Investigation of the development of tolerance to the actions of zolpidem and midazolam

doi:10.1016/0028-3908(87)90172-9

Neuropharmacology

Volume 26, Issue 10, October 1987, Pages 1513-1518

https://doi.org/10.1016/0028-3908(87)90172-9 Get rights and content

Abstract

It is well established that tolerance can develop very rapidly to the behaviour-suppressing effects of benzodiazepines. In previous studies, however, the depressant action of zolpidem, a novel hypnotic acting at the benzodiazepine receptor, on operant behaviour in rats was maintained after many injections. An experiment was carried out, therefore, to compare the effects of acute and chronic administration of zolpidem and midazolam. Rats were trained to press a lever in standard operant test chambers to obtain 45 mg food pellets on an FR 10 schedule. Dose-response curves were then established, before, immediately after and 4 weeks after the daily administration of midazolam (3.0 mg/kg s.c.) or zolpidem (1.0 mg/kg) for 10 days. In confirmation of previous work, marked tolerance developed to the response-rate-decreasing effect of midazolam, the dose-response curve being shifted to the right by a factor of 6 and also flattened. No significant dissipation of this tolerance occurred during a period of 4–6 weeks. In contrast, repeated administration of zolpidem produced only a small degree of tolerance, the dose-response curve being shifted by a factor of two. There was little evidence for cross tolerance between the two drugs, zolpidem-treated rats being sensitive to a dose of midazolam and midazolam-treated rats sensitive to a dose of zolpidem. Although the explanation for the development of tolerance to midazolam is unknown, these results suggest that the mechanisms of action of midazolam and zolpidem in reducing response rates are different.

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Citation Excerpt :
In addition to the significant changes in Delta sleep during the repeated administration of zolpidem, there was also a statistically significant increase in the suppression of light sleep (Fig. 5B1) during the reiteration of zolpidem administration. Previous work has shown the development of tolerance in operant conditioning tests that occurs during sub-chronic administration of a diazepine, midazolam, but not with zolpidem [28]. In the studies reported here, the sub-chronic administration of zolpidem appeared to enhance its efficacy during repeated administration 1 week after the original administration period (Fig. 5).
Gamma-aminobutyric acid_A receptor (GABA_AR) modulators constitute the majority of clinically relevant sedative-hypnotics. Animal studies have clearly demonstrated sedative efficacy for these compounds in acute studies. However, relatively less is known regarding their efficacy under brief periods of repeat administration or following intermittent dosing. Therefore zolpidem, a short-acting GABA_AR modulator with selectivity for the type-I (ω₁) benzodiazepine receptor, was studied for efficacy in altering rat sleep architecture as determined by electrocorticogram (ECoG) and electromyogram (EMG) activity over a 7-day sub-chronic administration period. Zolpidem caused significant reductions in wakefulness entries and rapid eye movement (REM) sleep entries and duration, with increases in Delta sleep duration throughout the administration period. Examination of sleep architecture 24 h after cessation of sub-chronic zolpidem administration revealed a decrease in Delta sleep, suggesting that repeated zolpidem administration might elicit enduring modifications to sleep organization. This was not seen following similar dosing of diazepam. The efficacy of sub-chronic administration of zolpidem to alter sleep architecture was enhanced when the administration regimen was repeated following a 7-day hiatus. Significant increases in Delta sleep duration, with significant decreases in light sleep and wakefulness were observed during the repeated exposure to zolpidem. Therefore, sub-chronic administration of zolpidem affected lasting modifications in sleep organization that appeared both 1 day following administration and during reiterated administration without eliciting tolerance.
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Radiotelemetry was utilized to compare zolpidem and lorazepam tolerance and withdrawal in rats. Locomotor activity, electromyographic activity (EMG), and body temperatures were used to assess the acute drug effects, and as measures of tolerance and withdrawal. Lorazepam, zolpidem, or vehicle was administered for 12 days, and data were recorded daily, immediately, after treatment. Data were also recorded immediately after flumazenil (25 mg/kg, IP) precipitated withdrawal and during 4 days of spontaneous withdrawal. Complete tolerance to the acute effects of lorazepam administration developed within 7 days of treatment and both flumazenil-precipitated and spontaneous withdrawal were observed. In contrast, there was no tolerance to the sedative actions of zolpidem administration after 12 days, but complete tolerance to the hypothermic and muscle relaxant effects was apparent after 8 days of treatment. Despite the presence of tolerance, no evidence of either spontaneous or flumazenil-induced withdrawal was recorded in these rats. In conclusion, this model suggests that as a sedative zolpidem has significant advantages over the classic benzodiazepines.
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Benzodiazepine hypnotics, the mainstay of pharmacological treatment for insomnia, have been associated with altered sleep architecture, psychomotor and memory impairment, rebound insomnia, withdrawal effects, tolerance, dependence, abuse potential and respiratory depression. Non-benzodiazepines, such as zolpidem, zopiclone and zaleplon, demonstrate hypnotic efficacy similar to that of benzodiazepines along with excellent safety profiles. Non-benzodiazepines generally cause less disruption of normal sleep architecture than benzodiazepines. Psychomotor and memory impairment may be less problematic with non-benzodiazepines, especially when compared to longer-acting benzodiazepines. Rebound insomnia and withdrawal symptoms occur infrequently upon discontinuation of non-benzodiazepines and may be less common and milder than those seen upon discontinuation of some benzodiazepines. For the long-term treatment of insomnia, which is generally not recommended, zolpidem and zopiclone are particularly good options because they do not develop tolerance rapidly and have a low abuse potential. Limited data indicate that zaleplon has low tolerance and abuse potential, although further experience is needed to determine its long-term efficacy and safety profile. Since non-benzodiazepines produce minimal respiratory depression, they may be safer than benzodiazepines in patients with respiratory disorders. The choice of which hypnotic to use should be based on the patient's primary sleep complaint, health history, adverse effects and cost.
Behavioral pharmacology of zolpidem relative to benzodiazepines: A Review
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Zolpidem, an imidazopyridine that purportedly binds selectively to certain GABA_A receptor subtypes, is the most commonly prescribed hypnotic. The present article critically reviewed the extant experimental literature to determine whether the behavioral pharmacologic profile of zolpidem also differs from that of benzodiazepines. Specific topics that are reviewed include: 1) reinforcing effects and abuse potential, 2) discriminative-stimulus effects, 3) subject-rated drug effects, 4) performance-impairing effects, 5) tolerance-producing effects, and 6) physiological dependence-producing effects. Studies that employed both nonhumans and humans are reviewed. Based on the available literature, the most parsimonious conclusion is that despite its unique neuropharmacological profile, the behavioral effects of zolpidem are generally similar to those of benzodiazepines. However, it is important to note the dearth of perspective, experimental studies that directly compared zolpidem and a benzodiazepine. Because of the clinical relevance and paucity of published studies, future research should focus explicitly on assessing the reinforcing effects, abuse potential, performance-impairing effects, tolerance-producing effects, and dependence-producing effects of zolpidem relative to a benzodiazepine. Important issues such as the selection of an appropriate comparison drug and subject population, and the doses tested needed to be considered in these future studies.

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Investigation of the development of tolerance to the actions of zolpidem and midazolam

Abstract

Eur. J. Pharmac.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Neuropharmacology

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Prog. Neuropsychopharmac. biol. Psychiat.

Pharmacological profile of zolpidem at benzodiazepine receptors and electrocorticogram in rats

Naunyn-Schmiedebergs Arch. Pharmac.

Behavioral tolerance

Zolpidem, a novel non-benzodiazepine hypnotic. I— Neuropharmacological and behavioral effects

J. Pharmac. exp. Ther.

Rapid development of tolerance to the sedative effects of lorazepam and triazolam in rats

Psychopharmacology

Conditioning factors in drug tolerance

Associative control of tolerance to the sedative and hypothermie effects of chlordiazepoxide

Psychopharmacology