Use of a novel mouse genotype to model acute benzodiazepine withdrawal.
Withdrawal from benzodiazepines in physically dependent rodents often requires that the drug be dislodged from its receptor with a competitive antagonist. Withdrawal Seizure-Prone (WSP) mice were selectively bred for their susceptibility to handling-induced withdrawal convulsions following chronic treatment with ethanol. Reflecting pleiotropic genetic influences, they also experience more severe withdrawal from other sedative-hypnotics including the benzodiazepine, diazepam. We used this susceptible genotype to test whether other benzodiazepine receptor (BZR) agonists also produce physical dependence following acute administration, comparing studies of spontaneous withdrawal with those where convulsions were precipitated by a BZR antagonist (flumazenil). Separate groups of mice were tested following a single injection of one of eight BZR agonists. Several doses of each drug were tested for spontaneous withdrawal, and a single dose of each drug was tested for precipitated withdrawal. Withdrawal convulsions were seen after all of the drugs by at least one method, suggesting that BZR agonists as a class elicit acute physical dependence in this susceptible genotype.
Metten
Pamela
P
Department of Behavioral Neuroscience, Portland Alcohol Research Center, Oregon Health & Science University, and Department of Veterans Affairs Medical Center, Portland, OR 97239, USA. mettenp@ohsu.edu
Buck
Kari J
KJ
Merrill
Catherine M
CM
Roberts
Amanda J
AJ
Yu
Chia-Hua
CH
Crabbe
John C
JC
D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity*; D001569:Benzodiazepines / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D058787:GABA-A Receptor Antagonists; D005838:Genotype; D051379:Mice; D008815:Mice, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000517:prevention & control; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000517:prevention & control; D013997:Time Factors
D014151:Anti-Anxiety Agents; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines