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Use of a Novel Mouse Genotype to Model Acute Benzodiazepine Withdrawal

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Abstract

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.

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Acknowledgments

The authors thank Drs. Cheryl Reed and Nathan Rustay, and Michelle Bobo for helpful comments, and Andy Cameron, Lauren Brown, Katie Mordarski, and Michelle Sorensen for assistance with data curation. This study was supported by National Institute on Alcohol Abuse and Alcoholism Grants AA10760 and AA06243, National Institute of Drug Abuse Grant DA05228, a grant from the Department of Veterans Affairs Medical Center, and a fellowship from the Tartar Trust. Pamela Metten was supported by National Institute on Drug Abuse Training Grant T32 DA07262.

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Authors and Affiliations

  1. Department of Behavioral Neuroscience, Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR, 97239, USA

    Pamela Metten, Kari J. Buck, Catherine M. Merrill, Chia-Hua Yu & John C. Crabbe

  2. Department of Veterans Affairs Medical Center, R&D-12, 3710 S.W. U.S. Veterans Hospital Road, Portland, OR, 97239, USA

    Pamela Metten, Catherine M. Merrill, Chia-Hua Yu & John C. Crabbe

  3. Department of Veterans Affairs Medical Center, R&D-40, 3710 S.W. U.S. Veterans Hospital Road, Portland, OR, 97239, USA

    Kari J. Buck

  4. Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Amanda J. Roberts

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  1. Pamela Metten
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  2. Kari J. Buck
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  3. Catherine M. Merrill
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  4. Amanda J. Roberts
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  5. Chia-Hua Yu
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  6. John C. Crabbe
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Correspondence to Pamela Metten.

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Edited by Andrew Holmes

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Metten, P., Buck, K.J., Merrill, C.M. et al. Use of a Novel Mouse Genotype to Model Acute Benzodiazepine Withdrawal. Behav Genet 37, 160–170 (2007). https://doi.org/10.1007/s10519-006-9094-3

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  • DOI: https://doi.org/10.1007/s10519-006-9094-3

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