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TITLE: Differential anxiolytic effects of neurosteroids in the mirrored chamber behavior test in mice.
AUTHOR: Reddy DS; Kulkarni SK
AUTHOR AFFILIATION: Department of Pharmacology, University Institute of Pharmaceutical Sciences, Punjab University, India.
SOURCE: Brain Res 1997 Mar 28;752(1-2):61-71
NLM CIT. ID: 97260321
ABSTRACT: This study examined the effects of neurosteroids on the behavior of mice in the mirrored chamber test of anxiety, and determined the potential mechanisms by which neurosteroids alter the behavior in animal models of anxiety. Allopregnanolone (AP) (0.5 and 1 mg/kg) and pregnenolone 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 the 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 mirrored chamber, and a decrease in the number of entries and time spent in the chamber. Progesterone (PROG) (1-10 mg/kg), a neurosteroid precursor, and 4'-chlordiazepam (4'-CD) (0.25-1 mg/kg), a specific ligand for the mitochondrial diazepam binding inhibitor (DBI) receptor (MDR), produced a clear dose-dependent anxiolytic response in the mirrored chamber. 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 picrotoxin. The 4'-CD-induced anxiolytic effect was prevented by pretreatment with 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 significant additive effect in the mirrored chamber test. The potent anxiolytic effect of dizocilpine (0.5 and 1 mg/kg), an NMDA receptor antagonist, was blocked by pretreatment with DHEAS (2 mg/kg). Neurosteroids evoked changes in mirrored chamber activities resembling those elicited by triazolam (0.25 and 0.5 mg/kg). However, these effects were seen at doses that did not markedly affect locomotor activity, thereby suggesting these changes in behavior represent anxiolytic actions. Together, these results provide evidence for differential behavioral actions of the neurosteroids AP, PS and DHEAS in the mirrored chamber test of anxiety. The anxiolytic effect of PROG may be imputed to its metabolism to neurosteroid AP, while the 4'-CD-induced anxiolytic response is related to its MDR-stimulated neurosteroidogenesis and subsequent modulation of GABA-A receptor. Further, these differential effects reaffirm the contention that neurosteroids could be involved in the homeostasis of stress response.
Behavior, Animal/*DRUG EFFECTS
Calcium Channel Blockers/PHARMACOLOGY
Dose-Response Relationship, Drug
Mice, Inbred BALB C
Motor Activity/DRUG EFFECTS
Reaction Time/DRUG EFFECTS
Support, Non-U.S. Gov't
Support, U.S. Gov't, P.H.S. Triazolam/PHARMACOLOGY
REGISTRY NUMBERS: 0 (Anti-Anxiety Agents)
0 (Calcium Channel Blockers)
0 (GABA Antagonists)
0 (GABA Modulators)
0 (Isoquinolines)
0 (Steroids)
124-87-8 (Picrotoxin)
21829-25-4 (Nifedipine)
28911-01-5 (Triazolam)
78755-81-4 (Flumazenil)
85340-56-3 (PK 11195)

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On Sabbatical!

When my office lease expired at the end of 2004, I decided to turn it into a "sabbatical" from my private practice. Many years ago, in my grandfather's 89th year of life, he told me, "John, it is important to smell the roses while you can still smell them." His life gave living a very good reputation. It is also true that the pursuit of that philosophy required my grandfather to to re-open his assay office/ore market in Wickenburg, Arizona as a 75-year-old because he had run a little short of retirement money. Thus, if blessed with his luck and health, I'll be back.. --jjh

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