JOURNAL OF SLEEP AND SLEEP DISORDERS RESEARCH ISSN 0161-8105 SLEEP

489 Pages·2013·5.38 MB·English

JOURNAL OF SLEEP AND SLEEP DISORDERS RESEARCH
ISSN 0161-8105
SLEEP
VOLUME 36, 2013 | abstraCt sUppLEMEnt
27th Annual Meeting of the
Associated Professional
Sleep Societies, LLC
Baltimore, Maryland
Scientific Highlights/Abstracts of
Original Investigations
Click on the buttons below to jump to sections.
Official publication of the
Associated Professional Sleep Societies, LLC
A joint venture of the
American Academy of Sleep Medicine
and the Sleep Research Society

SLEEP
JOUrnaL OF sLEEp anD sLEEp DIsOrDErs rEsEarCH
Volume 36, 2013 | Abstract Supplement
Official publication of the Associated Professional Sleep Societies, LLC. A joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.
EDITOR IN CHIEF
David F. Dinges, phD
Deputy Editors
Sonia Ancoli-Israel, phD Mary A. Carskadon, phD David S. Hui, MD, FCCp Allan I. Pack, phD, MbChb Jerome Siegel, phD
Thomas J. Balkin, phD Ronald D. Chervin, MD Andrew D. Krystal, MD Sanjay R. Patel, MD Michael H. Silber, MbChb
Mathias Basner, MD, phD, Msc Chiara Cirelli, MD, phD Samuel T. Kuna, MD Naresh M. Punjabi, MD, phD Virend K. Somers, MD, phD
Claudo L. Bassetti, MD Charles A. Czeisler, MD, phD Ralph Lydic, phD Stuart F. Quan, MD Fred Turek, phD
Ruth M. Benca, MD, phD Christopher J. Earley, MD, phD Carole L. Marcus, MbChb Susan Redline, MD Hans P. Van Dongen, phD
Donald L. Bliwise, phD Colin a. Espie, phD, Fbpss, FCs Emmanuel Mignot, MD, phD David B. Rye, MD, phD Matthew P. Walker, phD
Jan Born, phD Daniel J. Gottlieb, MD, MpH Charles M. Morin, phD Mark H. Sanders, MD Terry Young, phD
Daniel J. Buysse, MD David Gozal, MD Thomas E. Scammell, MD Phyllis C. Zee, MD, phD
Associate Editors
Roseanne Armitage, phD Charles F. George, MD Vishesh Kapur, MD Matthew T. Naughton, MD, FraCp Ronald S. Szymusiak, phD
Diane B. Boivin, MD, phD Daniel G. Glaze, MD Meir H. Kryger, MD Eric A. Nofzinger, MD, FaasM Eve V. Van Cauter, phD
Christian Cajochen, phD Namni Goel, phD Clete A. Kushida, MD, phD Mark R. Opp, phD Eus J.W. Van Someren, phD
Francesco Cappuccio, Mb bs, MD, Msc Nalaka S. Gooneratne, MD Carol A. Landis, rn, Dsn Sairam Parthasarathy, MD Takeshi Tanigawa, MD, phD
Michael W. L. Chee, MD, phD Allison G. Harvey, phD Atul Malhotra, MD Tarja Porkka-Heiskanen, phD Alexandros N. Vgontzas, MD
Peter Cistulli, MD, phD Steven J. Henriksen, phD Beth A. Malow, MD Dieter Riemann, phD James K. Walsh, phD
Ian M. Colrain, phD David Hillman, Mbbs Rachel Manber, phD Larry D. Sanford, phD Terri E. Weaver, phD
Subimal Datta, phD Michael Irwin, MD, phD Douglas McEvoy, MD Carlos H. Schenck, MD John R. Wheatley, MD, phD
Paul Franken, phD Barbara E. Jones, phD Jodi A. Mindell, phD Richard J. Schwab, MD John W. Winkelman, MD, phD
Executive Director Book Review Editor Managing Editor
Jerome A. Barrett Michael H. Bonnet, phD Andrew Miller
Editorial Board
Richard P. Allen, phD Leslie C. Dort, Msc, DDs Thomas S. Kilduff, phD Bruce O’Hara, phD Kazue Semba, phD
Mark S. Aloia, phD Christopher L. Drake, phD Elizabeth B. Klerman, MD, phD Maurice M. Ohayon, MD Paul J. Shaw, phD
Monica L. Andersen, phD Jeanne F. Duffy, phD Kristen L. Knutson, phD Lyle Olson, MD Priyattam J. Shiromani, phD
J. Todd Arnedt, phD Marie Dumont, phD Hans-Peter Landolt, phD Philippe Peigneux, phD Karine Spiegel, phD
Isabelle Arnulf, MD, phD Charmane Eastman, phD Peretz Lavie, phD Plamen D. Penev, MD, phD Arthur J. Spielman, phD
Alon Y. Avidan, MD, MpH Jeffrey M. Ellenbogen, MD Kathryn A. Lee, phD, rn Thomas Penzel, phD Edward J. Stepanski, phD
M. Safwan Badr, MD Raffaele Ferri, MD Kenneth L. Lichstein, phD Paul E. Peppard, phD Robert Stickgold, phD
Siobhan Banks, phD James Gangwisch, phD Steven W. Lockley, phD Michael L. Perlis, phD Kingman P. Strohl, MD
David Barnes, Mbbs, FCCp Thomas J. Geller, MD Mark Mahowald, MD Barbara A. Phillips, MD, MspH, FCCp Patrick J. Strollo, MD, FCCp, FaasM
Celyne H. Bastien, phD Sina A. Gharib, MD George Mashour, MD, phD Dante Picchioni, phD Deborah Suchecki, phD
Dean W. Beebe, phD Robert W. Greene, MD, phD W. Vaughn McCall, MD Giora Pillar, MD, phD Ariel Tarasiuk, phD
Richard B. Berry, MD Reut Gruber, phD Dennis J. McGinty, phD Thomas Pollmacher, MD Robert J. Thomas, MD
Edward O. Bixler, phD Christian Guilleminault, MD Thomas A. Mellman, MD Gina R. Poe, phD Adrienne Tucker, phD
Bjorn Bjorvatn, MD, phD Martica Hall, phD Ralph Mistlberger, phD Gregg S. Pressman, MD, FaCC Sigrid C. Veasey, MD
Robert Brouillette, MD Patrick Hanly, MD, D, abDsM Nicola Montano, MD, phD Hengyi Rao, phD Arthur S. Walters, MD
Julie Carrier, phD Rosemary S. Horne, phD Janet M. Mullington, phD David M. Rapoport, MD Nancy J. Wesensten, phD
Peter Catcheside, phD Luca Imeri, MD David N. Neubauer, MD Renata L. Riha, RPSGT, MD Amy R. Wolfson, phD
Thien Thanh Dang-Vu, MD, phD Shahrokh Javaheri, MD seiji nishino, MD, phD Timothy A. Roehrs, phD Kenneth P. Wright, phD
Yves Dauvilliers, MD, phD Athanasios G. Kaditis, MD Louise M. O’Brien, phD Avi Sadeh, Dsc James K. Wyatt, phD
Max Kelz, MD, phD Paula K. Schweitzer, phD
SLEEP (ISSN: Online 1550-9109; Website: Institutional Online (US and International): al Sales Account Executive at advertising@ associated with such permissions. Sleep Medicine, the Sleep Research Society,
www.journalsleep.org) is published on-line $425.00. Prorated subscriptions are not aasmnet.org for complete information. or of their officers, regents, members or em-
monthly plus abstract in May by the Associat- available. Subscriptions begin with the REPRINTS: For author reprints contact the ployees. The Editor-in-Chief, the Associated
ed Professional Sleep Societies, LLC, a joint January issue of the current year. Renew- PERMISSION TO REPRODUCE: Written APSS office. For commercial reprint orders Professional Sleep Societies, the American
venture of the American Academy of Sleep als should be secured as early in the year permission to reproduce, in print or electroni- contact Cenveo Publisher Services, 4810 Academy of Sleep Medicine, the Sleep Re-
Medicine and the Sleep Research Society as possible to avoid uninterrupted service. cally, whole articles or any parts of works, fig- Williamsburg Road, #2, Hurlock, MD 21643 search Society, and officers, regents, mem-
located at 2510 North Frontage Road, Darien, Questions about subscriptions (including ures or tables published in SLEEP must be or [email protected] bers and employees disclaim all responsibility
IL 60561-1511, phone [phone] and fax payments, billing procedures, or policy mat- obtained prior to publication. Permission for for any injury to persons or property resulting
[phone]. ters) should be directed to the APSS office at republication must be arranged through the DISCLAIMER: The statements and opinions from any ideas or products referred to in ar-
[phone]. Copyright Clearance Center, Inc., 222 Rose- contained in editorials and articles in this ticles contained in this journal.
annUaL sUbsCrIptIOn ratEs: sub- wood Drive, Danvers, MA 01923, phone (978) journal are solely those of the authors thereof
scription rates for Volume 36, 2013: Individ- ADVERTISING: Digital advertising is available 750-8400 or fax [phone] or URL http:// and not of the Associated Professional Sleep © 2013 Associated Professional Sleep Soci-
ual Online (US and International): $225.00; on journalsleep.org. Please contact the Nation- www.copyright.com. There are royalty fees Societies, LLC, the American Academy of eties, LLC.
EDITORIAL
This abstract supplement unites SLEEP and the science of SLEEP 2013 – the 27th Annual Meeting of the
Associated Professional Sleep Societies, LLC (APSS) – providing a glimpse into the new ideas and latest
research taking place in the field of sleep.
All abstracts presented at SLEEP 2013, held June 1-5, 2013, in Baltimore, Maryland, are included in this
special issue. This year, 1,270 abstracts will be presented at the meeting. 196 will be presented in an oral
presentation format, and the remainder will be presented in a poster format. In addition, individuals in
training programs will be presenting posters of case reports, which are contained in the supplement, and
abstracts, which, although not included in this supplement, will be an exciting portion of the meeting.
The abstracts are divided between basic and clinical sleep science and then assigned to one of 28 subcategories.
Each abstract has a unique four-digit number to facilitate identification and location both within this issue and
at SLEEP 2013. The four-digit number in the abstract supplement matches the four-digit code published in
the SLEEP 2013 Final Program.
The SLEEP meeting fosters an environment in which members and attendees obtain education on the
latest basic science, clinical science and technologies, which will further promote the continued growth
of the field through the dissemination of new knowledge. We look forward to sharing in the success of
this pivotal event.
David F. Dinges, PhD
Editor in Chief
SLEEP, Volume 36, Abstract Supplement, 2013 A2
Table of Contents
Abstracts by Category (click on any section to jump to it)
A3 SLEEP, Volume 36, Abstract Supplement, 2013
A. Basic Sleep Science I. Pharmacology and Biochemistry
0001 0002
WAKE-PROMOTING EFFECTS OF ONO-4127, A STIMULATION OF THE α2A ADRENERGIC RECEPTOR
PROSTAGLANDIN DP1 RECEPTOR ANTAGONIST, IN IN THE VENTROLATERAL PREOPTIC AREA PROMOTES
HYPOCRETIN DEFICIENT NARCOLEPTIC MICE AROUSAL
Sagawa Y1,2, Sato M1,2, Chikahisa S1,3, Chiba S1,4, Yamamoto J5, McCarren H1,2,5, Chalifoux MR1, Han B1, Fleisher MA1, Beck SG2,3,
Nishino S1 Wyner AJ4, Kelz M1,2,3,5
1Stanford Sleep and Circadian Neurobiology Laboratory, Stanford 1Anesthesia and Critical Care, University of Pennsylvania,
University School of Medicine, Palo Alto, CA, USA, 2Department of Philadelphia, PA, USA, 2Pharmacology, University of Pennsylvania,
Neuropsychiatry, Akita University School of Medicine, Akita, Japan, Philadelphia, PA, USA, 3Neuroscience, University of Pennsylvania,
3Department of Integrative Physiology, Institute of Health Biosciences, Philadelphia, PA, USA, 4Statistics, University of Pennsylvania,
The University of Tokushima Graduate School, Tokushima, Japan, Philadelphia, PA, USA, 5Center for Sleep and Circadian Neurobiolgy,
4Department of Otorhinolaryngology, Jikei University School University of Pennsylvania, Philadelphia, PA, USA
of Medicine, Tokyo, Japan, 5Minase Research Institute, Ono
Pharmaceutical Co., Ltd., Mishima, Japan Introduction: Anesthetic induced hypnosis arises in part from specific
actions of anesthetic drugs upon the endogenous circuits regulating sleep
Introduction: Amphetamines and modafinil are the two major classes and wakefulness. We have previously demonstrated that isoflurane di-
of compounds used for the treatment of excessive daytime sleepiness rectly depolarizes sleep-promoting ventrolateral preoptic (VLPO) neu-
(EDS) associated with narcolepsy. These treatments are not always sat- rons. Neighboring non-sleep active VLPO neurons are not depolarized
isfactory due to incomplete management and unpleasant side effects. by general anesthetics. However, the behavioral significance of these ef-
PGD2 or DP1 receptor agonists promote sleep, while a PGD2 synthase fects has been called into question. We hypothesized that acute pharma-
inhibitor promotes wakefulness in animals. It was recently reported that cologic modulation of adrenergic signaling in VLPO would counteract
ICV perfusion of ONO4127, a selective DP1antagonist, enhances wake- anesthetic-induced hypnosis both ex vivo and in vivo.
fulness in rats. In the current study, we evaluated the wake-promoting ef- Methods: Whole-cell current clamp recordings were conducted on
fects of ONO-4127 in orexin/ataxin-3 transgenic (Tg) narcoleptic, wild 200µm VLPO-containing slices obtained from C57B6/J mice. Cells
type, and DP1 receptor knockout (KO) mice and compared the efficacy were categorized as putative sleep-promoting based upon a hyperpolar-
with that of modafinil. izing response to norepinephrine (NE). To determine the mechanism of
Methods: Mice (n=6-8 for each genotype) were surgically attached to adrenergic-induced hyperpolarization, the highly specific alpha2A ago-
the headstage for EEG and EMG monitoring. Two drug doses (6.0 × nist, dexmedetomidine was bath applied. Indwelling bilateral cannulae
10-5 M, 2.9 ×10-4 M) or vehicle were administered at 1.0μl/min with were used to deliver 25nl of adrenergic drugs into VLPO of 0.8% iso-
a microdialysis probe aimed at the basal forebrain (BF; the horizontal flurane-anesthetized mice or into mice with bilateral cannulae implanted
limb of the diagonal band) in each mouse in light (ZT 2 to ZT8) and dark 500um more caudally. Arousal state behavioral scores ranging from 0
(ZT 14 to ZT 20) periods. Modafinil (30mg and 100mg/kg, p.o. at ZT 2 (no movement) to 4 (full return of righting reflex) were assigned for the
and ZT14) was administered in these mice for comparison. 10-minute period prior to drug and the 5-minutes following drug.
Results: The infusion of ONO-4127 to the BF markedly increased wake Results: In 7/7 NE hyperpolarized VLPO neurons, 100nM dexmedeto-
and reduced NREM and REM sleep in both WT and Tg mice. ONO- midine also elicited a hyperpolarization (-43±2.7mV to -50.0±2.3mV,
4127 at 6.0×10-5 M and 2.9×10-4 M, increased 6 hour cumulative wake p=0.0014). Multiplex RT-PCR performed on cytoplasmic aspirates from
amount by 45.8%, 62.4%, and reduced NREM by 30.2%, 41.4% and single neurons confirmed the presence of alpha2A, 2B, and 2C adre-
REM sleep by 32.5%, 42.7% (compared to the vehicle sessions) in WT noceptors in the dexmedetomidine-hyperpolarized neurons. Conversely,
mice in the light period, and increased wake by 37.6%, 51.9%, reduced in 3/3 NE depolarized VLPO neurons dexmedetomidine did not sig-
NREM by 32.0%, 47.8% and REM sleep by 63.8%, 71.4% in Tg mice. nificantly alter resting membrane potential. Having demonstrated that
In the dark period, ONO-4127 increased wake by 20.6%, 31.8%, re- dexmedetomidine hyperpolarizes putative sleep-promoting neurons, we
duced NREM by 36.9%, 56.4% and REM sleep by 14.5%, 30.6% in explored the effects of adrenergic ligands in vivo. Dexmedetomidine
WT mice, and increased wake by 24.5%, 38.7%, reduced NREM by infusion significantly increased arousal, while saline, α1 agonist phen-
38.3%, 59.5%, and reduced REM sleep by 31.6%, 59.9% in Tg mice. ylephrine, and NE did not (p<0.05). Dexmedetomidine failed to rouse
ONO-4127 produced no significant effects on temperature and locomo- animals exposed to a deeper state of isoflurane anesthesia.
tor activity. The wake promoting potency of ONO-4127 (2.9x10-4 M) Conclusion: These results suggest that stimulation of α2A adrenergic
is roughly comparable to that of modafinil (100mg/kg p.o). ONO-4127 receptors in VLPO promotes arousal.
reduced direct transition from wake to REM sleep (DREM) in Tg mice Support (If Any): T32 HL007713-18, R01 GM088156, Penn Depart-
(by 67.6%, 100%), while modafinil did not reduce DREM. The effects ment of Anesthesiology & Critical Care
of ONO-4127 were site specific, and perfusion of ONO-4127 to the
thalamus did not increase wake. 0003
Conclusion: Possible use of prostaglandin DP1 antagonists for the treat- CEREBRAL LACTATE CONCENTRATION PARALLELS
ment of EDS associated with narcolepsy is suggested. DP1 antagonists SLOW WAVE DYNAMICS ACROSS SLEEP/WAKE CYCLES
may also reduce cataplexy, as ONO-4127 reduced DREM in Tg mice. IN GENETICALLY-DISTINCT MOUSE POPULATIONS
Support (If Any): Research supported by Ono Pharmaceutical Co., Ltd. Wisor J1, Rempe M2, Schmidt MA1, Clegern WC1
1WWAMI Medical Education Program and Program in Neuroscience,
Washington State University, Spokane, WA, USA, 2Mathematics and
Computer Science, Whitworth University, Spokane, WA, USA
Introduction: Previously published work by Franken and colleagues
described a difference among mouse strains in the rate of accumulation
of sleep need. The rate at which slow wave activity (SWA) in the sleep
electroencephalogram (EEG) accumulates as a function of the duration
of prior wakefulness is greater in BALB/c mice than C57BL/6 mice. We
hypothesized that this strain difference is paralleled by a difference in
the rate of cerebral glucose utilization.
SLEEP, Volume 36, Abstract Supplement, 2013 A4
A. Basic Sleep Science I. Pharmacology and Biochemistry
Methods: Lactate concentration in the cerebral cortex was measured nist (1 and 3 mpk, p.o.) fully reversed the executive function deficit in
in real-time, using a lactate oxidase-based biosensor, to provide a read- the extradimensional shift induced by phencyclidine (PCP; 5 mpk bid ip
out of cerebral glucose utilization. Sleep/wake state and EEG SWA (1-4 for 7 d). In an object retrieval paradigm conducted in male Cynomolgus
Hz) were determined in 10-sec epochs by concurrent fronto-parietal macaques, partial (1-10 mpk, p.o.) and full (3 mpk, p.o.) TAAR1 ago-
electroencephalogram analysis. Changes in lactate concentration were nists increased accuracy in the difficult trials of this task.
measured across spontaneous sleep/wake intervals of varying duration Conclusion: These results demonstrate that TAAR1 partial agonists
(1,2,4,8,16,32 or 64-min) during which either slow wave sleep (SWS) promote wakefulness in a dose-dependent manner irrespective of time
or desynchronized states represented >80% of time. Normalized lactate of day or underlying sleep pressure by lengthening the duration of bouts
concentration was subjected to repeated measures ANOVA with strain of wakefulness without inducing hyperlocomotion or affecting Tb. Fur-
and interval duration as independent variables. Additionally, statisti- thermore, the procognitive effects and absence of hyperlocomotion of
cal relationships between EEG power in 3-Hz windows and change in TAAR1 agonists demonstrate the functional utility of TAAR1-mediated
lactate concentration were measured across 1-min intervals of SWS by alertness.
repeated measures ANOVA.
Results: The data yielded statistically significant strain X interval du- 0005
ration interaction affecting both lactate concentration and EEG SWA. THE BASAL FOREBRAIN CHOLINERGIC CELLS ARE
BALB/c mice exhibited a significant elevation of lactate concentration IMPORTANT FOR THE REGULATION OF BIOCHEMICAL
within two minutes of wakefulness, whereas C57BL/6 mice exhibited AND ELECTROPHYSIOLOGICAL MECHANISMS
significant elevation of lactate concentration only after 8 or more min- UNDERLYING SLEEP HOMEOSTASIS
utes of wakefulness. Additionally, declines in EEG SWA and lactate Kalinchuk A1, Porkka-Heiskanen T2, McCarley RW1, Basheer R1
concentration across intervals of SWS were greater in C57BL/6 than 1Department of Psychiatry, VA Boston Healthcare System, Harvard
BALB/c mice. In both strains, 1-4Hz EEG activity associated with an Medical School, Boston, MA, USA, 2Institute of Biomedicine,
accelerated decline in lactate concentration during SWS. Theta activity University of Helsinki, Helsinki, Finland
in SWS associated with accelerated decline in lactate concentration in
BALB/c only. Introduction: Recently, we reported a biochemical cascade, which is
Conclusion: These data document strain differences in the temporal triggered in the basal forebrain (BF) during sleep deprivation (SD) and
dynamics and state-dependence of cerebral glucose utilization across contributes to recovery sleep (RS); this cascade includes production of
sleep/wake states. inducible nitric oxide synthase (iNOS), followed by increases in NO
Support (If Any): Research supported by the National Institutes of and adenosine (AD). The level of lactate (Lac), the indicator of neuronal
Health grant RO1NS 78498 (JPW, PI). activation, also increases in the BF during SD. While the increase in cor-
tical Lac is suggested to be involved in sleep homeostasis, its role in BF
0004 is not clear. To compare the homeostatic role of different biochemical
TRACE AMINE-ASSOCIATED RECEPTOR 1 (TAAR1) markers in the BF, we performed simultaneous measurements of SD-
PARTIAL AGONISM: A NOVEL MECHANISM TO PROMOTE induced increases in NO, AD and Lac and correlated the changes with
WAKEFULNESS AND ENHANCE COGNITION waking EEG theta power (5-9Hz), a marker of homeostatic sleep pres-
Kilduff TS1, Morairty S1, Revel F2, Wallace TL1, Moreau J2, sure (HSP). Previously, we showed that RS is dependent on the presence
Wettstein JG2, Hoener M2 of cholinergic BF (ChBF) cells. Here, we further investigated the role of
1Center for Neuroscience, SRI International, Menlo Park, CA, USA, these cells in biochemical and EEG changes during SD.
2Neuroscience Research, F. Hoffman-La Roche, Basel, Switzerland Methods: Male rats were implanted with electrodes for EEG/EMG
recording and guide cannulae for microdialysis probes targeting BF.
Introduction: Trace amines (TAs) such as β-phenylethylamine, p-ty- Dialysates were analyzed for AD and Lac using HPLC, and for NO
ramine, octopamine and tryptamine are endogenous ligands for Trace metabolites nitrate/nitrite (NOx). Further, ChBF cells lesioning was
Amine-associated Receptor 1 (TAAR1). TAAR1 is a G protein-coupled performed using injections of 192-IgG saporin, and similar dialysis
receptor involved in modulation of dopaminergic, serotonergic and pos- measurements were repeated 2 weeks after the injection.
sibly glutamatergic activity. Because of the involvement of these neu- Results: We found that the increase in low frequency theta (LFT) power
rotransmitter systems in sleep/wake control, we evaluated the efficacy (5-7Hz), but not in high frequency theta (HFT) (7-9Hz) during SD cor-
of TAAR1 full and partial agonists on sleep and wakefulness in rats and related with the increase in NREM delta power during RS, suggestive
on cognition in both rats and non-human primates. that LFT is a better indicator of HSP. The SD-induced changes in NOx
Methods: Male Sprague-Dawley rats were implanted with telemetry and AD correlated with the increase in LFT, while the increase in Lac
devices for recording EEG, EMG, body temperature (Tb) and locomo- correlated with the increase in HFT. The lesion of ChBF cells prevented
tor activity (LMA). Several studies were performed in which each rat increases in NOx, AD and LFT, and hence impaired the correlation be-
received separate oral dosings (2 ml/kg) in a repeated measures design. tween these markers. However, it did not affect the increases in Lac and
In the first set of studies, dosing consisted of full and partial TAAR1 ago- HFT and correlation between them.
nists at different concentrations, a vehicle control (VEH; H2O + 0.3% Conclusion: Our data show that in BF increase in Lac, with and without
Tween80) and zolpidem (30 mpk) during the middle of the dark (active) ChBF lesions, correlated poorly with homeostatic EEG parameters, thus
period at ZT18 (ZT0=light onset; ZT12=light offset). In the second set suggesting it reflected the generalized increase in neuronal activation
of studies, rats received TAAR1 partial agonists at various concentra- during SD. In contrast, the SD-induced increase in AD and NOx showed
tions, VEH, and caffeine (10 mpk) during the middle of the light (rest) a strong correlation with LFT, confirming their role as HSP markers.
period at ZT6. ChBF lesions prevented the correlated increases in AD, NOx and LFT,
Results: Whereas the TAAR1 full agonist had little effect on sleep/ suggesting that ChBF cells are important for regulating biochemical and
wake when tested during the dark phase at ZT18, partial agonism dose- electrophysiological mechanisms during SD, and hence for the genera-
dependently increased wakefulness, reduced both NREM and REM tion of RS.
sleep, and increased the latency to REM sleep when administered at Support (If Any): VA Merit Award (RB), Academy of Finland (TPH),
ZT6. TAAR1 partial agonism also increased wakefulness and reduced Christian Gillin Research Grant (AK), NIMH Grant MH 39683 (RWM)
NREM sleep when administered at ZT18. LMA and Tb were unaffected
by TAAR1 full or partial agonism at either time of day. In an attentional
set-shifting task performed in male Long-Evans rats, a TAAR1 full ago-
A5 SLEEP, Volume 36, Abstract Supplement, 2013
A. Basic Sleep Science I. Pharmacology and Biochemistry
0006 EMG recordings. In rats, zolpidem (10mg/kg po) was administered in
THE TIMING OF OREXIN RECEPTOR ANTAGONIST combination with the OX2R antagonist JNJ-10397049 (10mg/kg sc) or
EFFICACY IS RESTRICTED TO THE INACTIVE PHASE BY A the OX1R antagonist GSK-1059865 (10mg/kg sc) at the onset of the
HIGH OX2R OCCUPANCY THRESHOLD dark phase. Mice from each genotype were orally dosed with zolpidem
Gotter AL1, Winrow CJ1, Brunner J1, Garson SL1, Tannenbaum PL2, (10mg/kg) at dark onset. Sleep-wake parameters were analyzed during
Cui D4, Tye SJ2, Uslaner J2, Coleman PJ3, Renger JJ1 the subsequent 12-h dark phase.
1Neuroscience, Merck Research Laboratories, West Point, PA, USA, Results: Rats treated with either zolpidem or the OX2R antagonist alone
2In Vivo Pharmacology, Merck Research Laboratories, West Point, PA, showed a significant reduction in NREM sleep latency and an increase
USA, 3Medicinal Chemistry, Merck Research Laboratories, West Point, in NREM sleep duration. These NREM sleep-promoting effects were
PA, USA, 4Pharmacokinetics and Drug Metabolism, Merck Research potentiated when the two compounds were co-administered. OX2R
Laboratories, West Point, PA, USA blockade, which had no effect on REM sleep by itself, did not alter the
REM sleep suppressing effect of zolpidem. The OX1R antagonist did
Introduction: Ideally, insomnia therapeutics promote normal sleep not affect any sleep parameter either alone or in combination with zolpi-
throughout the inactive period, while avoiding residual effects upon dem. Mice from each genotype exhibited a reduced NREM latency and
waking. The duration of sleep promoting efficacy is not only dependent a prolonged NREM sleep duration following zolpidem administration,
upon a compound’s pharmacokinetic properties, but also receptor oc- while REM sleep was minimally affected. However, the NREM sleep
cupancy required for in vivo effects. Dual orexin receptor antagonists increment was significantly more pronounced in OX2R KO relative to
(DORAs) block the arousal-promoting effects of orexin while GABA-A WT mice.
receptor modulators drive sleep through activation of inhibitory recep- Conclusion: The NREM sleep-increasing effects elicited by zolpidem
tors. were further enhanced with either the transient (pharmacological) or
Methods: Orexin-A levels, determined in CSF by meso-scale ELISA, permanent (knockout) blockade of OX2R, but not OX1R. These data
were correlated with wakefulness measured by polysomnography in demonstrate the potential synergistic sleep- promoting effects of the si-
telemeterized mice, rats, dogs and rhesus monkeys. The sleep promot- multaneous inhibition of arousal system and stimulation of sleep drive.
ing effects of DORA-22 and DORA-12, an analog of suvorexant, were
evaluated in rats during both the active and inactive phases. Active wake 0008
attenuation was correlated with compound exposure and ex vivo orexin GABA AGONISM REDUCES CATAPLEXY IN TWO MURINE
B
2 receptor (OX2R) occupancy across doses and time after treatment. MODELS OF NARCOLEPSY
Next day residual effects on rhesus monkey serial choice reaction and Wurts Black S1, Morairty S1, Chen T1, Yamanaka A2,3,4, Kilduff TS1
delay non-match to sample performance was evaluated the morning af- 1Biosciences, SRI International, Menlo Park, CA, USA, 2Research
ter pre-inactive phase DORA or GABA-A receptor modulator treatment. Institute of Environmental Medicine, Nagoya University, Nagoya,
Results: DORAs have greater efficacy during the active phase when Japan, 3National Institute for Physiological Science, Okazaki, Japan,
ligand levels are at their highest. Attenuation of active wake by multiple 4Japan Science and Technolology Agency, PRESTO, Tokyo, Japan
DORAs across species occurs at compound plasma exposures sufficient
to achieve OX2R occupancies above 80%. In contrast to GABA-A re- Introduction: Gammahydroxybutyrate (GHB) is an effective thera-
ceptor modulators whose occupancy threshold for efficacy is approxi- peutic for the excessive sleepiness and sudden loss of muscle tone
mately 27%, DORA levels sufficient to provide sleep maintenance are (cataplexy) associated with narcolepsy. The mechanism of action for
less likely to exceed OX2R occupancies sufficient for efficacy during the therapeutic effect is unknown, but is hypothesized to be GABA
B
the subsequent active phase. In Rhesus monkeys, residual next-day ef- receptor-dependent. Here, the effects of chronic administration of GHB
fects of GABA-A receptor modulators are associated with deficits in and the GABA agonist R-baclofen (BAC) on arousal state and cata-
B
attention and recognition memory while DORAs leave these measures plexy were compared in two models of narcolepsy: the orexin/ataxin-3
unaffected. mouse (Atax) and the orexin tTA/Tet-O diphtheria toxin mouse (DTA),
Conclusion: These preclinical studies demonstrate that the combina- in which hypocretin neurodegeneration is controlled by a tetracycline
tion of favorable pharmacokinetic properties and high OX2R occupancy transactivator system that is induced by withdrawal of dietary doxycy-
threshold for efficacy allow DORAs to promote sleep during normal cline.
resting phases while avoiding residual somnolence during subsequent Methods: Atax and DTA mice were prepared for EEG and EMG moni-
waking periods. toring using abdominally-implanted telemetry units. After 3 weeks
Support (If Any): All authors are supported by Merck Research Labo- recovery and, for the DTA mice, at least 5 weeks of doxycycline with-
ratories. drawal, mice began a treatment paradigm designed to model the twice-
nightly GHB dosing regimen used by human narcoleptics. Mice were
0007 dosed i.p. at ZT-2 and ZT-6 with GHB (150 mg/kg), BAC (2.8 mg/
PHARMACOLOGICAL OR GENETIC INHIBITION OF kg,) or vehicle (VEH) every day for 15 days. Physiological and video-
THE OREXIN-2 RECEPTOR ENHANCES THE SLEEP- recorded behavioral data were simultaneously acquired and manually
PROMOTING EFFECTS OF ZOLPIDEM scored as wake, rapid-eye movement (REM) sleep, non-REM (NREM)
Dugovic C, Shelton J, Yun S, Bonaventure P, Shireman B, Lovenberg T sleep, or cataplexy. Drug effects on these states were assessed for 24 h
Neuroscience, Janssen Research & Development, San Diego, CA, USA on a baseline day prior to treatment and on the last day of treatment.
Results: During baseline, DTA mice exhibited a 4-fold greater number
Introduction: Pharmacological blockade of the orexin-2 receptor of cataplexy bouts than Atax mice, despite similar percentages of time in
(OX2R) promotes sleep by inhibiting the output of wake active neurons sleep/wake states. In both models, cataplexy decreased from baseline in
in the brainstem and hypothalamus. In contrast, classical hypnotic agents 50% and 88% of mice after GHB and BAC, respectively, whereas cata-
such as zolpidem promote sleep by stimulating sleep active neurons in plexy increased in 83% of the mice after VEH. BAC, but not GHB, was
the ventral lateral preoptic area via enhanced GABA signaling. To in- associated with a greater reduction from baseline in the amount of time
vestigate the mutual interactions between these two systems, the effects spent in cataplexy on the last day of dosing compared to VEH. Only the
of zolpidem were examined in pharmacological and genetic models that BAC group showed a significant positive correlation between the num-
selectively inhibit either the OX2R or the OX1R. ber of cataplexy bouts during baseline and the change-from-baseline
Methods: A group of rats and four groups of mice (OX1R KO and WT; response on the last day of dosing.
OX2R KO and WT) were implanted with telemetric devices for EEG/
SLEEP, Volume 36, Abstract Supplement, 2013 A6
A. Basic Sleep Science I. Pharmacology and Biochemistry
Conclusion: Overall, the pattern of arousal state and cataplexy respons- 0010
es to GHB, BAC and VEH was the same for both models of narcolepsy. DEXMEDETOMIDINE-INDUCED SEDATION IS SIMILAR TO
At the doses tested, BAC suppressed cataplexy to a greater extent than NATURAL NREM SLEEP IN MICE
GHB. Mice with more severe cataplexy showed a greater therapeutic Van Dort CJ1,2,3, Toledano SJ2, Kenny JD1,2, Wilson MA2,3,
response to BAC than less symptomatic mice. Brown EN1,2,4,5
Support (If Any): NIH 1R01NS057464 1Department of Anesthesia, Critical Care, and Pain Medicine,
Massachusetts General Hospital, Harvard Medical School,
0009 Boston, MA, USA, 2Department of Brain and Cognitive Sciences,
RGS PROTEINS MODULATE ISOFLURANE-INDUCED Massachusetts Institute of Technology, Cambridge, MA, USA,
ALTERATIONS IN SLEEP AND WAKEFULNESS 3Picower Institute for Learning and Memory, Massachusetts Institute of
Zhang H1,3, Wheat H1, Jiang S1, Baghdoyan HA1, Neubig RR2, Shi X3, Technology, Cambridge, MA, USA, 4Harvard-MIT Division of Health
Lydic R1 Sciences and Technology, Massachusetts Institute of Technology,
1Anesthesiology, University of Michigan, Ann Arbor, MI, USA, Cambridge, MA, USA, 5Institute for Medical Engineering and Science,
2Pharmacology, University of Michigan, Ann Arbor, MI, USA, Massachusetts Institute of Technology, Cambridge, MA, USA
3Anesthesiology, Changzheng Hospital, 2nd Military Medical
University, Shanghai, China Introduction: Dexmedetomidine, an alpha 2a receptor agonist, is used
for sedation in the ICU and operating room. Electroencephalogram
Introduction: States of sleep and anesthesia are regulated by metabo- (EEG) recordings in humans, cats, and rats have demonstrated that dex-
tropic, G protein coupled receptors that, in turn, are modulated by regu- medetomidine induces slow waves and spindles similar to those seen
lators of G protein signaling (RGS) proteins. This study is testing the during non-rapid eye movement (NREM) sleep. Slow waves and sleep
hypothesis that RGS proteins contribute to normal sleep cycle control spindles show regional differences in frequency from anterior to poste-
and to sleep disruption that follows isoflurane anesthesia. rior portions of the cortex in humans. However, quantification of slow
Methods: States of sleep and wakefulness were recorded from transgen- wave and spindle properties across the cortex during dexmedetomidine-
ic mice having an RGS-insensitive allele that enhances Gai2 signaling. induced sedation have not been demonstrated. Therefore, this study
Recordings were obtained for 18.5h from wild type (WT) mice (n=7) is the first to quantify cortical activity across the brain during natural
and knock-in mice that are heterozygous (n=6) or homozygous (n=4) for NREM sleep compared to dexmedetomidine-induced sedation in mice.
the RGS allele. Every 10s of each 18.5h recording was scored as wake- Methods: Four mice were surgically implanted with 6 EEG electrodes
fulness, NREM sleep, or REM sleep to quantify percent state before across the cortex and 2 EMG electrodes. On the day of the experiment,
(control) and after 3h of exposure to 1.3% isoflurane. a tail vein cannula was inserted during isoflurane anesthesia. The mice
Results: During the initial 6.5h of the light cycle, control data re- were allowed to recover fully, then an IV injection of dexmedetomi-
vealed differences as a function of genotype for percent time spent dine (50, 200, or 400 µg/kg) was administered. The EEG, EMG and
in wakefulness: WT=(28.68), heterozygous=(36.50), homozy- video were recorded and used to score sleep, wakefulness, and dex-
gous=(41.91); NREM sleep: WT=(63.69), heterozygous=(58.14), ho- medetomidine-induced sedation. Spectral analysis of the EEG and the
mozygous=(52.44), and REM sleep: WT=(7.63), heterozygous=(5.36), Kolmogorov-Smirnov (KS) test were used to determine significant dif-
homozygous=(5.65). Recordings after isoflurane revealed prolonged ferences in power at a given frequency for dexmedetomidine-induced
disruption of the sleep/wake cycle. During the first 6h after isoflurane, sedation compared to NREM sleep in the same mouse.
percent change data show increased wakefulness: WT=(74.12), hetero- Results: At low concentrations of dexmedetomidine (50 µg/kg), there
zygous=(56.88), homozygous=(26.84). Percent change data showed a were spindles and slow waves similar to NREM sleep. At high concen-
decrease in NREM sleep: WT=(-29.11), heterozygous=(-34.37), homo- trations of dexmedetomidine (400 µg/kg), there were very large slow
zygous=(-18.34), and REM sleep WT=(-35.60), heterozygous=(-14.49), waves from 0.6-3.4 Hz (KS test with Bonferroni correction p < 0.05)
homozygous=(-28.92). During hours 6.5 through 12 after isoflurane that were larger than NREM sleep slow waves and very few spindles.
there was a rebound percent increase in NREM sleep: WT=(113.33), Quantification of differences across the cortex and spindle properties is
heterozygous=(61.83), homozygous=(34.29), and a corresponding per- ongoing.
cent decrease in wakefulness: WT=(-26.40), heterozygous=(-23.89), Conclusion: These data support the idea that low concentrations of dex-
homozygous=(-16.88). REM sleep percent rebound persisted for up to medetomidine produce a brain state that is neurophysiologically similar
18.5h after isoflurane: WT=(69.04), heterozygous=(33.52), homozy- to naturally occurring NREM sleep. Therefore, dexmedetomidine or
gous=(34.39). other alpha 2a receptor agonists may be useful tools for approximating
Conclusion: Sleep/wake recordings after isoflurane anesthesia revealed NREM sleep.
increased wakefulness and a REM sleep rebound, both of which varied Support (If Any): National Institutes of Health grants OD003646-01
as a function of RGS genotype. The results support the interpretation and TR01-GM104948
that RGS proteins contribute to the regulation of sleep and to disruptions
of the sleep/wake cycle after isoflurane anesthesia.
Support (If Any): Supported by HL65272 (RL), GM039561-24 (RRN),
MH45361 (HAB), and the Chinese Scholarship Council.
A7 SLEEP, Volume 36, Abstract Supplement, 2013
A. Basic Sleep Science I. Pharmacology and Biochemistry
0011 Methods: Adult, male obese (n=3) and lean (n=3) rats were housed
PANCREATIC UNCOUPLING PROTEIN-2 EXPRESSION in a 12-h light/dark cycle. Dependent measures were quantified before
AND GLUCOSE HOMEOSTASIS SYSTEM IN C57BL MICE (control) and after 7 days of olanzapine administered via subcutaneous
SUBMITTED TO INTERMITTENT HYPOXIA osmotic pump (7.5 mg/kg/day). Plasma levels of olanzapine were in the
Fiori CZ1, Vieira LR2, Righi CG1, Kim LJ5, Baum G3, da Silva RP1, therapeutic range (JPET 2003;305:625) for obese (144 ng/mL) and lean
Rosa DP2, Marroni NP7, Forgiarini LF6, Martinez D1,2,4 (85 ng/mL) rats.
1Cardiology and Cardiovascular Sciences, UFRGS, Porto Alegre, Results: Effect sizes for sleep responses to olanzapine are summarized
Brazil, 2Medical Sciences, UFRGS, Porto Alegre, Brazil, 3Biology, as percent change from control for obese vs lean rats. Dark phase: wake-
UFRGS, Porto Alegre, Brazil, 4Cardiology Division, Hospital de fulness -12% vs 22%; NREM 44% vs -27%; REM 40% vs -56%. Light
Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil, 5Biomedicine, phase: wakefulness 3% vs 23%; NREM 12% vs -21%; REM -52% vs
UFCSPA, Porto Alegre, Brazil, 6Medicine: Pneumology, UFRGS, -30%. In obese rats, EEG theta power during wakefulness was increased
Porto Alegre, Brazil, 7Grande do Sul, Brasil. Program in Genetic and in dark (34%) and light (57%) phases, and EEG delta power was de-
Toxicology, Universidade Luterana do Brasil, Porto Alegre, Brazil creased during wakefulness in dark (-22%) and light (-23%) phases. In
lean rats, delta power was decreased (-26%) in the dark phase. Obese
Introduction: Sleep apnea and intermittent hypoxia have been impli- rats responded to olanzapine with decreased locomotor activity in dark
cated in insulin resistance. Pancreatic uncoupling protein-2 (UCP-2) is a (-49%) and light (-60%) phases. Lean rats showed decreased locomotor
negative regulator of insulin secretion. The present study aims to inves- activity in the light phase (-53%).
tigate whether an animal model of sleep apnea influences insulin output Conclusion: Olanzapine caused sleep and EEG changes that differed
via UCP-2 expression. in obese and lean rats, supporting the interpretation that rats selectively
Methods: Male C57BL mice were exposed during 35 days to intermit- bred to emulate features of obesity/metabolic syndrome (Trends Car-
tent hypoxia (n=18) or to sham intermittent hypoxia (n=18). During 8 diovasc Med 2012;22:29) provide a powerful resource for studies de-
hours daily, the hypoxia group underwent 480 cycles of 30 seconds of signed to elucidate the mechanisms by which olanzapine alters sleep/
progressive hypoxia to an inspired oxygen concentration nadir of 8±1% wake states.
followed by 30 seconds of room air breathing. The UCP-2 mRNA ex- Support (If Any): National Institutes of Health Grants MH45361
pression in pancreas was assessed by real-time PCR. Insulin and glu- (HAB), ROD012098A (LGK, SLB), and Department of Anesthesiology
cagon levels were determined using ELISA method, and fasting serum
glucose, total cholesterol, HDL-cholesterol, and triglycerides were mea- 0013
sured by enzymatic colorimetric method. GLUCOSE TOLERANCE WERE NOT AFFECTED BY ACUTE
Results: The UCP-2 mRNA expression was 18% lower (P=0.14) in the SLEEP ENHANCEMENT BY ULTRA-SHORT ACTING
hypoxia than in the sham group. The glucose and glucagon levels were HYPNOTICS IN HEALTHY YOUNG MALES
respectively 13% (P=0.025) and 59% (P=0.023) lower in the hypoxia Tagaya H1,4, Kumagai Y2,4, Kuroyama M3,4, Wakisaka M4, Sato M4,
than in the sham group. The insulin levels were 5% higher (P=0.011) in Maeda M4
the hypoxia than in the sham group. HOMA index of insulin resistance 1Department of Health Science, Kitasato University, School of Allied
was 18% lower (P=0.09) in the hypoxia than in the sham group and the Health Sciences, Sagamihara, Japan, 2Department of Phamacology,
function of beta-cell was 21% higher (P=0.014) in hypoxia than in sham Kitasato University, School of Medicine, Sagamihara, Japan,
group. Body weight, adjusted for food intake, was maintained relatively 3Department of Clinical Pharmacy, Kitasato University, School
stable during the experiment. No significant differences in lipid profile of Pharmacy, Tokyo, Japan, 4Kitasato University East Hospital,
were found between groups. Sagamihara, Japan
Conclusion: The present study investigated the response of UCP2 to
intermittent hypoxia and found a non-significant reduction in expression Introduction: The aim of the study was to investigate the effects of
of this regulatory protein. Considering the moderate nadir of the oxygen acute sleep enhancement by ultra-short acting hypnotics on glucose tol-
concentration here utilized for the intermittent hypoxia protocol one can erance in healthy young males.
anticipate that severe hypoxia may be able to produce changes in the Methods: The study protocol was approved by intramural research
expression of pancreatic mRNA UCP2. ethics committee and registered to UMIN clinical trial registry. After
obtaining written informed consents, participants underwent 3 ex-
0012 perimental sessions. In every session, participants were administered
OBESE/METABOLIC SYNDROME RATS AND LEAN/FIT opaque capsule containing either placebo, 0.25mg triazolam (TRZ) or
RATS SHOW DIFFERENTIAL SLEEP, EEG POWER, AND 5mg zolpidem (ZLP) at 2230h. PSG were recorded between 2300h and
LOCOMOTOR ACTIVITY RESPONSES TO CHRONIC, 0700h. 75g OGTT was carried out between 0900h and 1100h. The first
SYSTEMIC ADMINISTRATION OF THE ANTIPSYCHOTIC session was served as placebo PSG recording , and subjects who filled
OLANZAPINE exclusion criteria for OSAS or PLMD were excluded from the study. In
Radzikowski S1,2, Shortal BP1, Watson CJ1, Koch LG1, Britton SL1, the second and third session, TRZ or ZLP were randomly administered
Baghdoyan HA1,2 by double blind crossover manner. Sleep variables and index of glucose
1Anesthesiology, University of Michigan, Ann Arbor, MI, USA, tolerance (HOMA) were analyzed by repeated measures ANOVA and
2Pharmacology, University of Michigan, Ann Arbor, MI, USA correlation analyses.
Results: Thirteen healthy young males aged 23.4 ± 3.2 years were com-
Introduction: Olanzapine, used to manage symptoms of schizophrenia, pleted the study. Total sleep time, sleep efficiency, sleep stage 2, sleep
increases slow wave sleep (J Clin Psychiatry 2005;66:450) and causes stage 4 and NREM sleep were increased and arousal index and sleep
daytime sleepiness (Schizophr Res 2012;135:123). Metabolic syndrome stage 1 were decreased by hypnotics, though there were no differences
and cardiovascular disease are prevalent in people with schizophrenia between TRZ and ZLP. No difference was found in HOMA. Negative
(Mol Psychiatry 2012;17:242), and weight gain caused by olanzapine correlation was found between sleep stage 2, whereas positive correla-
can worsen these comorbid conditions. This study is testing the hypoth- tion was found between sleep stage 4 and HOMA.
esis that olanzapine alters sleep, EEG power, and locomotor activity dif- Conclusion: Acute enhancement of sleep by ultra-short acting hypnotic
ferentially in a rat model of obesity/metabolic syndrome compared to did not affected glucose tolerance in healthy young males. Index of glu-
lean/fit rats. cose tolerance was positively correlated with amount of sleep stage 2.
SLEEP, Volume 36, Abstract Supplement, 2013 A8