Differential Effects of Sodium Oxybate and Baclofen on EEG, Sleep, Neurobehavioral Performance, and Memory

Abstract

Study Objectives: Sodium oxybate (SO) is a GABA B agonist used to treat the sleep disorder narcolepsy. SO was shown to increase slow wave sleep (SWS) and EEG delta power (0.75-4.5 Hz), both indexes of NREM sleep (NREMS) intensity and depth, suggesting that SO enhances recuperative function of NREM. We investigated whether SO induces physiological deep sleep. Design: SO was administered before an afternoon nap or before the subsequent experimental night in 13 healthy volunteers. The effects of SO were compared to baclofen (BAC), another GABA B receptor agonist, to assess the role of GABA B receptors in the SO response. Measurements and Results: As expected, a nap significantly decreased sleep need and intensity the subsequent night. Both drugs reversed this nap effect on the subsequent night by decreasing sleep latency and increasing total sleep time, SWS during the first NREMS episode, and EEG delta and theta (0.75-7.25 Hz) power during NREMS. The SO-induced increase in EEG delta and theta power was, however, not specific to NREMS and was also observed during REM sleep (REMS) and wakefulness. Moreover, the high levels of delta power during a nap following SO administration did not affect delta power the following night. SO and BAC taken before the nap did not improve subsequent psychomotor performance and subjective alertness, or memory consolidation. Finally, SO and BAC strongly promoted the appearance of sleep onset REM periods. Conclusions:The SO-induced EEG slow waves seem not to be functionally similar to physiological slow waves. Our findings also suggest a role for GABA B receptors in REMS generation.

GABABAgonism Promotes Sleep and Reduces Cataplexy in Murine Narcolepsy

“…Criteria for cataplexy were Ն10 s of EMG atonia, theta-dominated EEG, and video-confirmed behavioral immobility preceded by Ն40 s of W (Scammell et al, 2009). Some doses of GHB and R-BAC were associated with hypersynchronous slow waves and/or spike and wave discharge patterns in the EEG that could not be classified as any previously defined arousal state (Snead, 1984;Meerlo et al, 2004;Koek et al, 2007;Vienne et al, 2010). This drug-induced state occurred both before and following bouts of NREM sleep; began within the first hour after dosing; and was scored as a state distinct from wakefulness, NREM, or REM sleep or cataplexy.…”

“…Disruption of the hypocretin (Hcrt; orexin) system results in a narcoleptic phenotype (Chemelli et al, 1999;Lin et al, 1999;Nishino et al, 2000;Peyron et al, 2000). Degeneration of ϳ90% of the Hcrt-producing neurons underlies human narcolepsy (Thannickal et al, 2000) and is recapitulated in orexin/ataxin-3 (Atax) mice in which the Hcrt cells degenerate postnatally (Hara et al, 2001). A conditional model of Hcrt neuron ablation (orexin/tTA; TetO diphtheria toxin A or DTA mice) has recently been described (Tabuchi et al, 2014).…”

“…Although its physiological relevance has been debated (Meerlo et al, 2004;Vienne et al, 2010Vienne et al, , 2012, GHB increases slow-wave activity (SWA) during non-REM (NREM) sleep (Van Cauter et al, 1997;Black et al, 2010;Walsh et al, 2010;Boscolo-Berto et al, 2012), which has been hypothesized to mediate its therapeutic effectiveness. GHB is a controlled substance with abuse potential and possible neurotoxic and psychiatric side effects (Langford and Gross, 2011;van Amsterdam et al, 2012) and, due to its short half-life, must be administered in a split dose (Black et al, 2010), all of which underscore the need for improved narcolepsy pharmacotherapeutics. Despite its acute sedating effects, the therapeutic efficacy of GHB only develops after repeated administration and persists after an acute dose has been metabolized (Mamelak, 2009;Boscolo-Berto et al, 2012).…”

“…Despite its acute sedating effects, the therapeutic efficacy of GHB only develops after repeated administration and persists after an acute dose has been metabolized (Mamelak, 2009;Boscolo-Berto et al, 2012). The mechanism of action of GHB partially depends on the GABA B receptor (Brown and Guilleminault, 2011), as GABA B antagonists block GHB-induced inhibition of neurons (Jensen and Mody, 2001) and the GHB-prodrug ␥-butyrolactone fails to produce behavioral or EEG effects in mice lacking GABA B1 and GABA B2 subunits (Kaupmann et al, 2003;Vienne et al, 2010).…”

Understanding the Sleep-Wake Cycle: Sleep, Insomnia, and the Orexin System

“…Sodium oxybate (also called γ-hydroxybutyrate or GHB), a GABA B agonist, increases SWS and EEG delta power and limits nighttime awakenings. 70,71 The use of GHB is limited by its abuse potential and association with dependence and seizures. 72 Baclofen, a GABA B agonist used as a muscle relaxant and antispasmodic agent, has a sedative effect, increasing both REM and NREM sleep and reducing time awake after sleep onset.…”