title: The effects of repeated zolpidem treatment on tolerance, withdrawal-like symptoms, and GABAA receptor mRNAs profile expression in mice: comparison with diazepam.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors: The Department of Anatomy and Neurobiology, Neuroscience Institute, University of Tennessee Health Science Center, 855 Monroe Ave, Memphis, TN, 38163, USA.
authors: Brittany T
authors: BT
authors: Wright
authors: Catherine F
authors: CF
authors: Gluszek
authors: Scott A
authors: SA
authors: Heldt
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003975:Diazepam / Q000494:pharmacology*; D004361:Drug Tolerance / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D000077334:Zolpidem
chemical_list: D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D011725:Pyridines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D000077334:Zolpidem; D003975:Diazepam