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

Rationale: Zolpidem is a short-acting, non-benzodiazepine hypnotic that acts as a full agonist at α1-containing GABA_A 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 GABA _AR 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 GABA_AR 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.