National Library of Medicine: IGM
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TITLE:
Role of GABA-A and mitochondrial diazepam binding
inhibitor receptors in the anti-stress activity of neurosteroids in mice.
AUTHOR:
Reddy DS; Kulkarni SK
AUTHOR AFFILIATION:
Department of Pharmacology, Panjab University,
Chandigarh, India.
SOURCE:
Psychopharmacology (Berl) 1996 Dec;128(3):280-92
NLM CIT. ID:
97127797
ABSTRACT:
Neuroactive steroidal modulation of
immobilization-stress and possible involvement of GABA-A and mitochondrial diazepam
binding inhibitor (DBI) receptors (MDR) has been investigated in mice. Immobilization of
mice for 2 h induced intense antinociception, anxiety state, and associated with a fall in
adrenal ascorbic acid levels. Pretreatment with high dose of progesterone (10 mg/kg), a
precursor of neurosteroids, significantly decreased the stress-induced antinociception,
anxiety and fall in adrenal ascorbic acid, while low doses (1 and 5 mg/kg) or
hydrocortisone (10 and 100 mg/kg) were ineffective. In contrast, progesterone (1 mg/kg,
for 9 days) produced a significant antistress effect, which was blocked by GABA-A
antagonists picrotoxin (1 mg/kg) and bicuculline (1 mg/kg), but not by flumazenil (2
mg/kg), a specific benzodiazepine (BZD) antagonist. 4'-chlordiazepam (0.1 and 0.25 mg/kg),
a specific high affinity MDR agonist, produced significant anti-stress effect in a
flumazenil-insensitive manner, but was blocked by pretreatment with PK11195 (1.5 mg/kg), a
selective partial agonist of MDR, and with bicuculline (1 mg/kg), a potent GABA-A receptor
antagonist. At higher doses, progesterone and 4'-chlordiazepam which are effective in
immobilization stress also reduced locomotion. However, lower doses of progesterone (6.5
mg/kg) neither affected locomotion, nor produced any motor toxicity on rota-rod test. At
the lower doses, the MDR ligand 4'-chlordiazepam (50 micrograms/kg) decreased locomotor
activity, without altering motor toxicity on rota-rod test. Further, the per se effects of
these treatments on unstressed mice were not significantly different from those of
untreated controls, except for plus-maze test. The antistress profile of progesterone may
be attributed to the in vivo production of neurosteroid allopregnanolone, thus resembled
that of BZDs. Furthermore, the antistress actions are flumazenil-resistant, reaffirming
that there may be an increase in the levels of pregnane neurosteroids in vivo, which may
act on a specific allosteric site on GABA-A receptors distinct from BZD site. Because
4'-chlordiazepam binds to MDRs and stimulate mitochondrial neurosteroidogenesis, the
anti-stress effects of 4'-chlordiazepam may be imputed to its MDR-induced neurosteroids,
which then act on GABA-A receptors. These data suggest a pivotal role for GABA-A and
mitochondrial DBI receptors in the antistress actions of neurosteroids and reinforces
their ameliorative effect in physiological stress.
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
