SLEEP 2011 Abstract Supplement

A. Basic Science I. Pharmacology and Biochemistry
Support (If Any): This research was supported by the USC Magellan
Scholar Program (D. M. Elliott); HL71560, VA Merit (S. D. Youngstedt);
and NIH HL 71560 (S. D. Youngstedt). This study received no industry
support.
0013
PERIVASCULAR AND MENINGEAL MACROPHAGE
AFFECT SLEEP
Zielinski MR 1 , Davis CJ 1 , van Rooijen N 2 , Krueger JM 1
1
WWAMI Medical Education Program, Sleep and Performance
Research Center, Washington State University, Spokane, WA, USA,
2
Department of Cell Biology and Immunology, Vrije Universiteit of
Amsterdam, Amsterdam, Netherlands
Introduction: Perivascular and meningeal macrophages comprise a
large population of resident macrophages within the brain. These macrophages
are potent producers of pro-inflammatory cytokines including
interleukin-1 beta and tumor necrosis factor-alpha, which regulate sleep.
Perivascular and meningeal macrophages are involved with blood brain
barrier functioning and are likely involved with modulating peripheral/
CNS inflammatory interactions. Clodronate-treatment destroys these
cells. The goal of this research was to determine whether clodronate affects
sleep.
Methods: Male C57BL/6 mice were provided electroencephalogram
(EEG) electrodes over the somatosensory cortices on each brain hemisphere
and an electromyogram electrode in the nuchal muscles for polysomnographic
sleep analyses. In addition, mice were implanted with a
guide cannulae for intracerebroventricular (icv) injections. Mice were
injected with liposomes and sleep responses were recorded for 2 days.
Thereafter, mice were injected with clodronate encapsulated in liposomes
to eliminate perivascular and meningeal macrophages. Sleep was
recorded for 5 days. Sleep state and EEG slow-wave activity (SWA)
during non-rapid-eye-movement sleep (NREMS) were analyzed by
standard criteria.
Results: Mice injected with either liposomes, or clodronate encapsulated
in liposomes, exhibited significant diurnal variations in NREMS,
REMS, and NREMS EEG SWA. However, durations of NREMS and
REMS were significantly reduced in clodronate/liposome-treated mice
compared to liposome controls. These sleep reductions lasted for the 5
days of subsequent recording. In contrast, NREMS EEG SWA was significantly
enhanced the second day after the clodronate/liposome treatment
compared to liposome controls.
Conclusion: These results indicate that perivascular and meningeal
macrophages are involved in sleep and EEG SWA regulation.
Support (If Any): NIH NS025378, NS031453
0014
URINARY NEUROTRANSMITTERS AS POTENTIAL
BIOMARKERS OF POOR SLEEP QUALITY
Olson KL 1 , McManus C 1 , Marc DT 1 , Grude LA 1 , Bull MJ 1 , Wynveen P 2 ,
Mahabamunuge S 2 , Mork K 2 , Nichkova M 2 , Kellermann GH 1
1
Research & Development, NeuroScience, Inc., Osceola, WI, USA,
2
Research & Development, Pharmasan Labs, Inc., Osceola, WI, USA
Introduction: Although insomnia is a major pathological factor in a
number of diseases, limited data exists regarding the biochemistry of
poor sleepers compared to good sleepers. In particular, neurotransmitters
such as gamma-aminobutyric acid (GABA) and histamine are known to
be correlated with sleep quality. The current investigation examined the
relationships between validated sleep scores and urinary neurotransmitter
levels as well as sleep scores and advancing age.
Methods: Data analysis was performed on specimens submitted to
Pharmasan Labs, Inc. (Osceola, WI) for urinary neurotransmitters measurements.
The study included adult patients (18-63 years old; n=75; 48
females, 27 males) that had collected urine specimens before bedtime
and upon awakening, and had completed a Pittsburg Sleep Index (PSI)
questionnaire to assess sleep quality. All data were de-identified but retained
gender, age, and sleep index scores. PSI scores were compared to
neurotransmitter and hormone levels as well as to age.
Results: Wilcoxon rank sum tests suggested that norepinephrine, epinephrine,
GABA, glycine, phenylethylamine (PEA), serotonin and
histamine levels were higher in subjects with poor sleep quality (n=
22) compared to subjects with good sleep quality (n= 53). In addition,
simple linear regressions revealed a weak, positive relationship between
the PSI scores and histamine, GABA, glutamate, glycine and 3,4-dihydroxyphenylacetic
acid (DOPAC) levels. A multiple linear regressions
indicated that, DOPAC, dopamine, epinephrine, GABA, glycine, norepinephrine,
serotonin, 5-hydroxyindoleacetic acid (5-HIAA) and histamine
have a moderate positive association to PSI scores suggesting that,
when considered together, these biomarkers were better indicators of
poor sleep than when considered individually. Finally, there was a positive
relationship between PSI scores and advancing age.
Conclusion: These results indicate that subjects who have poor sleep
quality possess the highest levels of neurotransmitters, specifically
GABA and histamine. These neurotransmitters may function as predictive
markers for sleep issues while providing potential targets for
therapy.
0015
DIFFERENTIAL SLEEP EEG EFFECTS OF SLEEP
RESTRICTION VERSUS TEMAZEPAM IN HEALTHY
SUBJECTS AND PATIENTS WITH PSYCHOPHYSIOLOGICAL
INSOMNIA
Staner L 1 , Cornette F 1 , Pross N 1 , Trecherel C 1 , Girard N 2 ,
Mallet de Chauny E 2 , Metzger D 2 , Muzet A 1
1
R&D, FORENAP, Rouffach, France, 2 Pharma, FORENAP, Rouffach,
France
Introduction: Drugs enhancing GABAa transmission, such as temazepam,
and sleep restriction paradigms are both commonly used in the
treatment of patients suffering from insomnia. However little is known
about how the 2 treatments differ in terms of mechanism of action. The
present study compares their acute sleep EEG effects in healthy subjects
(HS) versus patients with psychophysiological insomnia (PI).
Methods: 10 female and 8 male subjects aged 36.3 +/9 years (9 HC
and 9 PI) were included in a 3-way randomized cross-over study after a
screening procedure comprising polysomnographic recordings. During
each of the 3 study periods, sleep was recorded during three consecutive
nights (baseline, treatment, and recovery). Treatment consisted either of
temazepam 20mg, placebo or a 4-h sleep restriction.
Results: Comparison of the baseline nights revealed that, compared to
HC, PI had lower sleep efficiency, total sleep time and increased wake
percentage. A main treatment effect was evidenced for most parameter,
mostly due to the sleep restriction treatment. However, latency to persistent
sleep, wake after sleep onset, sleep efficiency, and wake percentage
were significantly improved with sleep restriction in PI but not in
HC. Temazepam significantly decreased latency to persistent sleep and
increased stage 2 sleep in PI but not in HC, while it prolonged REM
latency in HC but not in PI.
Conclusion: Sleep restriction and temazepam have different effect on
visual sleep EEG parameter and these effects are not the same in HC vs
PI. It suggests that the 2 treatments act through different mechanisms
and that their different effects on HC vs PI relate to the fact that they
impact normal (HC) versus hyperaroused sleep (PI).
SLEEP, Volume 34, Abstract Supplement, 2011
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