Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2002-10-7
pubmed:abstractText
Potentiation of GABA(A) receptor activation through allosteric benzodiazepine (BZ) sites produces the anxiolytic, anticonvulsant and sedative/hypnotic effects of BZs. Using a mouse line lacking alpha1 subunit expression, we investigated the contribution of the alpha1 subunit to GABA(A) receptor pharmacology, function and related behaviors in response to BZ site agonists. Competitive [(3)H]flunitrazepam binding experiments using the Type I BZ site agonist, zolpidem, and the Type I and II BZ site non-specific agonist, diazepam, demonstrated the complete loss of Type I BZ binding sites in alpha1(-/-) mice and a compensatory increase in Type II BZ binding sites (41+/-6%, P<0.002). Chloride uptake analysis in alpha1(-/-) mice revealed an increase (108+/-10%, P<0.001) in the efficacy (E(max)) of flunitrazepam while the EC(50) of zolpidem was increased 495+/-26% (alpha1(+/+): 184+/-56 nM; alpha1(-/-): 1096+/-279 nM, P<0.01). An anxiolytic effect of diazepam was detected in both alpha1(+/+) and alpha1(-/-) mice as measured on the elevated plus maze; however, alpha1(-/-) mice exhibited a greater percentage of open arm entries and percentage of open arm time following 0.6 mg/kg diazepam. Furthermore, alpha1(-/-) mice were more sensitive to the motor impairing/sedative effects of diazepam (1-10 mg/kg) as measured by locomotor activity in the open field. Knockout mice were insensitive to the anticonvulsant effect of diazepam (1-15 mg/kg, P<0.001). The hypnotic effect of zolpidem (60 mg/kg) was reduced by 66% (P<0.001) in alpha1(-/-) mice as measured by loss of righting reflex while the effect of diazepam (33 mg/kg) was increased 57% in alpha1(-/-) mice (P<0.05). These studies demonstrate that compensatory adaptations in GABA(A) receptor subunit expression result in subunit substitution and assembly of functional receptors. Such adaptations reveal important relationships between subunit expression, receptor function and behavioral responses.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Anxiety Agents, http://linkedlifedata.com/resource/pubmed/chemical/Anticonvulsants, http://linkedlifedata.com/resource/pubmed/chemical/Benzodiazepines, http://linkedlifedata.com/resource/pubmed/chemical/Chlorides, http://linkedlifedata.com/resource/pubmed/chemical/Diazepam, http://linkedlifedata.com/resource/pubmed/chemical/Flunitrazepam, http://linkedlifedata.com/resource/pubmed/chemical/GABA Agonists, http://linkedlifedata.com/resource/pubmed/chemical/GABA Modulators, http://linkedlifedata.com/resource/pubmed/chemical/Gabra1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Hypnotics and Sedatives, http://linkedlifedata.com/resource/pubmed/chemical/Muscimol, http://linkedlifedata.com/resource/pubmed/chemical/Pyridines, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, GABA-A, http://linkedlifedata.com/resource/pubmed/chemical/zolpidem
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0028-3908
pubmed:author
pubmed:issnType
Print
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
685-94
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:12367614-Animals, pubmed-meshheading:12367614-Anti-Anxiety Agents, pubmed-meshheading:12367614-Anticonvulsants, pubmed-meshheading:12367614-Behavior, Animal, pubmed-meshheading:12367614-Benzodiazepines, pubmed-meshheading:12367614-Chlorides, pubmed-meshheading:12367614-Diazepam, pubmed-meshheading:12367614-Exploratory Behavior, pubmed-meshheading:12367614-Female, pubmed-meshheading:12367614-Flunitrazepam, pubmed-meshheading:12367614-GABA Agonists, pubmed-meshheading:12367614-GABA Modulators, pubmed-meshheading:12367614-Gene Deletion, pubmed-meshheading:12367614-Hypnotics and Sedatives, pubmed-meshheading:12367614-Male, pubmed-meshheading:12367614-Mice, pubmed-meshheading:12367614-Mice, Knockout, pubmed-meshheading:12367614-Motor Activity, pubmed-meshheading:12367614-Muscimol, pubmed-meshheading:12367614-Postural Balance, pubmed-meshheading:12367614-Pyridines, pubmed-meshheading:12367614-Radioligand Assay, pubmed-meshheading:12367614-Receptors, GABA-A, pubmed-meshheading:12367614-Seizures
pubmed:year
2002
pubmed:articleTitle
GABA(A) receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem.
pubmed:affiliation
Department of Pharmacology, University of North Carolina at Chapel Hill, 27599, USA.
pubmed:publicationType
Journal Article