Effects of eszopiclone and zolpidem on sleep-wake behavior, anxiety-like behavior and contextual memory in rats

Abstract

At present, eszopiclone and zolpidem are the most commonly prescribed drugs for treating insomnia. Despite the established relationship between sleep disturbance and anxiety, it remains unknown whether targeted treatment for insomnia may affect acute anxiety. Therefore, the objective of this study was to examine the effects of three different doses (1, 3, and 10mg/kg) of eszopiclone and zolpidem on the states of sleep and wakefulness, levels of anxiety-like behavior, and long-term contextual memory in footshock-induced anxious rats. The results of this study demonstrated that the administration of eszopiclone and zolpidem both were equally effective in attenuating footshock stressor-induced suppression of slow-wave sleep (SWS). The administration of eszopiclone at 1mg/kg or zolpidem at 1 and 3mg/kg doses showed a tendency for attenuating stressor-induced suppression of REM sleep. However, the REM sleep attenuating effects of these drugs disappeared when they were administered at higher doses. The administration of eszopiclone at 3 and 10mg/kg doses and zolpidem at all three doses reduced the power of electroencephalographic theta band frequencies during wakefulness. In addition, the administration of eszopiclone at 1 and 3mg/kg doses suppressed stressor-induced anxiety-like behavior. The administration of zolpidem at 1, 3, or 10mg/kg doses was not effective in attenuating stressor-induced anxiety-like behavior. Contextual memory after administration of eszopiclone at 1mg/kg dose had no effects, but was reduced significantly with increased dosage. Contextual memory after administration of zolpidem, at all three doses, was severely disrupted. The results of this study suggest that eszopiclone at a low dose could be used effectively to control anxiety and anxiety-induced insomnia.

Figure 1

Examples of sleep-wake architecture for the 6-h period starting immediately after eight different types of treatment in various rats. The treatments were: non-shocked vehicle-injected (C-NS), shocked and vehicle-injected (C-S), shocked and 1 mg/kg dose of eszopiclone-injected (S-Esz-1), shocked and 3 mg/kg dose of eszopiclone-injected (S-Esz-3), shocked and 10 mg/kg dose of eszopiclone-injected (S-Esz-10), shocked and 1 mg/kg dose of zolpidem-injected (S-Zol-1), shocked and 3 mg/kg dose of zolpidem-injected (S-Zol-3), and shocked and 10 mg/kg dose of zolpidem-injected (S-Zol-10). These eight 6-h continuous step histograms plot occurrence and duration of polygraphically and behaviorally defined wakefulness (W), slow-wave sleep (S), and REM sleep (R).

Figure 2

Effects of stressor and three different doses of eszopiclone on wakefulness. Bars represent percentages (mean + SE) of wakefulness during each of the 6-h periods after following treatments: non-shocked vehicle injected (C-NS), shocked and vehicle-injected (C-S), shocked and 1 mg/kg dose of eszopiclone-injected (S-Esz-1), shocked and 3 mg/kg dose of eszopiclone-injected (S-Esz-3), and shocked and 10 mg/kg dose of eszopiclone-injected (S-Esz-10). *Comparisons with non-shocked vehicle-injected (C-NS) and Δcomparisons with shocked and vehicle-injected (S-C). * or Δ: p<0.05; ** or ΔΔ: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 3

Effects of stressor and three different doses of zolpidem on wakefulness. Bars represent percentages (mean + SE) of wakefulness during each of the 6-h periods after following treatments: non-shocked vehicle-injected (C-NS), shocked and vehicle-injected (C-S), shocked and 1 mg/kg dose of zolpidem-injected (S-Zol-1), shocked and 3 mg/kg dose of zolpidem-injected (S-Zol-3), and shocked and 10 mg/kg dose of zolpidem-injected (S-Zol-10). *Comparisons with non-shocked vehicle-injected (C-NS) and Δcomparisons with shocked and vehicle-injected (S-C). * or Δ: p<0.05; ** or ΔΔ: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 4

Effects of stressor and three different doses of eszopiclone on slow-wave sleep. Bars represent percentages (mean + SE) of slow-wave sleep during each of the 6-h periods after following treatments: non-shocked vehicle injected (C-NS), shocked and vehicle-injected (C-S), shocked and 1 mg/kg dose of eszopiclone-injected (S-Esz-1), shocked and 3 mg/kg dose of eszopiclone-injected (S-Esz-3), and shocked and 10 mg/kg dose of eszopiclone-injected (S-Esz-10). *Comparisons with non-shocked vehicle-injected (C-NS) and Δcomparisons with shocked and vehicle-injected (S-C). Δ: p<0.05; ** or ΔΔ: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 5

Effects of stressor and three different doses of zolpidem on slow-wave sleep. Bars represent percentages (mean + SE) of slow-wave sleep during each of the 6-h periods after following treatments: non-shocked vehicle-injected (C-NS), shocked and vehicle-injected (C-S), shocked and 1 mg/kg dose of zolpidem-injected (S-Zol-1), shocked and 3 mg/kg dose of zolpidem-injected (S-Zol-3), and shocked and 10 mg/kg dose of zolpidem-injected (S-Zol-10). *Comparisons with non-shocked vehicle-injected (C-NS) and Δcomparisons with shocked and vehicle-injected (S-C). Δ: p<0.05; ** or ΔΔ: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 6

Effects of stressor and three different doses of eszopiclone on REM sleep. Bars represent percentages (mean + SE) of REM sleep during each of the 6-h periods after following treatments: non-shocked vehicle injected (C-NS), shocked and vehicle-injected (C-S), shocked and 1 mg/kg dose of eszopiclone-injected (S-Esz-1), shocked and 3 mg/kg dose of eszopiclone-injected (S-Esz-3), and shocked and 10 mg/kg dose of eszopiclone-injected (S-Esz-10). *Comparisons with non-shocked vehicle-injected (C-NS) and Δcomparisons with shocked and vehicle-injected (S-C). * or Δ: p<0.05; **: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 7

Effects of stressor and three different doses of zolpidem on REM sleep. Bars represent percentages (mean + SE) of REM sleep during each of the 6-h periods after following treatments: non-shocked vehicle-injected (C-NS), shocked and vehicle-injected (C-S), shocked and 1 mg/kg dose of zolpidem-injected (S-Zol-1), shocked and 3 mg/kg dose of zolpidem-injected (S-Zol-3), and shocked and 10 mg/kg dose of zolpidem-injected (S-Zol-10). *Comparisons with non-shocked vehicle-injected (C-NS) and Δcomparisons with shocked and vehicle-injected (S-C). Δ: p<0.05; ** or ΔΔ: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 8

Effects of stressor and three different doses of eszopiclone and zolpidem on slow-wave sleep latency (A), REM sleep latency (B), and total number of REM sleep episodes (C). Abbreviations: C-NS, non-shocked vehicle-injected group; C-S, shocked and vehicle-injected group; S-Esz-1, shocked and 1 mg/kg dose of eszopiclone-injected group; S-Esz-3, shocked and 3 mg/kg dose of eszopiclone-injected group; S-Esz-10, shocked and 10 mg/kg dose of eszopiclone-injected group; S-Zol-1, shocked and 1 mg/kg dose of zolpidem-injected group; S-Zol-3, shocked and 3 mg/kg dose of zolpidem-injected group; S-Zol-10, shocked and 10 mg/kg dose of zolpidem-injected group. *Comparisons with non-shocked vehicle-injected group (C-NS) and Δcomparisons with shocked and vehicle-injected group (S-C). * or Δ: p<0.05; ** or ΔΔ: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 9

Effects of three different doses of eszopiclone and zolpidem on elevated plus-maze (EPM) measures of stressor-induced anxiety. Bars in A represent number (mean + SE) of open arm entries and in B represent percent of times spent in the open arm. Abbreviations: C-NS, non-shocked vehicle-injected group; C-S, shocked and vehicle-injected group; S-Esz-1, shocked and 1 mg/kg dose of eszopiclone-injected group; S-Esz-3, shocked and 3 mg/kg dose of eszopiclone-injected group; S-Esz-10, shocked and 10 mg/kg dose of eszopiclone-injected group; S-Zol-1, shocked and 1 mg/kg dose of zolpidem-injected group; S-Zol-3, shocked and 3 mg/kg dose of zolpidem-injected group; S-Zol-10, shocked and 10 mg/kg dose of zolpidem-injected group. *Comparisons with non-shocked vehicle-injected group (C-NS) and Δcomparisons with shocked and vehicle-injected group (S-C). Δ: p<0.05; **: p<0.01; *** or ΔΔΔ: p<0.001.

Figure 10

Effects of three different doses of eszopiclone and zolpidem on contextual fear memory. Bars represent percentages (mean + SE) of freezing to the shocked context at 24 h following contextual fear conditioning training. Abbreviations: C-NS, non-shocked vehicle-injected group; C-S, shocked and vehicle-injected group; S-Esz-1, shocked and 1 mg/kg dose of eszopiclone-injected group; S-Esz-3, shocked and 3 mg/kg dose of eszopiclone-injected group; S-Esz-10, shocked and 10 mg/kg dose of eszopiclone-injected group; S-Zol-1, shocked and 1 mg/kg dose of zolpidem-injected group; S-Zol-3, shocked and 3 mg/kg dose of zolpidem-injected group; S-Zol-10, shocked and 10 mg/kg dose of zolpidem-injected group. *Comparisons with non-shocked vehicle-injected group (C-NS) and Δcomparisons with shocked and vehicle-injected group (S-C). * or Δ: p<0.05; ** or ΔΔ: p<0.01; *** or ΔΔΔ: p<0.001.