NDLI: Imidazenil and diazepam increase locomotor activity in mice exposed to protracted social isolation

Content Provider	PubMed Central
Author	Pinna, Graziano Agis-balboa, Roberto C. Zhubi, Adrian Matsumoto, Kinzo Grayson, Dennis R. Costa, Erminio Guidotti, Alessandro
Copyright Year	2006
Abstract	In cortex and hippocampus, protracted (>4 weeks) social isolation of adult male mice alters the subunit expression of GABA type A receptors (GABAA-Rs) as follows: (i) the mRNAs encoding GABAA-R α1, α2, and γ2 subunits are decreased by ≈50%, whereas those encoding α4 and α5 subunits are increased by ≈100%; (ii) similarly, the synaptic membrane expression of the α1 subunit protein is down-regulated, and that of the α5 subunit protein is up-regulated; and (iii) the binding of [3H]flumazenil to hippocampal synaptic membranes is decreased. Behaviorally, socially isolated (SI) mice are resistant to the sedative effects of the positive allosteric GABAA-R modulators diazepam (DZP) and zolpidem. This resistance seems to be attributable to the decrease of α1-containing GABAA-Rs. Paradoxically, DZP, which, unlike zolpidem, acts at α5-containing GABAA-Rs, increases the locomotor activity of SI mice. Imidazenil, which fails to modulate α1-, α4-, and α6-containing GABAA-Rs but is a selective positive allosteric modulator of α5-containing GABAA-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 α1/α2 and γ2 and an increase in α4 and α5 subunits) in the composition of the heteropentameric GABAA-R subunit assembly without a change in total GABAA-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 GABAA-Rs overexpressing α5 subunits. Benzodiazepine response mediated by α1-containing GABAA-Rs is expected to be silent or reduced.
Related Links	http://dx.doi.org/10.1073/pnas.0600329103
Ending Page	4280
Page Count	6
Starting Page	4275
File Format	PDF
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	2006-03-14
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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