DIFFERENTIAL ANXIOLYTIC EFFECTS OF NEUROSTEROIDS IN THE MIRRORED CHAMBER BEHAVIOR TEST IN MICE

This study examined the effects of neurosteroids on the behavior of mi ce in the mirrored chamber test of anxiety, and determined the potenti al mechanisms by which neurosteroids alter the behavior in animal mode ls of anxiety. Allopregnanolone (AP) (0.5 and 1 mg/kg) and pregnenolon e sulfate (PS) (0.5 and 2 mg/kg) significantly reduced the latency to enter the chamber, and increased both number of entries and total time spent in the chamber in a dose-dependent manner, without affecting th e spontaneous locomotor activity. In contrast, dehydroepiandrosterone sulfate (DHEAS) (1 and 2 mg/kg) increased motor activity and caused an anxiogenic response, i.e., an increase in latency to enter the mirror ed chamber, and a decrease in the number of entries and time spent in the chamber. Progesterone (FROG) (1-10 mg/kg), a neurosteroid precurso r, and 4'-chlordiazepam (4'-CD) (0.25-1 mg/kg), a specific ligand for the mitochondrial diazepam binding inhibitor (DBI) receptor (MDR), pro duced a clear dose-dependent anxiolytic response in the mirrored chamb er. The AP-, PROG- and 4'-CD-elicited anxiolytic behavior was blocked by picrotoxin (1 mg/kg), a GABA-A chloride channel antagonist, but not by flumazenil (2 mg/kg), a selective benzodiazepine (BZD) antagonist. In contrast, the anxiolytic effect of PS was not blocked by picrotoxi n. The 4'-CD-induced anxiolytic effect was prevented by pretreatment w ith PK11195 (2 mg/kg), a selective partial MDR antagonist. Nifedipine (2 and 5 mg/kg), a dihydropyridine-type Ca2+ channel blocker, produced a flumazenil-resistant anxiolytic effect. Combined administration of nifedipine (2 and 5 mg/kg) and PS (0.5 and 2 mg/kg) exerted a signific ant additive effect in the mirrored chamber test. The potent anxiolyti c effect of dizocilpine (0.5 and 1 mg/kg), an NMDA receptor antagonist , was blocked by pretreatment with DHEAS (2 mg/kg). Neurosteroids evok ed changes in mirrored chamber activities resembling those elicited by triazolam (0.25 and 0.5 mg/kg). However, these effects were seen at d oses that did not markedly affect locomotor activity, thereby suggesti ng these changes in behavior represent anxiolytic actions. Together, t hese results provide evidence for differential behavioral actions of t he neurosteroids AP, PS and DHEAS in the mirrored chamber test of anxi ety. The anxiolytic effect of PROC may be imputed to its metabolism to neurosteroid AP, while the 4'-CD-induced anxiolytic response is relat ed to its MDR-stimulated neurosteroidogenesis and subsequent modulatio n of GABA-A receptor. Further, these differential effects reaffirm the contention that neurosteroids could be involved in the homeostasis of stress response. (C) 1997 Elsevier Science B.V.