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Differential Effects of Ethanol on γ-Aminobutyric Acid-A Receptor-Mediated Synaptic Currents in Congenic Strains of Inbred Long and Short-Sleep Mice
Background: Ethanol enhances γ‐aminobutyric acid (GABA)A receptor‐mediated responses in the brain, and this enhancement is greater in a mouse line behaviorally more sensitive to ethanol (long sleep) than in a line (short sleep) behaviorally less ethanol sensitive (assayed by loss of righting; sleep...
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Published in: | Alcoholism, clinical and experimental research clinical and experimental research, 2004-09, Vol.28 (9), p.1277-1283 |
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description | Background: Ethanol enhances γ‐aminobutyric acid (GABA)A receptor‐mediated responses in the brain, and this enhancement is greater in a mouse line behaviorally more sensitive to ethanol (long sleep) than in a line (short sleep) behaviorally less ethanol sensitive (assayed by loss of righting; sleep time). Quantitative trait locus (QTL) analysis of inbred long sleep (ILS) and inbred short sleep (ISS) phenotypes revealed four chromosomal regions (Lore1, Lore2, Lore4, and Lore5) that together account for approximately 50% of ethanol‐induced sleep‐time variance. Congenic strains were generated, each of which is homozygous for one of four ISS Lore QTLs on the ILS background. These congenic mouse strains are ideally suited for asking which QTL regions might correlate with other phenotypes that differ between ILS and ISS mice. Here we used the congenics to investigate altered GABAA responses to ethanol.
Methods: Evoked GABAA receptor‐mediated inhibitory postsynaptic currents (IPSCs) were measured by whole‐cell voltage‐clamp recording procedures in CA1 pyramidal neurons in hippocampal brain slices.
Results: GABAA IPSC responses in hippocampal brain slices from ILS mice were significantly enhanced by 80 mM ethanol, whereas those from ISS mice were not affected. ILS.Lore2S and ILS.Lore5S congenic strains were significantly enhanced by 80 mM ethanol, similar to the background (control) ILS mice. However, ethanol had no significant effect on GABAA responses in ILS.Lore1S and ILS.Lore4S congenic mice, similar to the ISS mice, thus reflecting the influence of ISS alleles on the ILS phenotype.
Conclusions: Our results suggest that alleles located in the Lore1 and Lore4 QTL regions confer ethanol sensitivity of GABAA receptor‐mediated IPSCs. Thus, for these QTLs, GABAA IPSCs may represent an endophenotype of sedative/hypnotic sensitivity to ethanol. Although the Lore2 and Lore5 QTL regions have a significant effect on sleep time, they do not play a significant role in the differential ethanol enhancement of GABAA IPSCs between ILS and ISS mice. |
doi_str_mv | 10.1097/01.ALC.0000139816.32706.F1 |
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Methods: Evoked GABAA receptor‐mediated inhibitory postsynaptic currents (IPSCs) were measured by whole‐cell voltage‐clamp recording procedures in CA1 pyramidal neurons in hippocampal brain slices.
Results: GABAA IPSC responses in hippocampal brain slices from ILS mice were significantly enhanced by 80 mM ethanol, whereas those from ISS mice were not affected. ILS.Lore2S and ILS.Lore5S congenic strains were significantly enhanced by 80 mM ethanol, similar to the background (control) ILS mice. However, ethanol had no significant effect on GABAA responses in ILS.Lore1S and ILS.Lore4S congenic mice, similar to the ISS mice, thus reflecting the influence of ISS alleles on the ILS phenotype.
Conclusions: Our results suggest that alleles located in the Lore1 and Lore4 QTL regions confer ethanol sensitivity of GABAA receptor‐mediated IPSCs. Thus, for these QTLs, GABAA IPSCs may represent an endophenotype of sedative/hypnotic sensitivity to ethanol. Although the Lore2 and Lore5 QTL regions have a significant effect on sleep time, they do not play a significant role in the differential ethanol enhancement of GABAA IPSCs between ILS and ISS mice.</description><identifier>ISSN: 0145-6008</identifier><identifier>EISSN: 1530-0277</identifier><identifier>DOI: 10.1097/01.ALC.0000139816.32706.F1</identifier><identifier>PMID: 15365296</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Ethanol ; Ethanol - pharmacology ; Ethanol, Quantitative Trait Loci ; Inhibitory Postsynaptic Current ; Loss of Righting Reflex ; Male ; Mice ; Mice, Congenic ; Quantitative Trait Loci ; Receptors, GABA-A - genetics ; Receptors, GABA-A - physiology ; Synapses - drug effects ; Synapses - genetics ; Synapses - physiology ; Synaptic Transmission - drug effects ; Synaptic Transmission - genetics ; Synaptic Transmission - physiology ; γ-Aminobutyric Acid</subject><ispartof>Alcoholism, clinical and experimental research, 2004-09, Vol.28 (9), p.1277-1283</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4107-d47cdd96b154a9f929f018c9db32f0b8654740362b2da3a14e8db4ff355571e73</citedby><cites>FETCH-LOGICAL-c4107-d47cdd96b154a9f929f018c9db32f0b8654740362b2da3a14e8db4ff355571e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15365296$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Proctor, William R.</creatorcontrib><creatorcontrib>Wu, Peter H.</creatorcontrib><creatorcontrib>Bennett, Beth</creatorcontrib><creatorcontrib>Johnson, Thomas E.</creatorcontrib><title>Differential Effects of Ethanol on γ-Aminobutyric Acid-A Receptor-Mediated Synaptic Currents in Congenic Strains of Inbred Long and Short-Sleep Mice</title><title>Alcoholism, clinical and experimental research</title><addtitle>Alcohol Clin Exp Res</addtitle><description>Background: Ethanol enhances γ‐aminobutyric acid (GABA)A receptor‐mediated responses in the brain, and this enhancement is greater in a mouse line behaviorally more sensitive to ethanol (long sleep) than in a line (short sleep) behaviorally less ethanol sensitive (assayed by loss of righting; sleep time). Quantitative trait locus (QTL) analysis of inbred long sleep (ILS) and inbred short sleep (ISS) phenotypes revealed four chromosomal regions (Lore1, Lore2, Lore4, and Lore5) that together account for approximately 50% of ethanol‐induced sleep‐time variance. Congenic strains were generated, each of which is homozygous for one of four ISS Lore QTLs on the ILS background. These congenic mouse strains are ideally suited for asking which QTL regions might correlate with other phenotypes that differ between ILS and ISS mice. Here we used the congenics to investigate altered GABAA responses to ethanol.
Methods: Evoked GABAA receptor‐mediated inhibitory postsynaptic currents (IPSCs) were measured by whole‐cell voltage‐clamp recording procedures in CA1 pyramidal neurons in hippocampal brain slices.
Results: GABAA IPSC responses in hippocampal brain slices from ILS mice were significantly enhanced by 80 mM ethanol, whereas those from ISS mice were not affected. ILS.Lore2S and ILS.Lore5S congenic strains were significantly enhanced by 80 mM ethanol, similar to the background (control) ILS mice. However, ethanol had no significant effect on GABAA responses in ILS.Lore1S and ILS.Lore4S congenic mice, similar to the ISS mice, thus reflecting the influence of ISS alleles on the ILS phenotype.
Conclusions: Our results suggest that alleles located in the Lore1 and Lore4 QTL regions confer ethanol sensitivity of GABAA receptor‐mediated IPSCs. Thus, for these QTLs, GABAA IPSCs may represent an endophenotype of sedative/hypnotic sensitivity to ethanol. Although the Lore2 and Lore5 QTL regions have a significant effect on sleep time, they do not play a significant role in the differential ethanol enhancement of GABAA IPSCs between ILS and ISS mice.</description><subject>Animals</subject><subject>Ethanol</subject><subject>Ethanol - pharmacology</subject><subject>Ethanol, Quantitative Trait Loci</subject><subject>Inhibitory Postsynaptic Current</subject><subject>Loss of Righting Reflex</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Congenic</subject><subject>Quantitative Trait Loci</subject><subject>Receptors, GABA-A - genetics</subject><subject>Receptors, GABA-A - physiology</subject><subject>Synapses - drug effects</subject><subject>Synapses - genetics</subject><subject>Synapses - physiology</subject><subject>Synaptic Transmission - drug effects</subject><subject>Synaptic Transmission - genetics</subject><subject>Synaptic Transmission - physiology</subject><subject>γ-Aminobutyric Acid</subject><issn>0145-6008</issn><issn>1530-0277</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqVkcFu0zAchyMEYmXwCsjiwC3FjmM74USUtd2gA2kdgpvlxDYzpHZmO2J9EJ6E9-CZcNeKnfHFlv39vr_kX5a9QnCOYM3eQDRv1u0cpoVwXSE6xwWDdL5Ej7IZIhjmsGDscTaDqCQ5hbA6yZ6F8D3xZUXp0-wkQZQUNZ1lv86M1sorG40YwCKd-xiA02ARb4R1A3AW_PmdN1tjXTfFnTc9aHoj8wZcqV6N0fn8UkkjopJgs7NijIloJ79XBmAsaJ39pmy63EQvjL2XX9jOJ36dnoCwKXjjfMw3g1IjuDS9ep490WII6sVxP80-LxfX7Xm-_rS6aJt13pcIslyWrJeyph0ipah1XdQaoqqvZYcLDbuKkpKVENOiK6TAApWqkl2pNSaEMKQYPs1eH7yjd7eTCpFvTejVMAir3BQ4pem_CoQS-PYA9t6F4JXmozdb4XccQb4vhUPEUyn8oRR-Xwpf7sMvj1OmbqvkQ_TYQgLeHYCfZlC7_1Dzpl1coVR2UuQHhQlR3f1TCP-DU4YZ4V8-rvj7a8Q-nH0lfIX_Ajb-q3E</recordid><startdate>200409</startdate><enddate>200409</enddate><creator>Proctor, William R.</creator><creator>Wu, Peter H.</creator><creator>Bennett, Beth</creator><creator>Johnson, Thomas E.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200409</creationdate><title>Differential Effects of Ethanol on γ-Aminobutyric Acid-A Receptor-Mediated Synaptic Currents in Congenic Strains of Inbred Long and Short-Sleep Mice</title><author>Proctor, William R. ; Wu, Peter H. ; Bennett, Beth ; Johnson, Thomas E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4107-d47cdd96b154a9f929f018c9db32f0b8654740362b2da3a14e8db4ff355571e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Ethanol</topic><topic>Ethanol - pharmacology</topic><topic>Ethanol, Quantitative Trait Loci</topic><topic>Inhibitory Postsynaptic Current</topic><topic>Loss of Righting Reflex</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Congenic</topic><topic>Quantitative Trait Loci</topic><topic>Receptors, GABA-A - genetics</topic><topic>Receptors, GABA-A - physiology</topic><topic>Synapses - drug effects</topic><topic>Synapses - genetics</topic><topic>Synapses - physiology</topic><topic>Synaptic Transmission - drug effects</topic><topic>Synaptic Transmission - genetics</topic><topic>Synaptic Transmission - physiology</topic><topic>γ-Aminobutyric Acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Proctor, William R.</creatorcontrib><creatorcontrib>Wu, Peter H.</creatorcontrib><creatorcontrib>Bennett, Beth</creatorcontrib><creatorcontrib>Johnson, Thomas E.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Alcoholism, clinical and experimental research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Proctor, William R.</au><au>Wu, Peter H.</au><au>Bennett, Beth</au><au>Johnson, Thomas E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential Effects of Ethanol on γ-Aminobutyric Acid-A Receptor-Mediated Synaptic Currents in Congenic Strains of Inbred Long and Short-Sleep Mice</atitle><jtitle>Alcoholism, clinical and experimental research</jtitle><addtitle>Alcohol Clin Exp Res</addtitle><date>2004-09</date><risdate>2004</risdate><volume>28</volume><issue>9</issue><spage>1277</spage><epage>1283</epage><pages>1277-1283</pages><issn>0145-6008</issn><eissn>1530-0277</eissn><abstract>Background: Ethanol enhances γ‐aminobutyric acid (GABA)A receptor‐mediated responses in the brain, and this enhancement is greater in a mouse line behaviorally more sensitive to ethanol (long sleep) than in a line (short sleep) behaviorally less ethanol sensitive (assayed by loss of righting; sleep time). Quantitative trait locus (QTL) analysis of inbred long sleep (ILS) and inbred short sleep (ISS) phenotypes revealed four chromosomal regions (Lore1, Lore2, Lore4, and Lore5) that together account for approximately 50% of ethanol‐induced sleep‐time variance. Congenic strains were generated, each of which is homozygous for one of four ISS Lore QTLs on the ILS background. These congenic mouse strains are ideally suited for asking which QTL regions might correlate with other phenotypes that differ between ILS and ISS mice. Here we used the congenics to investigate altered GABAA responses to ethanol.
Methods: Evoked GABAA receptor‐mediated inhibitory postsynaptic currents (IPSCs) were measured by whole‐cell voltage‐clamp recording procedures in CA1 pyramidal neurons in hippocampal brain slices.
Results: GABAA IPSC responses in hippocampal brain slices from ILS mice were significantly enhanced by 80 mM ethanol, whereas those from ISS mice were not affected. ILS.Lore2S and ILS.Lore5S congenic strains were significantly enhanced by 80 mM ethanol, similar to the background (control) ILS mice. However, ethanol had no significant effect on GABAA responses in ILS.Lore1S and ILS.Lore4S congenic mice, similar to the ISS mice, thus reflecting the influence of ISS alleles on the ILS phenotype.
Conclusions: Our results suggest that alleles located in the Lore1 and Lore4 QTL regions confer ethanol sensitivity of GABAA receptor‐mediated IPSCs. Thus, for these QTLs, GABAA IPSCs may represent an endophenotype of sedative/hypnotic sensitivity to ethanol. Although the Lore2 and Lore5 QTL regions have a significant effect on sleep time, they do not play a significant role in the differential ethanol enhancement of GABAA IPSCs between ILS and ISS mice.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>15365296</pmid><doi>10.1097/01.ALC.0000139816.32706.F1</doi><tpages>7</tpages></addata></record> |
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subjects | Animals Ethanol Ethanol - pharmacology Ethanol, Quantitative Trait Loci Inhibitory Postsynaptic Current Loss of Righting Reflex Male Mice Mice, Congenic Quantitative Trait Loci Receptors, GABA-A - genetics Receptors, GABA-A - physiology Synapses - drug effects Synapses - genetics Synapses - physiology Synaptic Transmission - drug effects Synaptic Transmission - genetics Synaptic Transmission - physiology γ-Aminobutyric Acid |
title | Differential Effects of Ethanol on γ-Aminobutyric Acid-A Receptor-Mediated Synaptic Currents in Congenic Strains of Inbred Long and Short-Sleep Mice |
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