SLEEP 2011 Abstract Supplement

A. Basic Science I. Pharmacology and Biochemistry
30%, decreased NREM sleep by 44%, and decreased REM sleep by
68%. Coefficients of determination demonstrated that the concentration
of gaboxadol accounted for 96%, 94%, and 98% of the variance in the
amount of wakefulness, NREM sleep, and REM sleep, respectively.
Conclusion: The results suggest that tonic inhibition of sleep-promoting
neurons via extrasynaptic GABA A
receptors is one mechanism by which
GABA in rat PRF promotes wakefulness.
Support (If Any): J. Christian Gillin, MD Research Grant (GV), National
Institutes of Health grants MH45361 (HAB), and the Department
of Anesthesiology.
0010
GABAERGIC TRANSMISSION IN SPRAGUE-DAWLEY RAT
PONTINE RETICULAR FORMATION (PRF) MODULATES
TIME REQUIRED FOR THE GENERAL ANESTHETIC
PROPOFOL TO CAUSE LOSS OF WAKEFULNESS
Nemanis K, Vanini G, Baghdoyan HA, Lydic R
Anesthesiology, University of Michigan, Ann Arbor, MI, USA
Introduction: Most anesthetics potentiate GABAergic transmission but
the mechanisms by which anesthetics cause unconsciousness remain unknown.
Pharmacologically increasing or decreasing endogenous GABA
levels in rat PRF increases or decreases, respectively, time needed for
isoflurane to induce anesthesia (Anesthesiology 109:978, 2008). Similarly,
increasing GABA levels in rat PRF increases the amount of time
spent in wakefulness, whereas decreasing GABA levels in the PRF decreases
time awake (Sleep 31:453, 2008). Propofol is an intravenous
anesthetic that enhances transmission at GABA A
receptors (Mol Pharmacol
65:68, 2004) and is used for induction and maintenance of anesthesia.
This study is testing the hypothesis that microinjection of the
GABA uptake inhibitor nipecotic acid (NPA) or GABA synthesis inhibitor
3-mercaptopropionic acid (3-MPA) into the PRF of rat increases or
decreases, respectively, propofol induction time.
Methods: Adult, male rats (n=9) were implanted with jugular vein catheters
(JVC) and microinjection guide tubes aimed for the PRF. Rats received
randomized microinjections (100 nL) of Ringer’s (vehicle) and
NPA (1.29 μg; 10 nmol) or Ringer’s and 3-MPA (1.6 μg; 10 nmol). Fifteen
minutes after each microinjection, a continuous, intravenous infusion
of propofol (800 μg/kg/min) was started and induction time was
quantified as time to loss of righting response (LoRR).
Results: LoRR was significantly changed by injecting drugs that alter
GABA levels into the PRF. LoRR was increased (30%, P=0.03) by NPA
(n=5 rats) and decreased (17.7%, P=0.03) by 3-MPA (n=6).
Conclusion: This is the first demonstration that LoRR caused by an
intravenous anesthetic was altered by GABAergic mechanisms in the
PRF. The effects of NPA and 3-MPA on LoRR to propofol paralleled
their effects on LoRR to the volatile anesthetic isoflurane (Anesthesiology
109:978, 2008). These findings suggest that altering GABAergic
transmission in the PRF changes anesthesia induction time, and support
the interpretation that GABA in the PRF promotes wakefulness.
Support (If Any): NIH grants HL40881, MH45361, HL65272, and the
Department of Anesthesiology
0011
SYSTEMIC ADMINISTRATION OF DEXMEDETOMIDINE
(DEX) DISRUPTS SLEEP ARCHITECTURE AND
MICRODIALYSIS DELIVERY OF DEX TO RAT SUBSTANTIA
INNOMINATA (SI) DOES NOT INCREASE ADENOSINE
LEVELS
Lazar SB, Garrity AG, Wang P, Mashour GA, Baghdoyan HA, Lydic R
Anesthesiology, University of Michigan, Ann Arbor, MI, USA
Introduction: The alpha-2 adrenoceptor agonist DEX causes a state of
sedation and analgesia (Anesthesiology 98:428, 2003) that is often described
as sleep. We are conducting two sets of experiments to evaluate
the homology between DEX-induced sedation and spontaneous sleep.
The first study is testing the hypothesis that there is no difference in
sleep architecture between DEX-induced sedation and spontaneous
sleep. SI adenosine levels decrease during sleep and the second study
is testing the hypothesis that microdialysis delivery of DEX to the SI
decreases adenosine levels in the SI.
Methods: Adult, male rats (n=4) were implanted with EEG and EMG
recording electrodes. Following recovery and conditioning, rats received
DEX (0.1, 0.3, 0.5 mg/kg) or saline followed by a 48-h recording
of sleep and wakefulness. An experimenter blinded to drug condition
scored each 10-s epoch of the recording. A second group of isofluraneanesthetized
rats (n=4) was used to quantify the effect of DEX on adenosine
levels in the SI.
Results: DEX disrupted sleep architecture. During the first 24 h after
injection, the percent of time spent in wakefulness, NREM sleep, and
REM sleep was: 80.1, 16.0, and 3.9 (saline); 60.2, 36.9, and 2.9 (0.1 mg/
kg DEX); 53.7, 43.9, and 2.4 (0.3 mg/kg DEX); and 65.1, 34.2, and 0.7
(0.5 mg/kg DEX). The DEX-induced (0.5 mg/kg) increase in NREM
sleep was characterized by an 8.2% decrease in EEG delta power. During
the second 24 h after DEX there was a rebound increase in REM
sleep of 11.1% (0.3 mg/kg) and 374% (0.5 mg/kg) compared to the first
24 h. Microdialysis delivery of DEX to the SI did not alter adenosine
levels in the SI.
Conclusion: DEX-induced sedation is not a faithful replicate of spontaneous
sleep. Ongoing studies are quantifying the effect of systemically
administered DEX on SI adenosine levels in behaving animals.
Support (If Any): NIH grants HL40881, MH45361, HL65272, and the
Department of Anesthesiology
0012
INFLUENCE OF ESZOPICLONE ON POLYP FORMATION IN
APC3MIN+/- MICE
Reynolds AM, Elliott D, Youngstedt SD
Department of Exercise Science, University of South Carolina,
Columbia, SC, USA
Introduction: Habitual use of sleeping pills has been associated with
cancer-related mortality, and experimental studies have found carcinogenic
effects of supraphysiological doses of hypnotics. On the other
hand, disturbed sleep could potentially precipitate or exacerbate cancer
development, and conversely sleep treatments might attenuate these effects.
Further research is needed, particularly considering the high prevalence
of hypnotic use among cancer patients. The aim of this study was
to examine the effect of chronic administration of a normally-prescribed
hypnotic dose on polyp development in APCMin+/- mice. Because all
APCMin+/- mice develop colorectal cancer, progression of cancer in
these mice can be studied in a small fraction of the number of animals
that would be needed to establish cancer incidence in wild-type mice.
Methods: Twenty-seven 5-week old APCMin+/- mice were randomized
to one of two 10-week treatments: (1) N=14 received a daily dose
(0.30 mg/kg) of eszopiclone (Lunesta®), equivalent to approximately 2
mg/day in humans, adjusted for metabolism. (2) N=13 received a saline
placebo. The mice were sacrificed and polyps were measured blindly in
the intestine and colon.
Results: Mean total intestinal polyps count was about half as high following
eszopiclone (10.8±13.1) vs. placebo (21.3±21.2). In the colon,
few polyps were found, and the number was less following eszopiclone
(0.4±0.9) vs. placebo (0.9±1.1). However, these differences were not
statistically significant. Mice in the eszopiclone treatment had significantly
less weight gain, but weight changes differed by only 1 gram
between treatments, and were not correlated with polyp formation.
Conclusion: The data suggest that eszopiclone might have attenuated
colorectal cancer development in APCMin+/- mice. The data were limited
by small sample size and high variability in response. The data are
not consistent with FDA trials indicating carcinogenic effects of eszopiclone.
Further research is needed with more animals and more prolonged
treatment, and with other hypnotic medications.
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SLEEP, Volume 34, Abstract Supplement, 2011