The psychopharmacological data from both rodents and non-human primates suggest that zolpidem has a unique pharmacological profile when compared with classic BZs. The literature reviewed here provides an important framework for studying the role of different GABA(A)R subtypes in the behavioral effects of BZ-type drugs and helps guide the development of new pharmaceutical agents for disorders currently treated with BZ-type drugs.

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.

The observed effect of midazolam on anxiety is equivocal in part because previous studies have not ruled out pre-treatment differences in anxiety scores between patients who received midazolam and those who did not (controls). This study re-examines the anxiolytic effect of premedication with intramuscular midazolam using a sample size calculated to be of sufficient size to rule out population differences as a variable affecting treatment results. In the midazolam group (n = 49) anxiety scores were determined prior to administration of midazolam 0.07 mg/kg intramuscularly, and again 60 minutes later. In the control group (n = 47) anxiety scores were determined prior to intramuscular injection of a similar volume of matching placebo (midazolam vehicle), and again 60 minutes later. No differences in anxiety scores between groups either before treatments or 60 minutes after treatments were observed. Within both groups, anxiety scores at 60 minutes were no different from pre-treatment scores. In this study midazolam did not produce a statistically significant decrease in pre-operative anxiety scores at 60 minutes following intramuscular administration.

A double-blind comparison of lorazepam and placebo, lorazepam and pentobarbital, and a comparison of lorazepam IV drip versus lorazepam IV bolus as a premedicant showed this new agent to offer promise as a sedative premedicant. However, the potency of the drug demands caution, and its use for outpatient premedication is not recommended.

Zolpidem and benzodiazepines (BZs) potentiate the inhibitory action of gamma-Aminobutyric acid (GABA) by allosterically binding to GABAA receptors (GABAAR). Prolonged use of GABAAR positive allosteric modulators (PAM) can lead to behavioral tolerance, the diminished response to the same drug dose with repeated use, and withdrawal, a group of symptoms that occur due to abrupt end of drug treatment. Zolpidem is a short-acting, non-BZ GABAAR PAM whose potential for tolerance and withdrawal is unclear. Zolpidem demonstrates sedative efficacy similar to BZs and has become a main treatment of insomnia in lieu of BZs. Zolpidem replaced BZs due to lower incidences of tolerance and withdrawal after prolonged treatment and discontinuation. Despite reported lower incidences, some studies find the occurrence of tolerance and withdrawal similar between zolpidem and BZs. Tolerance and withdrawal symptoms are likely caused by drug-induced neuroadaptive changes in central nervous system (CNS) functioning, and these alterations may be similar between zolpidem and BZ. Past rodent research suggests that long term use of zolpidem and BZs may produce alterations in normal inhibitory GABAergic and excitatory glutamatergic functioning in the cortex, hippocampus, amygdala, and PFC and that these alterations may underlie sedative tolerance and withdrawal symptoms. viii TABLE OF CONTENTS CHAPTER 1. INSOMNIA TREATMENT ISSUES.