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The effects of repeated zolpidem treatment on tolerance, withdrawal-like symptoms, and GABAA receptor mRNAs profile expression in mice: Comparison with diazepam

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Abstract

Rationale

Zolpidem is a short-acting, non-benzodiazepine hypnotic that acts as a full agonist at α1-containing GABAA receptors. Overall, zolpidem purportedly has fewer instances of abuse and dependence than traditionally used benzodiazepines. However, several studies have shown that zolpidem may be more similar to benzodiazepines in terms of behavioral tolerance and withdrawal symptoms.

Objectives

In the current study, we examined whether subchronic zolpidem or diazepam administration produced deficits in zolpidem’s locomotor-impairing effects, anxiety-like behaviors, and changes in GABAAR subunit messenger RNA (mRNA).

Methods

Mice were given subchronic injections of either zolpidem (10 mg/kg), diazepam (20 mg/kg), or vehicle twice daily for 7 days. On day 8, mice were given a challenge dose of zolpidem (2 mg/kg) or vehicle before open field testing. Another set of mice underwent the same injection regimen but were sacrificed on day 8 for qRT-PCR analysis.

Results

We found that subchronic zolpidem and diazepam administration produced deficits in the acute locomotor-impairing effects of zolpidem and increased anxiety-like behaviors 1 day after drug termination. In addition, we found that subchronic treatment of zolpidem and diazepam induced distinct but overlapping GABAAR subunit mRNA changes in the cortex but few changes in the hippocampus, amygdala, or prefrontal cortex. Levels of mRNA measured in separate mice after a single injection of either zolpidem or diazepam revealed no mRNA changes.

Conclusions

In mice, subchronic treatment of zolpidem and diazepam can produce deficits in the locomotor-impairing effects of zolpidem, anxiety-like withdrawal symptoms, and subunit-specific mRNA changes.

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Acknowledgments

Support was provided by NIH (MH-086727), NARSAD, and a UTHSC base grant. Some of these results were reported at the meetings of the Society for Neuroscience (Smith et al. 2011). We would like to thank Jordan Marie Ross for her assistance with manuscript preparation and Regina Smith for assistance with data collection.

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  1. The Department of Anatomy and Neurobiology, Neuroscience Institute, University of Tennessee Health Science Center, 855 Monroe Ave, Memphis, TN, 38163, USA

    Brittany T. Wright, Catherine F. Gluszek & Scott A. Heldt

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  1. Brittany T. Wright
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  2. Catherine F. Gluszek
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  3. Scott A. Heldt
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Correspondence to Scott A. Heldt.

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mRNA expression levels in the amygdala (BLA) and prefrontal cortex (PFC) after sub-chronic treatment (VEH, DZP, or ZOLP). (PDF 301 kb)

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mRNA expression levels in the cortex, hippocampus, amygdala (BLA) and prefrontal cortex (PFC) after acute (1-day) administration (VEH, DZP, or ZOLP). (PDF 254 kb)

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Wright, B.T., Gluszek, C.F. & Heldt, S.A. The effects of repeated zolpidem treatment on tolerance, withdrawal-like symptoms, and GABAA receptor mRNAs profile expression in mice: Comparison with diazepam. Psychopharmacology 231, 2967–2979 (2014). https://doi.org/10.1007/s00213-014-3473-x

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  • DOI: https://doi.org/10.1007/s00213-014-3473-x

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