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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Pinna, Graziano Zhubi, Adrian Grayson, Dennis R. Agis-balboa, Roberto C. Matsumoto, Kinzo Guidotti, Alessandro Costa, Erminio |
| Description | Author Affiliation: Pinna G ( Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA. gpinna@psych.uic.edu); |
| Abstract | In cortex and hippocampus, protracted (>4 weeks) social isolation of adult male mice alters the subunit expression of GABA type A receptors (GABA(A)-Rs) as follows: (i) the mRNAs encoding GABA(A)-R alpha1, alpha2, and gamma2 subunits are decreased by approximately 50%, whereas those encoding alpha4 and alpha5 subunits are increased by approximately 100%; (ii) similarly, the synaptic membrane expression of the alpha1 subunit protein is down-regulated, and that of the alpha5 subunit protein is up-regulated; and (iii) the binding of [(3)H]flumazenil to hippocampal synaptic membranes is decreased. Behaviorally, socially isolated (SI) mice are resistant to the sedative effects of the positive allosteric GABA(A)-R modulators diazepam (DZP) and zolpidem. This resistance seems to be attributable to the decrease of alpha1-containing GABA(A)-Rs. Paradoxically, DZP, which, unlike zolpidem, acts at alpha5-containing GABA(A)-Rs, increases the locomotor activity of SI mice. Imidazenil, which fails to modulate alpha1-, alpha4-, and alpha6-containing GABA(A)-Rs but is a selective positive allosteric modulator of alpha5-containing GABA(A)-Rs, also increases locomotor activity in SI mice. Importantly, SI mice responded to muscimol, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one, and allopregnanolone similar to group-housed mice. These data suggest that a switch (a decrease in alpha1/alpha2 and gamma2 and an increase in alpha4 and alpha5 subunits) in the composition of the heteropentameric GABA(A)-R subunit assembly without a change in total GABA(A)-R number occurs during social isolation. Thus, the repertoire of DZP and imidazenil actions in SI mice appears to be elicited by the allosteric modulation of GABA(A)-Rs overexpressing alpha5 subunits. Benzodiazepine response mediated by alpha1-containing GABA(A)-Rs is expected to be silent or reduced. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 11 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Benzodiazepines Pharmacology Diazepam GABA Modulators Imidazoles Motor Activity Drug Effects Social Isolation Animals Frontal Lobe Physiology Gene Expression Hippocampus In Vitro Techniques Mice Protein Subunits Pyridines RNA, Messenger Genetics Metabolism Receptors, GABA-A Chemistry Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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