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

摘要

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.