Retrograde effects of triazolam and zolpidem on sleep-dependent motor learning in humans

Abstract

SUMMAR Y Drugs that act as allosteric activators at the benzodiazepine site of the gammaaminobutyric acid (GABA A ) receptor complex are used commonly to treat insomnia but relatively little is known of how such use affects learning and memory. Although anterograde effects on memory acquisition have been shown, possible retrograde effects on consolidation are more relevant when such agents are administered at bedtime. We tested the effects of two GABA A allosteric activators on sleep-dependent motor skill memory consolidation in 12 healthy male subjects. Subjects slept in a sleep laboratory for four consecutive nights (one accommodation night followed by three experimental nights). Placebo, triazolam 0.375 mg, and zolpidem 10 mg were given to each subject in counterbalanced order on the experimental nights. Polysomnographic (PSG) sleep measurement and sleep-dependent motor learning were assessed at each condition. Triazolam was associated with longer total sleep time and increased Stage 2 sleep. Both zolpidem and triazolam were associated with increased latency to rapid eye movement (REM) sleep. Overnight motor learning correlated with total sleep time in the placebo condition but not in the triazolam or zolpidem conditions. A statistically significant impairment in motor performance occurred overnight in the triazolam condition only. Triazolam, given in sufficient doses to prolong sleep in healthy people, affected overnight motor learning adversely. Zolpidem, in a dose sufficient to prolong REM onset latency but without other effects on PSG-measured sleep, degraded the relationship between total sleep time and overnight motor learning. These data indicate that non-selective or a1-preferring benzodiazepine site allosteric activators can interfere with sleep-dependent memory consolidation.

About Sleep's Role in Memory

“…In rats, administration of the GABA A agonists eszopiclone and zolipem after learning before sleep impaired contextual memory tested 24 h later (577). Two more recent studies in humans showed similarly impairing effects of triazolam and zolpidem on sleep-dependent consolidation of finger sequence tapping skills (835,836). This is remarkable, as the impairment in motor skill consolidation was paralleled by robust increases in the amount of non-REM sleep stage 2 and spindle activity as well as REM sleep in these studies.…”

The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats

“…However, numerous adverse effects associated with ZOL usage have been reported including driving impairment (Verster et al, 2006; Gunja, 2013), effects on balance and postural tone (Zammit et al, 2008), interference with memory consolidation (Balkin et al, 1992; Wesensten et al, 1996, 2005; Mintzer and Griffiths, 1999; Morgan et al, 2010) and increased incidence of complex behaviors during sleep (Hoever et al, 2010). Some studies investigated the effects of daytime administration of ZOL and tested psychomotor function upon arousal from naps (Wesensten et al, 2005; Storm et al, 2007), a protocol which our experiments closely mimic.…”

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

“…5,21 In this test, subjects are asked to type a 5-digit number sequence as quickly and as accurately as possible with the fingers of the nondominant hand by pressing 4 adjacent numeric keys on a standard computer keyboard. Subjects are instructed to look at the number sequence displayed on the computer screen while typing.…”

“…Finally, Morgan et al reported significant impairment of sleep-dependent memory on a motor task with triazolam (0.375 mg), but not with zolpidem immediate release (10 mg). 21 However, the dose of triazolam is rather high and the detected effect may be a direct influence of drug on motor performance during the morning testing period, rather than interference with SDMC. Additionally, the small sample (N = 12) may have provided insufficient power to detect an effect with the dose of zolpidem employed.…”