βCCT, an antagonist selective for α(1)GABA(A) receptors, reverses diazepam withdrawal-induced anxiety in rats

The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiaz...

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Bibliographic Details
Published in:Brain research bulletin 2013-02, Vol.91, p.1
Main Authors: Divljaković, Jovana, Milić, Marija, Namjoshi, Ojas A, Tiruveedhula, Veera V, Timić, Tamara, Cook, James M, Savić, Miroslav M
Format: Article
Language:English
Subjects:
Animals
Anxiety - chemically induced
Anxiety - drug therapy
Carbolines - pharmacology
Diazepam - adverse effects
Flumazenil - pharmacology
GABA-A Receptor Antagonists - pharmacology
Hypnotics and Sedatives - adverse effects
Male
Maze Learning - drug effects
Rats
Rats, Wistar
Receptors, GABA-A - drug effects
Substance Withdrawal Syndrome - drug therapy
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Summary:The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiazepine binding site of GABA(A) receptors was capable of preventing and reversing the increased anxiety during benzodiazepine withdrawal in animals and humans in some, but not all studies. On the other hand, a number of data suggest that GABA(A) receptors containing α(1) subunits are critically involved in processes developing during prolonged use of benzodiazepines, such are tolerance to sedative effects, liability to physical dependence and addiction. Hence, we investigated in the elevated plus maze the level of anxiety 24 h following 21 days of diazepam treatment and the influence of flumazenil or a preferential α(1)-subunit selective antagonist βCCt on diazepam withdrawal syndrome in rats. Abrupt cessation of protracted once-daily intraperitoneal administration of 2 mg/kg diazepam induced a withdrawal syndrome, measured by increased anxiety-like behavior in the elevated plus maze 24 h after treatment cessation. Acute challenge with either flumazenil (10mg/kg) or βCCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABA(A) receptors may reverse the withdrawal-induced anxiety involves the α(1) subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABA(A) receptors.
ISSN:1873-2747
DOI:10.1016/j.brainresbull.2012.10.011