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2-adrenergic
receptors
Department of Comparative Biosciences and Center for Neuroscience, University of Wisconsin, Madison, Wisconsin 53706
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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We investigated the effects of repeated
hypercapnic episodes (inspired CO2
fraction = 0.10) on posthypercapnic respiratory nerve discharge.
Anesthetized (urethan), vagotomized, and artificially ventilated rats
were presented with three consecutive 5-min episodes of hyperoxic
hypercapnia, separated by 5 min of hyperoxic normocapnia (inspired
O2 fraction = 0.5). Respiratory
nerve discharge and blood gases were recorded before and 30 and 60 min
after the final hypercapnic episode. Posthypercapnia, arterial
PCO2 was maintained within 1 Torr of
initial baseline values. Integrated phrenic and hypoglossal burst
amplitudes decreased posthypercapnia by up to 46 ± 17 and 55 ± 13% of baseline values, respectively, and remained reduced for at
least 1 h [long-term depression (LTD)]. The protocol was
repeated in rats pretreated with the
2-adrenergic antagonists
yohimbine HCl (0.5 mg/kg; n = 7) or
2-[2-(2-methoxy-1,4-benzodioanyl)]imidazoline (RX-821002) HCl (0.25 mg/kg; n = 3).
Both drugs attenuated LTD in the phrenic and hypoglossal neurograms.
Results indicate that episodic hypercapnia elicits a yohimbine- and
RX-821002-sensitive LTD of respiratory nerve activity in rats,
suggesting that LTD requires
2-receptor activation.
respiratory control; catecholamines; yohimbine; RX-821002; phrenic nerve; hypoglossal nerve; norepinephrine
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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EPISODIC CAROTID BODY chemoreceptor activation with hypoxia, or episodic electrical stimulation of carotid sinus nerve afferent fibers, results in a long-lasting enhancement of ventilatory activity, referred to as long-term facilitation (9, 14, 20). Long-term facilitation of phrenic and hypoglossal nerve activity is dependent on serotonin receptor activation and has been observed for at least 1 h after stimulus cessation (1, 26).
Increases in arterial PCO2 (PaCO2; or decreases in blood pH) also activate carotid chemoafferent neurons, although not to the same degree as does hypoxia (15). If carotid chemoafferent neuron activation per se is sufficient to elicit long-term facilitation, then hypercapnia may induce the underlying mechanism. Morris et al. (29) observed long-term facilitation of phrenic nerve activity after repeated intracarotid arterial injections of CO2-saturated saline in anesthetized cats. However, when carotid body-denervated cats were exposed to a single (10-min) hypercapnic episode, long-term facilitation was not observed (26). The episodic nature of the stimulus, as well as the integrity of the carotid chemoafferent neurons, may be important for the induction of long-term facilitation.
We hypothesized that episodic exposure to severe, systemic hypercapnia would elicit long-term facilitation in anesthetized rats with intact carotid bodies. Instead, we found that episodic hypercapnia (PaCO2 = 80-95 Torr) resulted in a long-lasting depression of phrenic and hypoglossal nerve activity that persisted for at least 1 h after the final hypercapnic episode. We refer to this new neural mechanism as long-term depression. The purpose of this study is to characterize this phenomenon and certain aspects of its underlying mechanism.
Hypercapnia could activate an inhibitory mechanism to override the
manifestation of long-term facilitation elicited by episodic carotid
chemoafferent activation. For example, it is known that hypercapnia
activates brain stem noradrenergic neurons (8, 17, 19). Norepinephrine
released from these neurons can inhibit respiratory output by
activating 2-adrenergic
receptors (10). We hypothesized that hypercapnia-induced release of
norepinephrine overrides long-term facilitation by acting on
2-adrenergic receptors to cause
long-term depression.
Thus the specific purposes of the present study were
1) to characterize long-term
depression of hypoglossal and phrenic motor outputs after episodic
hypercapnia in carotid body-intact rats and
2) to determine whether long-term
depression requires activation of
2-adrenergic receptors. To
address these questions, we studied responses to episodic hypercapnia
in phrenic and hypoglossal motor activity, before and after systemic
pretreatment with two
2-adrenergic-receptor antagonists: 17-hydroxyyohimban-16-carboxylic acid methyl ester hydrochloride (yohimbine HCl) and
2-[2-(2-methoxy-1,4-benzodioxanyl)] imidazoline
hydrochloride (RX-821002 HCl).
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Experimental preparation.
Experiments were conducted on 27 adult male rats (Harlan Sprague
Dawley, Madison, WI) with weights ranging from 318 to 782 g. The
animals were anesthetized initially with isoflurane (2.5-3.0% in
50% O2-balance
N2) and slowly converted to
urethan anesthesia (1.3-1.6 g/kg iv) over a period of ~30 min.
The adequacy of anesthesia was assessed by testing corneal reflexes and
blood pressure responses to toe pinch. Supplemental urethan was usually
not necessary but could be administered as needed through a catheter
implanted in a femoral vein. To maintain acid-base and fluid balance, a
slow infusion of sodium bicarbonate (5.0%) and lactated Ringer
solution (50:50, 1.7 ml · kg
1 · h1)
was initiated 30 min after venous catheter placement.
Experimental protocol. After completion of the surgical preparation, 60 min were allowed for the nerve signal to stabilize in hyperoxia [inspired O2 fraction (FIO2) = 0.50; arterial PO2 (PaO2) > 150 Torr] and normocapnia (~3 Torr above the apneic threshold; see Table 1). Baseline nerve activity was achieved by manipulating inspired CO2 and respiratory pump rate and/or volume while PETCO2 levels were monitored until both phrenic and hypoglossal nerve activity attained low but stable levels of activity. The CO2 thresholds for hypoglossal and phrenic nerve activity were nearly the same in these rats (~39 Torr for both nerves). The protocol began with a baseline (control) arterial blood sample (0.3 ml drawn into a 0.5-ml heparinized glass syringe; unused blood was injected into the animal). All subsequent blood samples were compared with this initial baseline value. Baseline nerve activity was recorded, followed by three 5-min episodes of hyperoxic hypercapnia [inspired CO2 fraction (FICO2) = 0.10; PETCO2 = 80-95 Torr] separated by 5 min of hyperoxic normocapnia. The focus of our analysis was the poststimulus response; therefore, blood samples were not taken during hypercapnic episodes (to minimize overall blood volume removed from the animals). Nerve activities were recorded, and blood samples were drawn at 30 and 60 min posthypercapnia.
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2-receptor antagonist yohimbine HCl (0.5 mg/kg; n = 9; 2 of the
animals were studied with background normoxia instead of hyperoxia) or
with the more specific
2-receptor antagonist RX-821002
HCl (0.25 mg/kg; n = 3). Both drugs
were given intravenously (in saline vehicle) 20 min before the first hypercapnic episode. Another group of rats
(n = 5) was given systemic norepinephrine injections (0.1-10.0 µg/kg iv) to determine the ventilatory effects of circulating norepinephrine.
The protocol was repeated in a group of untreated rats exposed
to more moderate episodic hypercapnia
(FICO2 
0.05; PETCO2 60 Torr;
n = 3). Sham experiments, in which the
protocol was repeated in rats that were prepared and treated identically to the other groups but were never exposed to episodic hypercapnia, were conducted previously by using this preparation (1)
and showed no ventilatory effects because of time-dependent factors
(e.g., changes in blood pressure or anesthetic depth).
Data analysis. Peak amplitude and frequency (bursts/min) of phrenic and hypoglossal nerve activity were averaged over 50 bursts for each recorded data point. Averaged amplitude data were then normalized as a percent change from baseline activity, and as a change expressed as a percentage of the (CO2-stimulated) maximum nerve activity. The latter form of normalization obviates concerns about expressing data in terms of the percent increase above an arbitrary (low) baseline value (14). Statistical analysis was conducted by using paired t-tests with the Bonferroni correction for multiple comparisons. Differences were considered significant if P < 0.05; values are described as means ± SE.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Episodic hypercapnia decreased poststimulus phrenic and hypoglossal nerve activities for at least 1 h after the final hypercapnic episode. As shown in Fig. 1, baseline activities were initially recorded from the phrenic and hypoglossal nerves, followed by three episodes of hypercapnia (only the first is shown). In Fig. 1A, the amplitudes of both integrated phrenic and hypoglossal nerve bursts were depressed below baseline levels at all posthypercapnic time points. This depression persisted for the 60 min observed. It is unknown how long this effect lasts or whether it is reversible because we only followed the response for 1 h. Over longer periods, we were concerned that deterioration of the preparation or of our neural recordings would obscure the behavior. Data were not included in our analyses if PaCO2 was >1 Torr from the baseline value (Table 1). Therefore, changes in PaCO2 are unlikely to be responsible for changes in phrenic or hypoglossal nerve activity observed after episodic hypercapnia. It is necessary to adhere to such rigid criteria because rats (as well as other mammals) respond briskly to small (1.5- to 2.0-Torr) fluctuations in PaCO2 near the apneic threshold, which could augment or obscure the degree of long-term depression observed.
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In the rat represented in Fig. 1A, detectable neural activity was in fact completely absent at 30 min posthypercapnia. Respiratory nerve activity was restored by 1 h, although at a reduced burst frequency and amplitude. A slight yet persistent decrease in blood pressure is evident after episodic hypercapnia in this rat, although it remained within 20 mmHg of baseline at all times. Blood pressure tended to increase during the hypercapnic exposures and then return to prestimulus levels several minutes later. We did not attempt to control blood pressure during hypercapnic stimulations.
Figure 1B shows a representative recording in an animal after yohimbine pretreatment. In this rat, the amplitude and frequency of phrenic and hypoglossal bursts posthypercapnia were no longer depressed from baseline values.
These observations from individual rats were consistent with mean
responses. When phrenic and hypoglossal nerve amplitudes are expressed
as percent changes from baseline values (Fig.
2, A and
B), the amplitudes of both nerves
remained significantly depressed for at least 60 min after the final
hypercapnic episode. Phrenic burst amplitude decreased by 46 ± 17 and 34 ± 15% at 30 and 60 min posthypercapnia, respectively;
hypoglossal burst amplitude decreased by 55 ± 13 and 37 ± 12%
at 30 and 60 min posthypercapnia, respectively (all
P < 0.05). To minimize normalization
artifacts caused by variable baseline nerve activities, data were also
expressed as a change from baseline, normalized as a percentage of the
maximal CO2-stimulated nerve burst
amplitude (see Ref. 14 for discussion). Analyzed in this way, the
results were qualitatively similar (data not shown). After pretreatment
with yohimbine, phrenic and hypoglossal nerve amplitudes were no longer
depressed after episodic hypercapnia when normalized in either manner.
In fact, hypoglossal burst amplitude was significantly elevated at 1 h
posthypercapnia (15 ± 6%; P < 0.01), a possible expression of long-term facilitation (1). Decreases
in nerve burst frequency also played a significant role in long-term
depression (Fig. 2C). Phrenic (and
hypoglossal) burst frequency decreased by 21 ± 6 bursts/min at 30 min posthypercapnia (P < 0.05); at
60 min, the apparent depression was no longer significant. Rats
pretreated with yohimbine showed no tendency to decrease nerve burst
frequency after episodic hypercapnia. Pretreatment with another, more
specific 2-antagonist
(RX-821002 HCl) also attenuated long-term depression of burst amplitude
(Fig. 3, A and B) and frequency (data not
shown). Apparent increases in phrenic and hypoglossal
burst amplitude posthypercapnia were not significant. One hour after
the third hypercapnic episode, the response to a final hypercapnic
episode was unchanged from values observed during episodic hypercapnia.
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In one study conducted in normoxia
(FIO2 0.21),
phrenic burst amplitude and frequency still decreased 30 and 60 min after episodic hypercapnia, similar to experiments conducted in hyperoxia (data not shown). In two additional rats, yohimbine pretreatment before episodic normoxic hypercapnia revealed long-term facilitation (vs. depression) of phrenic and hypoglossal nerve activities after hypercapnia.
In experiments that consisted of episodic exposure to 3.0-5.0% inspired CO2, none of these animals (n = 3) displayed long-term depression after episodic hypercapnia (Fig. 4). Thus severe hypercapnia is necessary to elicit long-term depression.
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To test the peripheral effects of norepinephrine on phrenic nerve activity in rats, we treated five animals with bolus injections of norepinephrine. The response of one rat to norepinephrine (2 µg/kg iv) is shown in Fig. 5. End-tidal CO2 was monitored and held as constant as possible. This response was qualitatively similar in all rats, regardless of the dose administered. Systemic norepinephrine resulted in a transient (~30-s) depression of phrenic and hypoglossal nerve activity coincident with an increase in blood pressure (perhaps reflecting the baroreceptor reflex). This depression was followed by a gradual rise in nerve amplitude over the next 5 min, reaching a value above baseline that lasted for at least 30 min. Blood pressure had returned to baseline values within 5 min of norepinephrine injection.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study demonstrates the existence of a unique mechanism, elicited
by repeated exposures to high levels of inspired
CO2 and resulting in a long-term
depression of respiratory nerve activity. This mechanism requires the
activation of 2-adrenergic
receptors, although probably not acting at the peripheral
chemoreceptors. The results are consistent with the hypothesis that
norepinephrine is involved in the neuromodulation of upper airway
(hypoglossal) as well as spinal (phrenic) respiratory motor output in
rats, although the site of these effects remains uncertain.
Episodic hypercapnia depresses phrenic and hypoglossal nerve activity. Our original hypothesis was that episodic hypercapnia would elicit long-term facilitation of respiratory motor output similar to that observed after episodic hypoxia (1, 20). Carotid chemoafferent activation is sufficient to elicit long-term facilitation under most circumstances, and, because both hypercapnia and hypoxia increase the firing frequency of carotid chemoafferent neurons (2, 13), we predicted that severe hypercapnia would elicit long-term facilitation as long as the carotid body chemoreceptors were intact. Surprisingly, rats exhibited a prolonged decrease in phrenic and hypoglossal burst amplitude and frequency after episodic hypercapnia.
Our findings contrast with the results of Morris et al. (29), who observed that episodic intracarotid hypercapnia causes long-term facilitation of phrenic nerve activity in anesthetized cats. However, this apparent difference can be explained by differences in protocol, because they injected CO2-saturated saline directly into the carotid artery, thereby activating the carotid chemoreceptors with minimal, direct effects on the central nervous system. In this way, they may have activated long-term facilitation while avoiding the potential inhibitory influence of central hypercapnia. The present study exposed rats to systemic hypercapnia, which stimulates both central and peripheral chemoreceptors, as well as exerting effects on other central nervous system structures. Thus systemic hypercapnia may activate mechanisms that underlie both long-term facilitation and long-term depression. Severe CO2 (i.e., FICO2 0.10) may preferentially activate inhibitory mechanisms
(long-term depression), creating an imbalance between excitation and
inhibition that masks long-term facilitation.
The majority of our experiments were conducted in hyperoxia
(FIO2 = 0.50) to avoid
exposing the rats to hypoxia during and between hypercapnic episodes.
However, high background levels of
O2 may also affect the relative
expression of long-term facilitation and long-term depression.
Hyperoxia may have blunted the effect of hypercapnia, because increased
inspired O2 levels inhibit the action of CO2 at the peripheral
chemoreceptors (13). Nevertheless, in one animal studied during
normoxia, long-term depression was still evident and indistinguishable
from long-term depression produced in hyperoxia. Yohimbine blocked
long-term depression in two normoxic rats exposed to episodic
hypercapnia as expected but also revealed long-term facilitation of
hypoglossal and phrenic nerve activity. Thus hypercapnia may be capable
of eliciting both long-term facilitation and long-term depression of
respiratory nerve activity: long-term depression via a central
noradrenergic mechanism and long-term facilitation via peripheral
chemoreceptor activation (i.e., activating raphe serotonergic neurons).
Long-term depression may mask the expression of long-term
facilitation unless 2-adrenergic receptors are
blocked, allowing hypercapnic activation of the peripheral
chemoreceptors to be expressed (particularly during normoxic
hypercapnia).
CO2 has long been thought to
stimulate central chemoreceptors via changes in extracellular fluid pH
(11). Hypercapnia-induced increases in extracellular
HCO3 concentration ([HCO3]), sampled from
cerebrospinal fluid and homogenized brain tissue, have been associated
with decreases in ventilation in awake rats (30). In principle,
increased [HCO3] could
persist after normocapnic conditions had been restored, thereby
accounting for the decreased ventilatory activity observed in the
present study. However, Nattie (30) observed that reduced ventilation
occurred only after 3 h of continuous 11.0%
CO2. Ventilation did not decrease
in rats after 15 min of hypercapnia, although some increase in
extracellular fluid [HCO3] had already occurred by this time
(HCO3 levels were measured during the
hypercapnic exposure and not after return to normocapnia). Because the
hypercapnic stimuli used in the present study were short (5-min
duration) and long-term depression occurred up to 1 hour after the
hypercapnic stimulus was removed, it is unlikely that brain pH
regulation is responsible for long-term depression. Furthermore,
arterial pH was constant at all recorded data points.
Yohimbine and RX-821002 block hypercapnia-induced long-term
depression.
Systemic pretreatment with yohimbine blocked long-term depression of
phrenic and hypoglossal nerve activity, thereby suggesting that
2-adrenergic receptors are
necessary in the underlying mechanism. Yohimbine primarily antagonizes
2-adrenergic receptors, but it is also a suspected antagonist at serotonergic and dopaminergic receptors (34), making it difficult to conclude with certainty that the
2-receptor is necessary for
long-term depression. However, because a more specific drug, RX-821002
HCl (25), also blocked long-term depression, it seems that
2-receptors are necessary in
the underlying mechanism.
2-mediated tonic inhibitory effect, although the lack of a similar effect after RX-821002 casts
doubt on this possibility. Hilaire et al. (22) hypothesized that a
tonic noradrenergic depression of respiratory rhythm originates in the
pons, because 2-receptor
antagonists increase respiratory activity in in vitro neonatal rat
preparations that include the pons and medulla but not in medullary
preparations.
Episodic 5.0% inspired CO2 does not result in long-term depression. Because episodic exposure to 5.0% inspired CO2 did not result in long-term depression of phrenic or hypoglossal nerve activity, it appears that long-term depression requires severe episodic hypercapnia. Thus the role of long-term depression in awake, active animals is doubtful. Still, animals are often exposed to high levels of CO2 during experimental protocols, assuming, perhaps incorrectly, that there are no long-lasting effects from this treatment.
Other investigators have shown that episodes of 5.0% inspired CO2 have little effect on interepisode ventilation. For example, Gozal et al. (16) exposed normal children to episodic hypercapnia (5.0%) and saw no difference in normocapnic ventilation between episodes. However, they did not record ventilation for >5 min poststimulation, which is not long enough to observe long-term depression in rats (data not shown). Because CO2 stores had not yet reached steady state within 5 min after a hypercapnic episode, it was not possible to determine whether the mechanism of long-term depression had been elicited between hypercapnic episodes in the present study. Millhorn et al. (26) did not observe long-term depression in anesthetized cats after a single 10-min exposure to 5.0% inspired CO2. Their protocol, however, precluded making direct comparisons with the present study: 1) they used cats, a species for which there is (as yet) no evidence of long-term depression; 2) the cats used in their study were exposed to a single episode of moderate (vs. episodes of severe) hypercapnia; and 3) their animals were carotid denervated.Systemic norepinephrine injections do not result in long-term
depression.
In principle, increased circulating norepinephrine could be responsible
for long-term depression by acting at the peripheral chemoreceptors via
inhibitory 2-receptors (24).
Previous studies have shown that increases in circulating
norepinephrine have different effects on ventilation depending on
species. For example, norepinephrine stimulates ventilation in primates
(5), but intracarotid infusions of norepinephrine depress ventilation
via -receptor activation in goats (31). The effect of systemic
norepinephrine injections in anesthetized rats has not been previously
investigated to our knowledge. In this study, systemic norepinephrine
caused a brief depression (in s) of respiratory nerve activity,
followed by a long-lasting increase, suggesting that hypercapnic
stimulation of systemic norepinephrine release is not a likely
explanation for long-term depression.
Possible mechanisms of long-term depression. Our working hypothesis is that episodic hypercapnia, at least in part, elicits long-term depression via activation of noradrenergic neurons with inhibitory projections to medullary sites involved in ventilatory control. Norepinephrine is produced and released from several discrete regions in the brainstem. At least two of these, the A5 nucleus (in the caudal ventrolateral pons) and the locus coeruleus (A6), increase their firing rates when exposed to hypercapnia (8, 17). Furthermore, there is evidence that the A5 region and the locus coeruleus send projections to relevant respiratory centers. Dobbins and Feldman (7) have shown that A5 and locus coeruleus neurons send direct projections to brainstem respiratory neurons, thus indicating the necessary neural pathways for an involvement in long-term depression.
Phrenic nerve activity increases when acetazolamide (a carbonic anhydrase inhibitor) is injected locally near the locus coeruleus (4), suggesting that activation of locus coeruleus noradrenergic cells by local increases in H+/CO2 facilitates (vs. depresses) respiratory motor activity. In seeming contrast to this study (4), our results suggest that increased brain CO2 or H+ levels activate a noradrenergic mechanism that ultimately inhibits phrenic and hypoglossal motor activity. Either species differences or activation of distinct noradrenergic cell groups (e.g., locus coeruleus vs. A5) may account for inhibitory vs. excitatory effects on respiratory motor output, thus accounting for these apparent differences in results. Previous studies have shown that norepinephrine, and the2-adrenergic receptor
specifically, is involved in inhibition of respiratory nerve activity.
Hilaire et al. (22) and Homma et al. (23) observed that norepinephrine
tonically inhibits activity of the medullary respiratory rhythm
generator via 2-receptors. Hilaire et al. (22) also hypothesized that a tonic noradrenergic depression of respiratory rhythm originates in the pons of rats because
2-receptor antagonists increase
respiratory activity in in vitro neonatal rat preparations that include
the pons and medulla. Bulbar respiratory neurons treated directly with
norepinephrine and clonidine, an
2-receptor agonist, decrease
their firing frequency (3). Inhibition of neural activity by
norepinephrine may be mediated by
1)
2-autoreceptors, which regulate
further norepinephrine release; 2)
2 heteroreceptors, which have
been found on serotonergic raphe neurons and inhibit serotonin release
(18); and/or 3) 2-receptors on a variety of postsynaptic sites (6,
28). Norepinephrine could be acting through any or all of the above 2-adrenergic receptor sites to cause a long-lasting
reduction in phrenic and hypoglossal nerve activity.
Hypercapnia-induced release of norepinephrine could block long-term
facilitation by acting on
2-adrenergic receptors located on raphe serotonergic neurons. Long-term facilitation is serotonin dependent in rats (1), and norepinephrine can act on raphe cell bodies
and terminals to inhibit raphe excitability and serotonin release (33).
Noradrenergic synaptic contacts have been identified on serotonergic
neurons in the caudal raphe nuclei of the cat and rat by using
immunocytochemistry (32, 35). It is possible that
2-receptor antagonists block
long-term depression by antagonizing inhibitory receptors on serotonin
terminals, increasing serotonin release, and enhancing long-term
facilitation. In other words, 2-receptor antagonism may tip
the scales from long-term depression toward long-term facilitation.
This "push-pull" system makes sense from a control perspective,
because long-term modulatory phenomena such as long-term facilitation
and long-term depression may require a high degree of regulation
to prevent wide, unchecked, and inappropriate swings in ventilatory
drive.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institutes of Health Grants HL-36780 and HL-53319 and Neuroscience Training Program Grant GM-07507.
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FOOTNOTES |
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Address for reprint requests: G. S. Mitchell, Dept. of Comparative Biosciences, Univ. of Wisconsin, 2015 Linden Dr. West, Madison, WI 53706.
Received 9 June 1997; accepted in final form 17 February 1998.
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REFERENCES |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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) in untreated (
;
n = 7) and yohimbine-treated (
; 0.5 mg/kg; n = 7) rats. In untreated
animals, Phr and XII nerve amplitude and frequency are significantly
less than baseline values (dashed line) after final hypercapnic
episode, returning toward but still well below baseline at 60 min
posthypercapnia. Similar depression was not seen after hypercapnia in
yohimbine-treated rats. Changes in Phr and XII nerve amplitude are
expressed as %change from prehypercapnic, baseline values.
* Different from baseline, P < 0.05. Isocapnia was maintained within 1 Torr at all recorded data
points (see Table 
; 0.25 mg/kg;
n = 3). Change in amplitude is
expressed as %baseline (prehypercapnic) amplitude. No depression was
seen after hypercapnia in RX-821002-treated rats. Apparent increases in
Phr and XII nerve amplitude posthypercapnia were not significant.
Untreated (
) nerve amplitude after moderate episodic hypercapnia (inspired
CO2 fraction 