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1 Neuroscience Laboratory, Department of Neurology, China Medical College Hospital, Taichung 404, Taiwan; and 2 Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109-0615
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Corticotropin-releasing hormone (CRH) mediates responses to a variety of stressors. We subjected rats to a 1-h period of an acute stressor, physical restraint, and determined the impact on subsequent sleep-wake behavior. Restraint at the beginning of the light period, but not the dark period, increased waking and reduced rapid eye movement sleep without dramatically altering slow-wave sleep (SWS). Electroencephalogram (EEG) slow-wave activity during SWS and brain temperature were increased by this manipulation. Central administration of the CRH receptor antagonist astressin blocked the increase in waking after physical restraint, but not during the period of restraint itself. Blockade of CRH receptors with astressin attenuated the restraint-induced elevation of brain temperature, but not the increase of EEG slow-wave activity during subsequent SWS. Although corticosterone increased after restraint in naive animals, it was not altered by this manipulation in rats well habituated to handling and injection procedures. These results suggest that under these conditions central CRH, but not the hypothalamic-pituitary-adrenal axis, is involved in the alterations in sleep-wake behavior and the modulation of brain temperature of rats exposed to physical restraint.
hypothalamic-pituitary-adrenal axis; electroencephalogram; neuropeptide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CORTICOTROPIN-RELEASING
HORMONE (CRH) is well documented as the major, although not only,
mediator of behavioral, physiological, and autonomic responses to a
variety of stressors. CRH, expressed in widely distributed regions of
the central nervous system (CNS), mediates the
hypothalamic-pituitary-adrenal (HPA) axis and central autonomic
components of responses to stressors (11, 30). Sleep is a
fundamental CNS process that is regulated by complex interactions between neural and humoral systems and altered in response to a variety
of stressors (for review, see Ref. 26). Previous reports (6, 10, 32) indicate that brief periods of exposure to physical restraint at the beginning of the dark period increase rapid
eye movement sleep (REMS) in rats. This REMS enhancement is modulated
by the CRH receptor antagonist 
-helical CRH-(9-41) (-hCRH)
(10), suggesting a role for CRH in these responses. A new
CRH receptor antagonist, astressin, is now commercially available.
Astressin,
cyclo(30-33) [D-Phe12,Nle21,38,Glu30,Lys33]-rat/human-CRH-(12-41),
is more potent than -hCRH and exhibits little if any intrinsic
agonist activity (15). Astressin effectively blocks
responses to a variety of stressors, including CRH- and alcohol-induced
increases in ACTH (33), and stressor-induced alterations
in gastric and colonic motor function (20). The present
study was designed to further elucidate the role of CRH in responses to
physical restraint by determining the effectiveness of a different CRH
receptor antagonist in modulating responses to this stressor. In
addition, we (28, 29, 36) have previously shown that the
impact of immune challenge on sleep-wake behavior depends on the time
of day at which the challenge occurs. In this study, we extend previous
observations of responses to physical restraint to include
manipulations at a different circadian time: the beginning of the light
period of the light-dark cycle. We now report that 1 h of physical
restraint differentially affects subsequent sleep-wake behavior,
electroencephalogram (EEG) slow-wave activity (SWA) during slow-wave
sleep (SWS), and brain temperature (Tbr), depending when the stressor
is applied. Selective CRH receptor blockade with astressin abolishes or
attenuates some, but not all, responses to this stressor. Our results
suggest that under the conditions of this study central CRH, but not
the HPA axis, is involved in restraint-induced waking and, in part, in
the stressor-induced elevation of Tbr.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Substances
Stock solutions of astressin, (Bachem, Torrance, CA) were prepared in pyrogen-free saline (PFS). Aliquots of these stock solutions were stored at
70°C until use, when they were then
brought to an appropriate injection volume. We used 2.5 µg (0.7 nmol)
astressin in these experiments. This dose of astressin does not alter
spontaneous sleep-wake behavior during the first 6 h after
intracerebroventricular (ICV) administration (7).
Animals
Male Sprague-Dawley rats (250-300 g; Harlan, Indianapolis, IN) were anesthetized (ketamine/xylazine, 87:13, mg/kg) and injected with an analgesic [butorphanol tartrate (Torbugesic)] and a broad spectrum antibiotic [penicillin G benzathine (Bicillin)]. Depending on the particular protocol (see Experimental Protocol), surgical procedures included the implantation of EEG screw electrodes, a guide cannula directed into the lateral ventricle, and a calibrated 30-k
thermistor (model no. 44008, Omega Engineering, Stamford, CT)
to monitor Tbr at the surface of the cortex. All procedures have been
previously described (27). The animals were allowed to
recover for 7 days before the initiation of experiments. The rats were
housed in individual recording cages, with two cages in each
environmentally controlled chamber (model no. 352601; Hotpack,
Philadelphia, PA), and maintained at 23 ± 1°C with a 12:12-h
light-dark cycle (25-W incandescent bulb; ~200 lx at cage height).
Food and water were available ad libitum. All procedures performed in
these studies were approved by the local animal care and use committee
in accordance with the United States Department of Agriculture Animal
Welfare Act and the United States Public Health Service Policy on
Humane Care and Use of Laboratory Animals.
On the second postsurgical day, the rats used in behavioral studies were connected to the recording apparatus (see Apparatus and Recording) via a flexible tether. Three days after surgery, the patency and free drainage of the ICV cannulas was assessed by administering 200 ng angiotensin II (human angiotensin II octapeptide; Peninsula Laboratories); angiotensin elicits a drinking response mediated by structures in the preoptic area (12). For the next 4-5 days, the animals were habituated by daily handling and ICV injections of PFS timed to coincide with scheduled experimental administrations. At the end of each experimental protocol, all rats were again injected with angiotensin; only data from those rats that exhibited a positive drinking response were included in the subsequent analyses.
Apparatus and Recording
Signals from the EEG electrodes and thermistors were fed into amplifiers (models S75-01 and S71-20, respectively; Colbourn Instruments, Lehigh Valley, PA). The EEG was amplified (factor of 3,000) and analog bandpass filtered between 0.1 and 40 Hz (frequency response, ±3 dB; filter frequency roll off, 12 dB/octave). Gross body movements were detected by custom-built ultrasonic detectors (Biomedical Instrumentation, University of Tennessee, Memphis, TN). These conditioned signals (EEG, Tbr), as well as those from the movement detectors, were subjected to analog-to-digital conversion with 12-bit precision at a sampling rate of 128 Hz (AT-MIO-64F5; National Instruments, Austin, TX). The digitized EEG waveform, Tbr samples, and integrated values for body movements were stored as binary computer files until subsequent analyses.Postacquisition determination of vigilance state was done by visual scoring of 12-s epochs using custom software (Icelus; M. R. Opp) written in LabView for Windows (National Instruments) as previously described (27). The behavior of the animal was classified as either SWS, REMS, or wakefulness, based on previously defined criteria (27).
Experimental Protocol
Two experiments were conducted in this study. Experiment 1 was conducted to determine the effects of 1-h restraint on subsequent sleep-wake behavior. Rats used in this experiment (n = 16) were divided into two subgroups: dark onset (n = 8) and light onset (n = 8). These rats were handled each day and habituated to injection procedures by receiving ICV injections of vehicle at the same time that experiments were scheduled to begin. This habituation period lasted 1 wk, after which 24-h baseline recordings were obtained from undisturbed animals. On the day after baseline recordings, four rats from each group were injected ICV with vehicle, and the other four rats received 2.5 µg (0.7 nmol) astressin. These rats were then immediately placed individually in Plexiglas Broome-style rodent restrainers (Kent Scientific, Litchfield, CT) for 1 h. During this restraint period, the restrainer was placed in the rats' home cage, and the animals were connected via the tether to the recording system. After restraint, the rats were removed from the restrainer and placed back in their home recording cage. Recordings were made during the 1-h restraint period and for 23 h after restraint. Two days later, this protocol was repeated, but the substance injected was switched. Thus each rat was restrained only twice and served as its own control. The injection volume used for these animals was 3 µl, and the injections were given over an ~2-min period.In experiment 2, we determined the effects of 1-h
restraint on circulating corticosterone. All animals used in this
experiment were maintained under the same conditions, in the same
environmental chambers as those animals used in experiment
1. Two groups of rats were used in this experiment. A group of
naive rats (n = 36) was composed of animals that were
not subjected to any surgical procedure and not handled or otherwise
habituated before experiments. The naive rats served as controls for
handling and injection procedures. Habituated rats (n = 72) were surgically implanted only with an ICV guide cannula. During
the 1-wk postsurgical period, these rats were habituated in the same
manner as the rats used in experiment 1; they were handled
daily and given ICV injections of vehicle at the same time that
experiments were scheduled to begin. However, they were not placed in
or habituated to the restrainers before the beginning of the
experiment. The experimental protocol for this experiment consisted of
killing animals either before the planned period of restraint
(time 0), immediately at the end of the restraint period
(time 1), or 1 h after the end of restraint (time
2). Naive rats were simply placed into the restrainers and killed
at the indicated times with no additional manipulation. Habituated rats
were injected with either vehicle (n = 36) or astressin
(n = 36) 15 min before restraint. This 15-min interval was designed to match the time interval between injections and the
beginning of physical restraint used in experiment 1. It is the amount of time required in experiment 1 to handle,
inject, and place groups of rats into the restrainer tubes and connect them to the recording system. As such, the protocol used in
experiment 2 was identical to that of experiment
1. Six rats were killed at each time point (time 0,
1, and 2) for each condition (vehicle and
astressin). All manipulations in this experiment were conducted twice,
once at the beginning of the light period and once at the beginning of
the dark period, using separate groups of rats. Trunk blood was
collected into EDTA-containing tubes (Vacutainer; Becton Dickinson,
Franklin Lakes, NJ), and centrifuged for 15 min at 4°C. Plasma was
then aliquoted and stored at 80°C until RIA.
Corticosterone RIA
Total plasma corticosterone was measured using a commercially available RIA kit (ICN Biomedicals, Costa Mesa, CA).Statistical Analyses
Experiment 1.
All values are presented as means ± SE. Repeated measures ANOVA
were used to reveal differences in the duration of each vigilance state
(SWS, REMS, and wakefulness), for EEG SWA during SWS, Tbr values, and
sleep architecture parameters. The primary analyses were done across
the 11-h recording period after physical restraint. Secondary analyses
consisted of repeated measures ANOVA restricted to specific time blocks
comprising the major periods of the study: the 5 h immediately
after restraint (hours 2-6 of protocol clock time) and the 6-h time blocks comprising the remainder of the recording
period. Secondary analyses of data obtained during the 1-h period of
physical restraint were done using one-way ANOVA. In all ANOVA, the
main effect (between subjects) consisted of manipulation (undisturbed,
ICV vehicle with restraint, and ICV astressin with restraint). If
statistically significant differences were detected, Scheffé's
post hoc multiple comparisons test was used to determine which
manipulation during experimental conditions deviated from values
obtained from the same animals during control conditions. An level
of P
0.05 was taken to indicate a statistically significant departure from values obtained during control conditions.
Experiment 2.
Circulating corticosterone concentrations are presented as means ± SD
(in ng/ml). One-way ANOVA was used to reveal statistically significant
differences between the values obtained in response to restraint. The
main effect consisted of manipulation (naive, ICV vehicle with
restraint, and ICV astressin with restraint). If statistical
significance was achieved, Scheffé's post hoc multiple
comparisons test was used to determine which manipulation contributed
to the variance. An level of P 0.05 was taken to indicate statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1
Effects of restraint during light period.
Physical restraint for 1 h at the beginning of the light period
altered the sleep-wake behavior of rats (Fig.
1). While in the restrainer tube, rats
spent more time awake and less time asleep relative to values obtained
from the same animals left undisturbed in their recording cages (Fig.
1). Post hoc analyses indicated that the amount of time spent awake did
not depend on whether the animals had been injected with vehicle or 2.5 µg (0.7 nmol) astressin, i.e., this CRH receptor antagonist did not
alter waking during the restraint period. Alterations in sleep-wake behavior were apparent for 5 h after the animals were removed from
the restraining device. During this 5-h time block after physical
restraint (protocol hours 2-6), the amount of time
spent awake increased and REMS was reduced; SWS was not statistically altered (Fig. 1). This restraint-induced increase in the amount of time
spent awake was blocked by astressin, whereas the restraint-induced REMS suppression was not (Fig. 1). During postmanipulation hours 7-12, sleep-wake behavior was not
statistically altered, although there was a tendency for
increased REMS when the rats were injected with vehicle before physical
restraint (Fig. 1).
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Effects of restraint during the dark period. One hour of physical restraint at the beginning of the dark period did not alter subsequent sleep-wake behavior, although REMS was reduced during the restraint period (Fig. 1).
Analyses of sleep-wake architecture parameters indicated that the number of wakefulness bouts was modestly increased during the first 5-h postmanipulation time block, although the bout duration and the time spent awake were not altered. In addition, transitions from one vigilance state to another were increased after 1-h restraint, indicating that the sleep that did occur was fragmented (Table 1). Astressin did not alter the restraint-induced changes in sleep architecture parameters. EEG SWA during SWS was not altered by 1-h restraint during the dark period (data not shown). Tbr was increased in response to physical restraint, and this increase in Tbr was not altered by astressin (data not shown).Experiment 2
Effects of restraint on circulating corticosterone concentrations.
In naive unoperated rats that were not handled or disturbed before
restraint, corticosterone concentrations increased regardless of the timing of the manipulation (Fig.
3). Corticosterone concentrations of
naive rats returned to basal concentrations 1 h after restraint ended (time 2, Fig. 3). Corticosterone concentrations of
habituated rats injected with vehicle 15 min before light onset and
then killed at light onset (time 0, Fig. 3) were greater
than those of naive rats killed at the same time. The differences in
corticosterone between these groups of rats at this time stem from the
handling of the injected rats. However, the tendency for increased
corticosterone after 1-h restraint during the light period in
habituated animals injected with vehicle did not achieve statistical
significance. Corticosterone concentrations did not differ between
naive and habituated animals when the manipulations were done at dark
onset. ICV administration of 2.5 µg astressin did not alter
circulating corticosterone concentrations after restraint during either
the light or the dark period (Fig. 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There is now an abundance of evidence (1, 4, 5, 11, 13, 16,
26) that CRH mediates endocrine, autonomic, immune, and
behavioral responses to acute and chronic stressors. Sleep is altered
in response to stressors of many modalities (31). Chronic
stress significantly decreases the amount of SWS and REMS and the
length of individual SWS and REMS sleep episodes and alters the
circadian patterning of sleep (18). Some acute stressors, such as physical restraint, are reported to primarily induce a REMS
rebound (21, 31, 32). Rampin et al. (32)
first reported that a 2-h period of physical restraint applied to rats
at the beginning of the dark period induces a significant increase in REMS during the remaining 10 h of the dark period, without
altering SWS. Subsequent reports from the same laboratory
(10) indicate that ICV administration of the CRH receptor
antagonist -hCRH reduces the increase in REMS that follows restraint
at the beginning of the dark period, indicating that endogenous CRH may
be involved in these responses.
In some respects, the results of the current study contrast with previous findings by del C. Gonzalez and Valatx (10) and Rampin et al. (32). In the present study, 1-h restraint at the beginning of the dark period (active period) did not alter subsequent SWS, wakefulness, or REMS, whereas the same manipulation during the light period increased wakefulness and reduced REMS for 5 h postmanipulation. To allow recordings of the EEG and other parameters to be obtained during the physical restraint period, the rats were restrained in their home recording cages. Under these conditions, the rats slept while in the restrainer tubes, albeit less than normal. One potential explanation for differences with respect to the impact of restraint on REMS observed in our present study and those of the aforementioned reports may be the methods and/or location in which the animals were physically restrained. Novelty is a critical feature of constructs that describe the continuum of responses to stressors. The continuum of responses to stressors ranges from arousal to pathology, depending on the magnitude and duration of the stressor (e.g., see Ref. 19). There are numerous studies (17, 22) indicating that novel environments, for example, exposure to an open field or elevated-plus maze, constitute stressors for rodents and that the CRH system is involved in mediating responses to these stressors. There is no information provided in the previous studies to which we refer concerning the environment in which the manipulations occurred. For example, if rats are placed in restrainer tubes outside their home recording cages in the general laboratory environment, the stressor would include a component in addition to physical restraint, i.e., being in a novel environment. We did not intend at the outset of this study to develop a stressor that was of greater or lesser magnitude than those previously used. We restrained the animals in their home recording cages to allow an assessment of responses during application of the stressor itself. As such, we believe it likely that our methodology resulted in a stressor of less magnitude than if the manipulation been performed in an environment outside the home recording cage. The impact on subsequent sleep-wake behavior was as such reduced.
The fact that many procedures used as stressors also result in sleep deprivation is often thought problematic for interpretation of results from such studies (but see, for example, Ref. 2). Although beyond the scope of this discussion, one philosophic response to such suggestions is that no attempts should be made to separate the impact of acute stressors from that of loss of sleep per se, insofar as sleep-wake behavior may be viewed as a reflection of the status of the whole animal. Nevertheless, under the conditions of the present study, EEG SWA during SWS increased for the duration of the recording period after restraint when the manipulation occurred at the beginning of the light period. EEG SWA during SWS is thought to reflect both sleep debt and intensity (3) and is a characteristic homeostatic response to sleep deprivation. As such, the increase in SWA during SWS that we observed could conceivably be a response to sleep loss per se, rather than to physical restraint. Our findings that EEG SWA increases after restraint at the beginning of the light period are in agreement with previous observations by Meerlo and colleagues (21) of mice manipulated during the middle of the light period. However, we do not feel that the increase in SWA during subsequent SWS observed in our present study is due to sleep loss. Relative to the amount of SWS the rats obtained during the first hour of the light period when undisturbed in their home cages, SWS loss during the restraint period only amounted to 27 min on average. We are not aware of sleep deprivation studies in which rats were deprived of so little sleep, but it is not likely that the increase in SWA during SWS observed after restraint in this study is due to a 27-min sleep loss. For example, Tobler and Borbély (35) demonstrate that 3 h (180 min) of total sleep deprivation of rats by gentle handling at the beginning of the light period does not alter SWA during subsequent SWS and has little impact on the amount of time spent in vigilance states. Furthermore, 1-h physical restraint of BALB/cJ mice during the middle of the light period increases SWA during subsequent SWS by an amount greater than that observed after 1-h sleep deprivation by gentle handling (21). For these reasons, we believe the increase in SWA during SWS after physical restraint observed in this study is a response to the acute stressor rather than loss of sleep per se. Astressin does not affect the increases of EEG SWA during SWS, although it reduces restraint-induced increases in waking. These observations suggest that increased SWA during SWS is not mediated by the central CRH system, although additional studies are necessary to elucidate the precise mechanisms responsible for these effects.
We (7, 8) have previously targeted the CRH system of
well-habituated rats in their home recording cages. Two consistent finding emerge from these studies (7, 8). First, under the conditions of our studies (7, 8), antagonizing the CRH
system in the absence of overt stressors selectively alters waking and SWS, not REMS. Similar results are obtained when using antisense knockdown strategies to modulate CRH peptide expression; waking is
reduced and SWS is increased (unpublished observations). The fact that
none of the strategies we have employed to target the CRH system in
spontaneously behaving rats alters REMS suggests to us that the CRH
system plays little, if any, role in the regulation of this arousal
state. As such, our interpretation of data from previous studies
(6, 10, 32) reporting an increase in REMS after acute
periods of physical restraint is that these responses are likely
mediated by other systems. There are several candidate neuropeptides that could mediate the effects of acute physical restraint on subsequent REMS. One of these candidate neuropeptides is
prolactin (PRL). PRL is well documented for its ability to enhance REMS
(24, 25, 34). PRL is elevated in response to stressors,
including restraint (21), and has been implicated in ether
vapor stress-induced increases in REMS (2). Because acute
periods of physical restraint increase PRL (21) and PRL enhances REMS (24, 25, 34), restraint-induced increases in
REMS may in fact be mediated by this peptide. In addition, CRH induces
PRL secretion (23). Collectively, the findings that PRL
secretion is induced by CRH, CRH and PRL are elevated by physical restraint, and PRL enhances REMS suggest that the findings of del C. Gonzalez and Valatx (10) may be attributed to PRL rather than CRH directly. As such, pretreatment with the CRH receptor antagonist -hCRH may block restraint-induced increases in REMS (10), because CRH receptor blockade reduces the impact of
CRH on PRL release.
The second finding from our previous studies (7, 8) that is relevant to this discussion is that blockade of CRH receptors of well-habituated, nonstressed rats with appropriate doses of selective CRH receptor antagonists alters sleep-wake behavior only if injections are given before the dark (active) period of the light-dark cycle. Under the conditions of the current study, 1 h of restraint affects subsequent waking and sleep only when the manipulation occurs at the beginning of the light period of the light-dark cycle. The differences in responses to restraint depending on timing of the manipulation may be due to the circadian rhythmicity of the CRH and/or other neurotransmitter/neuropeptide systems. During the dark period, the activity of the CRH system of entrained rats is at its highest (see e.g., Ref. 14); any additional modulation by an acute stressor may result in only a minimal increase in CRH activity with little subsequent influence on waking. Conversely, an acute period of restraint during the light period is expected to increase CRH activity to a greater extent, since the activity of the system is at its lowest during this time. Increasing CRH, a potent inducer of waking, at a time when it would normally be low would be expected to increase waking and reduce sleep. This point is illustrated by the responses of rats to ICV administration of CRH; the proportional increase in waking after low doses of CRH is greater when injections are given before light onset than before dark onset (7). Although circulating corticosterone concentrations, reflective of CRH activity, increase in naive animals regardless of the timing of restraint, the proportional increase is greater when restraint occurs before the light period. These restraint-induced increases in corticosterone of naive, unhabituated rats suggest that the alteration of sleep-wake behavior in response to this manipulation may be due to increased central CRH activity and/or HPA axis activity. However, rats habituated to handling and injection procedures do not exhibit as large a change in corticosterone after restraint as naive rats, and blockade of CRH receptors by ICV administration of astressin into habituated rats reduces restraint-induced increases in waking without altering circulating corticosterone concentrations. The finding that under the conditions of this study ICV administration of the CRH receptor antagonist astressin blocks restraint-induced increases in waking, but not circulating, corticosterone suggests that alterations in waking and sleep by this acute stressor are not greatly modulated by the HPA axis. As such, these responses are likely mediated by other neuropeptide systems, such as PRL as previously mentioned, or central mechanisms, such as CRH actions on the locus ceruleus, which has been implicated in restraint-induced increases in REMS (9). Additional experiments are necessary to determine if there are differences in restraint-induced increases in PRL depending on the timing of the manipulation, and whether or not the differential responsiveness of CRH and the HPA axis to this manipulation affects PRL secretion.
In conclusion, our results indicate that under the conditions of the current study exposure of rats to physical restraint for 1 h at the beginning of the light period, but not the dark period, increases waking and EEG SWA during SWS and reduces REMS. Blockade of central CRH receptors abolishes restraint-induced alterations in waking, but not REMS, a finding consistent with our previous observations that antagonizing CRH in nonstressed rats does not alter REMS. Collectively, the data derived from this study implicate CRH in some, but not all, responses to this acute manipulation.
Perspectives
The concept of stress and responses to stressors has proven difficult to precisely define; there is often disagreement as to what does or does not constitute a stressor and how the magnitude of a stressor may best be determined. One aspect of research on responses to stressors that is generally agreed on is that stressor-induced increases in HPA axis activity reflect the magnitude of the stressor, as perceived by the animal. Although autonomic markers may be used to define responses to stressors, it is ACTH and glucocorticoids that are most frequently referred to as "stress hormones." If the impact of stressors on behavior is the focus of study, there are multiple levels at which outcome measures may be obtained. The selection of readout parameters other than ACTH and/or glucocorticoids does not invalidate the use of the HPA axis as a measure of responses to stressors, nor does the use of other outcome measures redefine the concept of stress. The results presented in this study illustrate some aspects of this approach. Our finding that rats sleep when placed for the first time in a restrainer tube in their home recording cage suggests to us that under these conditions this manipulation is not perceived by the rat as overly stressful. It is difficult to conceptualize how a healthy animal that is not subjected to a drug would sleep during an event perceived as stressful. Therefore, we believe the extent to which sleep and other complex behavior are altered during or after manipulations thought by the investigator to be stressful reliably serves as a readout of the perception of the animal to that manipulation.| |
ACKNOWLEDGEMENTS |
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We gratefully acknowledge the technical assistance of K. Overgaard, W. Dalmeida, and S. Fullwood.
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FOOTNOTES |
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This work was supported in part by National Institute of Mental Health Grant MH-52275.
Address for reprint requests and other correspondence: M. R. Opp, Dept. of Anesthesiology, Univ. of Michigan, M-7433 Medical Sciences Bldg. 1, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0615 (E-mail: mopp{at}umich.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
April 18, 2002;10.1152/ajpregu.00758.2001
Received 26 December 2001; accepted in final form 10 April 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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