Elsevier

Brain Research

Volume 1010, Issues 1–2, 4 June 2004, Pages 45-54
Brain Research

Research report
Sub-chronic administration of zolpidem affects modifications to rat sleep architecture

https://doi.org/10.1016/j.brainres.2004.02.067Get rights and content

Abstract

Gamma-aminobutyric acidA receptor (GABAAR) 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 GABAAR 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.

Introduction

In the mammalian central nervous system (CNS), γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter. The central γ-aminobutyric acidA receptor (GABAAR) is a pentameric ligand-gated chloride channel composed of multiple classes of subunits including α, β, γ, δ and ε [4]. GABAAR regulatory binding sites have been previously described and include, among others, those for GABA, ethanol, picrotoxin, barbiturates, and benzodiazepines [4], [20], [21], [33]. The interactions of agonistic modulators at the GABAAR benzodiazepine binding site allosterically enhance the binding of GABA to its binding site, leading to enhancement of GABA's inhibitory efficacy [10]. The administration of benzodiazepines has diverse pharmacological effects including sedative, anxiolytic, and muscle relaxant activities [3].

Zolpidem, N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo [1,2-a] pyridine-3-acetamide hemitartrate, appears to preferentially interact with the central α1 subunit containing Type-I (ω1) GABAAR complexes over the α23-containing Type-II (ω2) GABAAR complexes [2]. The classic benzodiazepines, including diazepam, do not appear to show similar selectivity [2], [21], [29], [33]. The receptor subtype selectivity of zolpidem confers beneficial therapeutic properties over the classic benzodiazepines, including maintenance of sedation with reduction in myorelaxant and anticonvulsant properties [11], [26]. The localization of specific GABAAR types to particular structures within the CNS, as has been shown for localization of the GABAA2 but not GABAA1 within the rat spinal cord [27], elucidates how the GABAA1 selectivity of zolpidem confers the therapeutically advantageous benefit of sedation with reduced myorelaxant effects.

The benzodiazepines are effective in both the induction and maintenance of sleep. However, the development of tolerance to these compounds can occur [16]. Treatment of insomnia with these agents is often intermittent and usually administration endures for less than 4 weeks of continued daily use [3]. For this reason, studies which provide insight into effects of sub-chronic and intermittent administration regimens are of practical relevance. Clinical studies that have examined the subjective efficacy of zolpidem in intermittent versus continuous administration in insomniac patients have demonstrated that patients report similar improvements in sleep measures under both chronic daily treatment schedules and intermittently disrupted administration schedules [9], [32]. However, little objective electroencephalographic (EEG) data has accumulated to demonstrate the effectiveness for these compounds over intermittent sub-chronic drug administration schedules.

The present study was designed to investigate the changes in sleep architecture that occur with sub-chronic once-daily administration of zolpidem prior to the inactive phase of the rat circadian cycle, approximating the typical course of use of this compound in humans. In order to evaluate the alterations in rat sleep stage architecture which occur under sub-chronic administration, sleep stage data over a 1-week once-daily administration study were analyzed for the GABAA1-selective zolpidem and compared with the non-selective benzodiazepine, diazepam, using a crossover study design. The experiments reported here confirm the effectiveness of zolpidem and diazepam as sedative hypnotics over sub-chronic intervals of use and directly address the question of whether discontinuous episodic administration influences the efficacy of the GABAA1-selective modulator, zolpidem, to alter sleep architecture.

Section snippets

Materials and methods

All experimental procedures were reviewed and approved by the Merck Institutional Animal Care and Use Committee (West Point, PA) and were performed in accordance with the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council, 1996).

General organization of wakefulness and sleep architecture in the rat

Staging the arousal levels of the rat data over 4 days of continuous recording (Fig. 1A) confirmed the nocturnal nature of this animal model. A statistically significant increase in the mean amount of time scored as active wake occurred during the dark phase (i.e. reversed light cycle of 4 a.m.–4 p.m.) of the circadian cycle (Fig. 1B). Both the mean duration of time spent in active wake (47±7.4 min in light versus 146.5±30.4 min in dark (n=6 animals): p<0.05) and the number of times that the

Discussion

These studies demonstrate that two sedative hypnotics, diazepam and zolpidem, modified sleep architecture in the rat over 7 days of sub-chronic oral administration. Zolpidem lacked tolerance effects over brief periods of intermittent administration of sub-chronic drug exposure, but lead to effects on rat sleep architecture, which endured beyond the period of administration. Reiteration of sub-chronic exposure to zolpidem led to enhanced efficacy in the modification of sleep structure when

Acknowledgements

We wish to thank the Dept. of Laboratory Animal Resources, especially Angela Zeoli, Daniel Pisacreta, Parker Mathers, Hunter Euler and Patty Rebbeck for surgical, technical, and animal husbandry assistance.

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