Loading…

The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole

The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a...

Full description

Saved in:
Bibliographic Details
Published in:The European journal of neuroscience 2006-07, Vol.24 (1), p.167-174
Main Authors: Groves, James O, Guscott, Martin R, Hallett, David J, Rosahl, Thomas W, Pike, Andrew, Davies, Amy, Wafford, Keith A, Reynolds, David S
Format: Article
Language:English
Subjects:
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites
container_end_page 174
container_issue 1
container_start_page 167
container_title The European journal of neuroscience
container_volume 24
creator Groves, James O
Guscott, Martin R
Hallett, David J
Rosahl, Thomas W
Pike, Andrew
Davies, Amy
Wafford, Keith A
Reynolds, David S
description The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive beta2 subunit (beta2N265S) to determine the role of this subunit in mediating the sedative and anticonvulsive effects of loreclezole. Sedation was assessed by measuring spontaneous locomotor activity and beam walking performance, and anticonvulsant efficacy was determined by pentylenetetrazole (PTZ) and amygdala kindling-induced seizures. The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance. However, loreclezole also failed to provide significant protection against PTZ-induced seizures in the beta2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in beta2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors.
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_68707330</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>68707330</sourcerecordid><originalsourceid>FETCH-LOGICAL-p544-6abcd8180cb4810f919aba16315fc897057cfd5335834324546ba668c1c3818d3</originalsourceid><addsrcrecordid>eNo1kD1PwzAQhjOAaCn8BeSJLZIdf8QZSwUFqRJLB7bIds5g5NohdirBr8cVZbqv931OdxfVEnec1pKIt0V1ndInxlgKxq-qBRFSNpiwZXXcfwCaogcULdquH9YasmpQmvUcXK5NDFm54MI7msDAmOOUkAvoAINT-dTOxa9CdkV5nH0qaSkHlGAo8yMgsBZMTie8j4Xh4adsu6kurfIJbs9xVe2fHveb53r3un3ZrHf1yBmrhdJmkERio5kk2HakU1oRQQm3RnYt5q2xA6eUS8powzgTWgkhDTG02Aa6qu7_sOMUv2ZIuT-4ZMB7FSDOqReyxS2luAjvzsJZl9v6cXIHNX33_4-iv5ktZL4</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>68707330</pqid></control><display><type>article</type><title>The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole</title><source>Wiley-Blackwell Read &amp; Publish Collection</source><creator>Groves, James O ; Guscott, Martin R ; Hallett, David J ; Rosahl, Thomas W ; Pike, Andrew ; Davies, Amy ; Wafford, Keith A ; Reynolds, David S</creator><creatorcontrib>Groves, James O ; Guscott, Martin R ; Hallett, David J ; Rosahl, Thomas W ; Pike, Andrew ; Davies, Amy ; Wafford, Keith A ; Reynolds, David S</creatorcontrib><description>The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive beta2 subunit (beta2N265S) to determine the role of this subunit in mediating the sedative and anticonvulsive effects of loreclezole. Sedation was assessed by measuring spontaneous locomotor activity and beam walking performance, and anticonvulsant efficacy was determined by pentylenetetrazole (PTZ) and amygdala kindling-induced seizures. The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance. However, loreclezole also failed to provide significant protection against PTZ-induced seizures in the beta2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in beta2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors.</description><identifier>ISSN: 0953-816X</identifier><identifier>PMID: 16882014</identifier><language>eng</language><publisher>France</publisher><subject>Animals ; Anticonvulsants - pharmacology ; Female ; Hypnotics and Sedatives - pharmacology ; Male ; Mice ; Mice, Mutant Strains ; Point Mutation ; Receptors, GABA - genetics ; Receptors, GABA - physiology ; Triazoles - pharmacology</subject><ispartof>The European journal of neuroscience, 2006-07, Vol.24 (1), p.167-174</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16882014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Groves, James O</creatorcontrib><creatorcontrib>Guscott, Martin R</creatorcontrib><creatorcontrib>Hallett, David J</creatorcontrib><creatorcontrib>Rosahl, Thomas W</creatorcontrib><creatorcontrib>Pike, Andrew</creatorcontrib><creatorcontrib>Davies, Amy</creatorcontrib><creatorcontrib>Wafford, Keith A</creatorcontrib><creatorcontrib>Reynolds, David S</creatorcontrib><title>The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole</title><title>The European journal of neuroscience</title><addtitle>Eur J Neurosci</addtitle><description>The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive beta2 subunit (beta2N265S) to determine the role of this subunit in mediating the sedative and anticonvulsive effects of loreclezole. Sedation was assessed by measuring spontaneous locomotor activity and beam walking performance, and anticonvulsant efficacy was determined by pentylenetetrazole (PTZ) and amygdala kindling-induced seizures. The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance. However, loreclezole also failed to provide significant protection against PTZ-induced seizures in the beta2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in beta2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors.</description><subject>Animals</subject><subject>Anticonvulsants - pharmacology</subject><subject>Female</subject><subject>Hypnotics and Sedatives - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Point Mutation</subject><subject>Receptors, GABA - genetics</subject><subject>Receptors, GABA - physiology</subject><subject>Triazoles - pharmacology</subject><issn>0953-816X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNo1kD1PwzAQhjOAaCn8BeSJLZIdf8QZSwUFqRJLB7bIds5g5NohdirBr8cVZbqv931OdxfVEnec1pKIt0V1ndInxlgKxq-qBRFSNpiwZXXcfwCaogcULdquH9YasmpQmvUcXK5NDFm54MI7msDAmOOUkAvoAINT-dTOxa9CdkV5nH0qaSkHlGAo8yMgsBZMTie8j4Xh4adsu6kurfIJbs9xVe2fHveb53r3un3ZrHf1yBmrhdJmkERio5kk2HakU1oRQQm3RnYt5q2xA6eUS8powzgTWgkhDTG02Aa6qu7_sOMUv2ZIuT-4ZMB7FSDOqReyxS2luAjvzsJZl9v6cXIHNX33_4-iv5ktZL4</recordid><startdate>200607</startdate><enddate>200607</enddate><creator>Groves, James O</creator><creator>Guscott, Martin R</creator><creator>Hallett, David J</creator><creator>Rosahl, Thomas W</creator><creator>Pike, Andrew</creator><creator>Davies, Amy</creator><creator>Wafford, Keith A</creator><creator>Reynolds, David S</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>200607</creationdate><title>The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole</title><author>Groves, James O ; Guscott, Martin R ; Hallett, David J ; Rosahl, Thomas W ; Pike, Andrew ; Davies, Amy ; Wafford, Keith A ; Reynolds, David S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p544-6abcd8180cb4810f919aba16315fc897057cfd5335834324546ba668c1c3818d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Anticonvulsants - pharmacology</topic><topic>Female</topic><topic>Hypnotics and Sedatives - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Point Mutation</topic><topic>Receptors, GABA - genetics</topic><topic>Receptors, GABA - physiology</topic><topic>Triazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Groves, James O</creatorcontrib><creatorcontrib>Guscott, Martin R</creatorcontrib><creatorcontrib>Hallett, David J</creatorcontrib><creatorcontrib>Rosahl, Thomas W</creatorcontrib><creatorcontrib>Pike, Andrew</creatorcontrib><creatorcontrib>Davies, Amy</creatorcontrib><creatorcontrib>Wafford, Keith A</creatorcontrib><creatorcontrib>Reynolds, David S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>The European journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Groves, James O</au><au>Guscott, Martin R</au><au>Hallett, David J</au><au>Rosahl, Thomas W</au><au>Pike, Andrew</au><au>Davies, Amy</au><au>Wafford, Keith A</au><au>Reynolds, David S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole</atitle><jtitle>The European journal of neuroscience</jtitle><addtitle>Eur J Neurosci</addtitle><date>2006-07</date><risdate>2006</risdate><volume>24</volume><issue>1</issue><spage>167</spage><epage>174</epage><pages>167-174</pages><issn>0953-816X</issn><abstract>The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive beta2 subunit (beta2N265S) to determine the role of this subunit in mediating the sedative and anticonvulsive effects of loreclezole. Sedation was assessed by measuring spontaneous locomotor activity and beam walking performance, and anticonvulsant efficacy was determined by pentylenetetrazole (PTZ) and amygdala kindling-induced seizures. The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance. However, loreclezole also failed to provide significant protection against PTZ-induced seizures in the beta2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in beta2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors.</abstract><cop>France</cop><pmid>16882014</pmid><tpages>8</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0953-816X
ispartof The European journal of neuroscience, 2006-07, Vol.24 (1), p.167-174
issn 0953-816X
language eng
recordid cdi_proquest_miscellaneous_68707330
source Wiley-Blackwell Read & Publish Collection
subjects Animals
Anticonvulsants - pharmacology
Female
Hypnotics and Sedatives - pharmacology
Male
Mice
Mice, Mutant Strains
Point Mutation
Receptors, GABA - genetics
Receptors, GABA - physiology
Triazoles - pharmacology
title The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T17%3A47%3A52IST&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=The%20role%20of%20GABAbeta2%20subunit-containing%20receptors%20in%20mediating%20the%20anticonvulsant%20and%20sedative%20effects%20of%20loreclezole&rft.jtitle=The%20European%20journal%20of%20neuroscience&rft.au=Groves,%20James%20O&rft.date=2006-07&rft.volume=24&rft.issue=1&rft.spage=167&rft.epage=174&rft.pages=167-174&rft.issn=0953-816X&rft_id=info:doi/&rft_dat=%3Cproquest_pubme%3E68707330%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-p544-6abcd8180cb4810f919aba16315fc897057cfd5335834324546ba668c1c3818d3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=68707330&rft_id=info:pmid/16882014&rfr_iscdi=true