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TITLE:
Neurosteroid coadministration prevents
development of tolerance and augments recovery from benzodiazepine withdrawal anxiety and
hyperactivity in mice.
AUTHOR:
Reddy DS; Kulkarni SK
AUTHOR AFFILIATION:
Department of Pharmacology, University Institute
of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Neurosteroids are potent and specific modulators
of the GABAA receptors which regulate the neuronal activity through diverse
neurotransmitter mechanisms. In the present study we investigated the effects of
concomitant treatment with various neurosteroids on the development of tolerance and
recovery from withdrawal anxiety and hyperactivity to chronic benzodiazepines. Long-term
treatment of mice with full allosteric modulator (triazolam 0.25 mg/kg/day for 8 days) or
selective allosteric modulator (diazepam 20 mg/kg/day for 21 days) of GABAA receptor
induced tolerance to behavioral sedation on actimeter and anxiolytic effects on plus-maze,
and produced a marked withdrawal anxiety and hyperactivity syndrome upon abrupt cessation
of treatment, respectively. Concomitant progesterone (10 mg/kg, s.c.), a neurosteroid
precursor, of 4'-chlordiazepam (0.25 mg/kg, i.p.), a mitochondrial diazepam binding
inhibitor (DBI) receptor (MDR) ligand, prevented the development of tolerance and
significantly augmented the recovery from withdrawal-induced anxiety and hyperlocomotion
to diazepam. When administered alone for 21 days, neither progesterone nor
4'-chlordiazepam produced any per se effects on actimeter or plus-maze when tested on
post-withdrawal days. Coadministration of neurosteroid allopregnanolone (AP) (0.25 and 0.5
mg/kg), or pregnenolone sulfate (PS) (2 mg/kg), but not dehydroepiandrosterone sulfate (2
mg/kg), abolished the development of tolerance and attenuated withdrawal-induced anxiety
and hyperlocomotion due to triazolam, without producing any per se behavioral effects when
tested at 1 and 2 days after the last injection. Coadministration of flumazenil (5 mg/kg),
progesterone (10 mg/kg), 4'-chlordiazepam (0.25 mg/kg), hydrocortisone (100 mg/kg) or
nifedipine (2 mg/kg) also prevented the development of tolerance and suppressed the
triazolam withdrawal syndrome. However, pretreatment with PK11195 (2 mg/kg), a MDR partial
antagonist, reversed the effects of 4'-chlordiazepam on triazolam tolerance and recovery
from chronic triazolam. When injected simultaneously, nifedipine, a Ca2+ channel
antagonist, potentiated the progesterone- and 4'-chlordiazepam-induced attenuation of
triazolam tolerance and withdrawal behavior. These findings suggest that coadministration
of neurosteroids allopregnanolone, pregnenolone sulfate and progesterone, and MDR ligand
4'-chlordiazepam prevents the development of tolerance to benzodiazepines and augments the
recovery from chronic benzodiazepines. These results indicate that coadministration of
neurosteroids may facilitate discontinuation of benzodiazepines in long-term therapy.
MAIN MESH SUBJECTS:
Benzodiazepinones/*THERAPEUTIC USE
Convulsants/*THERAPEUTIC USE
Diazepam/*ADVERSE EFFECTS
GABA Modulators/*ADVERSE EFFECTS
Progesterone/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE
Substance Withdrawal Syndrome/*DRUG THERAPY
Triazolam/*ADVERSE EFFECTS
ADDITIONAL MESH SUBJECTS:
Animal
Anxiety/DRUG THERAPY
Comparative Study
Drug Combinations
Drug Tolerance
Male
Mice
Motor Activity/DRUG EFFECTS
Support, Non-U.S. Gov't
Support, U.S. Gov't, P.H.S.
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
