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

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 GABAA-R ␣1, ␣2, and ␥2 subunits are decreased by Ϸ50%, whereas those encoding ␣4 and ␣5 subunits are increased by Ϸ100%; (ii) similarly, the synaptic membrane expression of the ␣1 subunit protein is down-regulated, and that of the ␣5 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 ␣1-containing GABAARs. Paradoxically, DZP, which, unlike zolpidem, acts at ␣5-containing GABA A-Rs, increases the locomotor activity of SI mice. Imidazenil, which fails to modulate ␣1-, ␣4-, and ␣6-containing GABAA-Rs but is a selective positive allosteric modulator of ␣5-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 ␣1͞␣2 and ␥2 and an increase in ␣4 and ␣5 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 ␣5 subunits. Benzodiazepine response mediated by ␣1-containing GABAA-Rs is expected to be silent or reduced. GABAA receptors ͉ nested RT-PCR

Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder

“…In the mouse cortex and hippocampus, protracted social isolation alters the subunit expression of GABA A receptors, with a decrease in ␣ 1 , ␣ 2 , and ␥ 2 subunit expression and an increase in ␣ 4 and ␣ 5 subunits (39). As a consequence, there also was a decrease of [ 3 H]flumazenil binding to hippocampal synaptic membranes and resistance to the sedative effects of classical benzodiazepines, including diazepam and zolpidem (39).…”

“…As a consequence, there also was a decrease of [ 3 H]flumazenil binding to hippocampal synaptic membranes and resistance to the sedative effects of classical benzodiazepines, including diazepam and zolpidem (39).…”

Schizophrenia-Like Features in Transgenic Mice Overexpressing Human HO-1 in the Astrocytic Compartment

“…The animals were tested for nonspatial memory (olfaction) (Wong and Brown, 2007), motor coordination and balance (rotarod) (Li et al, 2010), locomotor activity (Pinna et al, 2006), anxiety (Thatcher-Britton paradigm), and startle response [prepulse inhibition (PPI)] (Wood et al, 1998).…”

Effect of Diazepam on the Runway Method Using Priming Stimulation of Intracranial Self Stimulation Behavior

“…The dosage of flumazenil used was a general dosage at which competing action against diazepam was demonstrated by other researchers. It is well known that flumazenil reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site and acts as an antagonist of the full positive allosteric modulators of GABA-evoked Cl − currents (8). On the other hand, diazepam binds to a specific subunit at a GABA A receptor on the benzodiazepine receptor and enhances the actions of the neurotransmitter GABA on the GABA A receptor (9).…”

“…This report suggests that diazepam reduces the release and metabolism of DA in the nucleus accumbens. Moreover, it has already been known that the diazepam at low dosage acts as an accelerative on ICSS behavior and it acts inhibitively in a high dose (8). Therefore, diazepam at a low dose maybe activates DA neurons via GABA A receptors and a high dose maybe inhibits.…”