib><creatorcontrib>MCDONALD, Terrence P</creatorcontrib><creatorcontrib>HODGSON, Robert</creatorcontrib><title>Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats</title><title>Neuropsychopharmacology (New York, N.Y.)</title><addtitle>Neuropsychopharmacology</addtitle><description>Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>FOX, Steven V</au><au>GOTTER, Anthony L</au><au>LIHANG YAO</au><au>BOWLBY, Mark R</au><au>KUDUK, Scott D</au><au>COLEMAN, Paul J</au><au>HARGREAVES, Richard</au><au>WINROW, Christopher J</au><au>RENGER, John J</au><au>TYE, Spencer J</au><au>GARSON, Susan L</au><au>SAVITZ, Alan T</au><au>USLANER, Jason M</au><au>BRUNNER, Joseph I</au><au>TANNENBAUM, Pamela L</au><au>MCDONALD, Terrence P</au><au>HODGSON, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats</atitle><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle><addtitle>Neuropsychopharmacology</addtitle><date>2013-11</date><risdate>2013</risdate><volume>38</volume><issue>12</issue><spage>2401</spage><epage>2408</epage><pages>2401-2408</pages><issn>0893-133X</issn><eissn>1740-634X</eissn><coden>NEROEW</coden><abstract>Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague-Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep.</abstract><cop>Basingstoke</cop><pub>Nature Publishing Group</pub><pmid>23722242</pmid><doi>10.1038/npp.2013.139</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0893-133X |
| ispartof | Neuropsychopharmacology (New York, N.Y.), 2013-11, Vol.38 (12), p.2401-2408 |
| issn | 0893-133X 1740-634X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3799059 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | Animals Azabicyclo Compounds - administration & dosage Azabicyclo Compounds - pharmacology Biological and medical sciences Brain - drug effects Brain - physiology Electroencephalography Eszopiclone Eye movements Foxes GABA-A Receptor Agonists - administration & dosage GABA-A Receptor Agonists - pharmacology Insomnia Laboratory animals Male Medical sciences Nervous system Neurosciences Orexin Receptor Antagonists Original Piperazines - administration & dosage Piperazines - pharmacology Piperidines - administration & dosage Piperidines - pharmacology Pyridines - administration & dosage Pyridines - pharmacology Rats Rats, Sprague-Dawley Sleep Sleep Stages - drug effects Sleep Stages - physiology Triazoles - administration & dosage Triazoles - pharmacology |
| title | Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T01%3A15%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Quantitative%20Electroencephalography%20Within%20Sleep/Wake%20States%20Differentiates%20GABAA%20Modulators%20Eszopiclone%20and%20Zolpidem%20From%20Dual%20Orexin%20Receptor%20Antagonists%20in%20Rats&rft.jtitle=Neuropsychopharmacology%20(New%20York,%20N.Y.)&rft.au=FOX,%20Steven%20V&rft.date=2013-11&rft.volume=38&rft.issue=12&rft.spage=2401&rft.epage=2408&rft.pages=2401-2408&rft.issn=0893-133X&rft.eissn=1740-634X&rft.coden=NEROEW&rft_id=info:doi/10.1038/npp.2013.139&rft_dat=%3Cproquest_pubme%3E3099752061%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1442194299&rft_id=info:pmid/23722242&rfr_iscdi=true |