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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.
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
