Evaluation of Zolpidem (Ambien®) as a Selective Benzodiazepine Agonist in a Primate Model
Carter, Lawrence P.
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Anxiety and insomnia are two of the most prevalent behavioral disorders in society. The molecular basis of these illnesses is not well known, however two classes of drugs are effective in the treatment of these disorders: benzodiazepines (BDZ's) and serotonin agonists. Zolpidem (Ambien®) is a BDZ agonist that is widely used in the clinic as an anxiolytic (anti-anxiety) and sedative (sleep inducing) because of its effectiveness and low abuse liability. Zolpidem's low potential for abuse is hypothesized to be due to its selectivity for the benzodiazepine-l (BDZ-l) receptor subtype. To test and quantify this hypothesis, this study compared the ability of BDZ-l selective, 𝛽-carboline-3- carboxylate-t-butyl ester (𝛽-CCt) to antagonize the discriminative-stimulus effects of zolpidem and the non-selective BDZ, midazolam. Three rhesus monkeys were trained to discriminate 0.56 mg/kg of midazolam from saline under a schedule of stimulus-shock termination. 𝛽-CCt dose-dependently shifted the midazolam and zolpidem dose effect curves to the right. Unexpectedly, 𝛽-CCt was more effective in antagonizing the discriminative-stimulus effects of midazolam than zolpidem, even though both zolpidem and 𝛽-CCt are BDZ-l selective. However, slopes of Schild plots failed to conform to unity for midazolam and zolpidem, suggesting that the interactions were not simple or that there may be other pharmacokinetic issues at work. Further investigation of the interaction between zolpidem and 𝛽-CCt will most likely elucidate their mechanisms of action and generate a pA2 value for the interaction of these two compounds. As these molecular mechanisms of action become clearer, we can develop drugs that retain the clinical utility of classical BDZ's while having a reduced abuse liability. Novel drugs with lower reinforcing effects will be less likely to be abused.