E over the circadian period in a brain-region dependent manner [33, 34], suggesting that eCB signaling may be under circadian regulation. In fact, levels of AEA and 2-AG are lowest in cortical and hypothalamic tissues at the onset of the DP [33], and in the present work, administration of CB1 antagonists at this time point produced smaller effects on sleep architecture. Thus, our findings provide evidence that changing levels of the molecular components of the eCB system have functional consequences for eCB regulation of vigilance states.eCBs and EEG Power Oroxylin AMedChemExpress 6-Methoxybaicalein SpectraNREM delta power has been used as an index for sleep homeostatic drive because of the correlation of this measure with the difference in cumulative time awake versus asleep [44, 50, 51]. However, as Davis et al [65] point out, some pharmacological manipulations can dissociate alterations in delta power and changes in vigilance states, thus confounding NREM delta power as a metric of sleep homeostatic drive. This situation is clearly applicable to the current dataset, where CB1 antagonists increased delta power across all vigilance states without changing total sleep time. On the contrary, CB1 antagonists fragment NREM sleep, and this may lead one to speculate that the augmentation of delta is a response to poor sleep quality, and therefore, an increase in sleep drive. In fact, sleep fragmentation protocols are associated with increasing homeostatic sleep drive [66?8]. However, evidence from the current dataset arguesPLOS ONE | DOI:10.1371/journal.pone.0152473 March 31,31 /Endocannabinoid Signaling Regulates Sleep Stabilityagainst the hypothesis that the CB1 antagonist-induced increase in delta power is indicative of an 1471-2474-14-48 increase in sleep homeostatic processes. First, the time course for augmented delta does not reflect a gradual increase that one would expect if homeostatic sleep drive were building over time with reduced sleep quality. Second, the rebound in total NREM sleep following 6 Hr sleep deprivation was not occluded by CB1 antagonists. Third, blockade of CB1 did not alter the rate of recovery from sleep deprivation. It should be noted that we did not normalize our power spectral data as in other reports [17, 28, 29, 32], and our presentation of raw power spectral results may explain some discrepancies between our findings and those of others. It is not clear why other researchers have not observed the large augmentation of delta and theta power following administration of CB1 antagonists reported here. In fact, several reports have observed reduced delta and theta power following administration of CB1 antagonists [19, 28] while others have concluded that these drugs have little or no effect on the EEG power spectrum [29, 32]. We can only speculate that the variability in methods used to normalize power spectral bandwidths has contributed to these inconsistencies. Win 63843 chemical information Although we observed no changes in low-frequency oscillations following fpsyg.2016.01448 drugs that activate eCB signaling (JZL, AM3506, CP47), gamma oscillations were consistently reduced, particularly during NREM and REM sleep. This result is consistent with previous reports suggesting reduced gamma power is a robust effect of increased CB1 activation [69?3]. Another consistent effect of cannabinoid agonists is to facilitate high-voltage spindles/spike wave discharges (HVS) [74?6], but in the present study, power spectral analysis found no changes in the HVS bandwidth. This is not surprising given that spindles are rare in C5.E over the circadian period in a brain-region dependent manner [33, 34], suggesting that eCB signaling may be under circadian regulation. In fact, levels of AEA and 2-AG are lowest in cortical and hypothalamic tissues at the onset of the DP [33], and in the present work, administration of CB1 antagonists at this time point produced smaller effects on sleep architecture. Thus, our findings provide evidence that changing levels of the molecular components of the eCB system have functional consequences for eCB regulation of vigilance states.eCBs and EEG Power SpectraNREM delta power has been used as an index for sleep homeostatic drive because of the correlation of this measure with the difference in cumulative time awake versus asleep [44, 50, 51]. However, as Davis et al [65] point out, some pharmacological manipulations can dissociate alterations in delta power and changes in vigilance states, thus confounding NREM delta power as a metric of sleep homeostatic drive. This situation is clearly applicable to the current dataset, where CB1 antagonists increased delta power across all vigilance states without changing total sleep time. On the contrary, CB1 antagonists fragment NREM sleep, and this may lead one to speculate that the augmentation of delta is a response to poor sleep quality, and therefore, an increase in sleep drive. In fact, sleep fragmentation protocols are associated with increasing homeostatic sleep drive [66?8]. However, evidence from the current dataset arguesPLOS ONE | DOI:10.1371/journal.pone.0152473 March 31,31 /Endocannabinoid Signaling Regulates Sleep Stabilityagainst the hypothesis that the CB1 antagonist-induced increase in delta power is indicative of an 1471-2474-14-48 increase in sleep homeostatic processes. First, the time course for augmented delta does not reflect a gradual increase that one would expect if homeostatic sleep drive were building over time with reduced sleep quality. Second, the rebound in total NREM sleep following 6 Hr sleep deprivation was not occluded by CB1 antagonists. Third, blockade of CB1 did not alter the rate of recovery from sleep deprivation. It should be noted that we did not normalize our power spectral data as in other reports [17, 28, 29, 32], and our presentation of raw power spectral results may explain some discrepancies between our findings and those of others. It is not clear why other researchers have not observed the large augmentation of delta and theta power following administration of CB1 antagonists reported here. In fact, several reports have observed reduced delta and theta power following administration of CB1 antagonists [19, 28] while others have concluded that these drugs have little or no effect on the EEG power spectrum [29, 32]. We can only speculate that the variability in methods used to normalize power spectral bandwidths has contributed to these inconsistencies. Although we observed no changes in low-frequency oscillations following fpsyg.2016.01448 drugs that activate eCB signaling (JZL, AM3506, CP47), gamma oscillations were consistently reduced, particularly during NREM and REM sleep. This result is consistent with previous reports suggesting reduced gamma power is a robust effect of increased CB1 activation [69?3]. Another consistent effect of cannabinoid agonists is to facilitate high-voltage spindles/spike wave discharges (HVS) [74?6], but in the present study, power spectral analysis found no changes in the HVS bandwidth. This is not surprising given that spindles are rare in C5.
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