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

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.