Cerebral blood flow and energy metabolism
during stress
ROBERT M. BRYAN, JR. Departments of Surgery (Division of Neurosurgery) and Cellular and Molecular Physiology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033
BRYAN, ROBERT M., JR. Cerebral blood flow and energy metabolism during stress. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H269-H280, 1990.Many, but not all, stressful events are accompanied by increases in cerebral blood flow and/or energy metabolism. The stressful events include pharmacological paralysis, footshock, conditioned fear, hypotension, hypoglycemia, hypoxia, noise, and ethanol withdrawal. These increases are significant because 1) all brain regions are often affected, i.e., certain stressful events have global effects on cerebral blood flow and energy metabolism; and 2) various stressful events appear to have a common adrenergic mechanism for increasing cerebral blood flow and energy metabolism. The adrenergic mechanism involves ,&adrenergic receptor stimulation by either epinephrine secreted from the adrenal medulla or possibly norepinephrine endogenous to the brain. While adrenergic mechanisms are not the only mechanism controlling flow and metabolism for a given stressful condition, they do appear to be common to many situations. At least part of the increase in cerebral blood flow and energy metabolism during many conditions appears to be the result of the stress response and not directly a result of the condition itself.
stress; ,&adrenergic
receptors;
catecholamines;
FORTY YEARS AGO, Seymour Kety, a pioneer in the area
of brain blood flow and energy metabolism, measured the cerebral metabolic rate for oxygen (CMROZ) in a single patient on five different occasions (54). On one of these occasions, Kety noted that the patient was in a state of “grave apprehension.” At that time CMROa was elevated by approximately 36% when compared with the other measurements obtained during less stressful states . Was this elevation in CMROa related to stress associated with the “grave apprehension ?” This article will focus on this and related questions by reviewing the literature mostly from the 40 years subsequent to Kety’s initial observation. This article will show that many, but not all, stressful events imposed on laboratory animals and humans are accompanied by increases in cerebral blood flow (CBF) and cerebral energy metabolism [as measured by the cerebral metabolic rate for glucose (CMRGlu) and CMR02]. Part or all of the increase in flow and metabolism during many of these stressful events can be linked to a common mechanism involving the stimulation of ,& adrenergic receptors. At least part of the increase in CBF and energy metabolism may be due to a stress response brought on by the condition and not necessarily from the condition itself. 0363-6135/90
$1.50 Copyright
epinephrine;
norepinephrine
Definition of Stress For the layman and the scientist alike, the general term “stress” is one that is understood by all but difficult to define. A definition acceptable to behaviorists, physiologists, and pharmacologists engaged in the study of stress has been a difficult undertaking. Given the above information, a very general definition has been chosen for this review. Stress will be defined as a nonspecific response of an organism to a stimuli (stressor). The stimuli must be either an actual event that endangers the organism or one that is perceived to be endangering. The concept of stress arose from the pioneering work of Hans Selye (85), who showed that similar physiological reactions including glandular alterations, cardiovascular changes, ulcers, and elevated secretions of corticosteroids and catecholamines are common reactions to damaging or potentially damaging stimuli. Relationship Between CMROZ, CMRGlu, and CBF The relationship between CMR02, CMRGlu, and CBF must be clarified before further treatment of the topic. Both CMROa and CMRGlu are indirect measures of the rate at which ATP is utilized. The energy stored in ATP
0 1990 the American
Physiological
Society
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REVIEW
1. Cerebral energy metabolism (CMRGlu and CMR02) and blood flow in laboratory animals during stressful conditions
TABLE
Condition
Species
Pharmacological paralysis (spontaneous or tactileinduced stress response)
Method
Cerebral
Energy
Rat
K/S 133Xe with av O2
85% increase
Rat
[“Cl
34-145% increase in CMRGlu depending on region; 24 of 26 regions significant
Rabbit
Iodoantipyrine
Rabbit
Thermal
Rat
Rat
133Xe clearance with av O2 Microspheres with av O2 2-Deoxyglucose
Rat
Iodoantipyrine
SH rat
Iodoantipyrine
Rat
2-Deoxyglucose
Rat Rat
[ 14C] glucose Lactographyb
Rat
2-Deoxyglucose
Rat Rat
2-Deoxyglucose [ 14C] glucose
Rat
Iodoantipyrine
Rat
K/S 133Xe with av O2 CBF (estimated)” with av O2 K/S 133Xe with av Og K/S 133Xe with av O2 133Xe clearance with av O2
No change
Rat
K/S 133Xe with av O2
No change
02 content = 14,8, and 4 ~01%~
Dog
Venous outflow with av O2
Pao, (25-28
Rat
K/S 133Xe with av O2 2-Deoxyglucose
30-40% increase in CMRO, at 14 vol/lOO ml, no change at 8 and 4 vol/lOO ml for hypoxic hypoxia 97% increase in CMROZ 30% increase in CMRO, 39-95% increase in CMRGlu depending on region; 25 of 28 regions significant
Alcohol
withdrawal
Rat
Four-limb
Hindlimb
Restraint
restraint
restraint
in hammock
Hypercapnia Pace, (80 Torr) Ventilation
with
20% CO,
Rat
Pace, (72 Torr)
Rat
Pacoz (80 Torr)
Rat
Pace, (81-88 Hypoxia Pao, (23-40
Pao, (28 Torr)
Torr)
Torr)
Torr)
Rat
Rat
glucose
Cerebral
Metabolism
in CMROZ
clearance
25% increase
in CMRO,
40% increase
in CMROg
113%
Blood
Flow
increase
19
10
39-82% increase depending on region 32% increase in caudate (no other regions measured) 20% increase NS
60
38-49% increase on region
72
depending
28-165% increase in CMRGlu depending on region
18 and 25% decrease in CMRGlu in anteroventral nucleus of thalamus and hippocampus, 42% increase in habenula; no change in other regions No change in CMRGlu Increased CMRGlu in hippocampus (no other regions measured) Decrease in CMRGlu (7-35%) in 12 regions; no change in 12 regions No change in CMRGlu 9-14% decrease in CMRGlu in sensory cortex, motor cortex, and cerebellum; no change for other regions
CMROz
increased
No change
30%
in CMRO,
78
43
27 17% decrease in two regions, 8-14% decrease in 12 regions but NS” Frontal lobe increased 21%, other regions NS”
in CMROZ
Reference
75
76 91
9 82
84
91 9
No change for most regions; 13 and 17% decrease in frontal and parietal cortices
61
365%
increase
32
220%
increase
67
399%
increase
73
22% increase
in CMROz
516%
increase
7
35% increase
in CMROz
250%
increase
44
in CMRO,
106% increase for Pao, of 40 Torr 363% increase for Pao, of 23 Torr 34-176% increase
487% 374%
increasee increase
50
96
6 95
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l.-Continued.
TABLE
Condition
Pao, (30-35
Torr)
Species
Method
Rat
2-Deoxyglucose
Baboon
1502 washout av O2
Dog Rat
Microspheres av O2 Iodoantipyrine
Rat
[ 14C] Glucose
Footshock
Rat
[ 14C] Glucose
Handling
Rat Rat
[ 14C] Glucose Lactographyb
Cold
Rat
Lactographyb
Hypoventilation
Cat
Noise
Rat
Microspheres av 0, 2-Deoxyglucose
Hypotension
Conditioned
fear
stress
Moderate Plasma 2.14 1.76
Cerebral
with
with
with
Energy
Metabolism
40-90% increase in CMRGlu depending on region 10% increase in CMRO, during hemorrhagic hypotension; 17% increase in CMROz during nitroprusside-induced hypotension 60% increase hemorrhagic
in CMROz during hypotension
ll-31% increase in CMRGlu depending on region; 19 of 30 regions significant lo-36% increase in CMRGlu depending on brain region No change in CMRGlu Increased CMRGlu in hippocampus (no other structure measured) Increased CMRGlu in hippocampus (no other structure measured) 46% increase in CMRO,
Cerebral
Blood
Flow
50-180% depending on region No change during hemorrhagic hypotension; 21% decrease during nitroprusside-induced hypotension Significant increase in 4 of 10 regions 30-55% increase in auditory regions, 40-53% increase in limbic regions, 7-43% increase in other regions but NS
Reference
4 37
20 62
12
13 12 82
82
579%
increase
20-198% increase in CMRGlu depending on regionf
3 51
hypoglycemia glucose, pmol/ml Rat Rat Rat
K/S 133Xe with av O2 Iodoantipyrine
No change
54% decrease
1.50
Rat
Butanol indicatorfractionation with av O2 Iodoantipyrine
1.45
Rat
Iodoantipyrine
in CMROz
in CMRO,
68109% increase depending on region 40-220% increase depending on region No change
38138% increase depending on region 60-209% increase depending on region
74 1 34
11 46
K/S, Kety/Schmidt technique; NS, not statistically significant; SH rat, spontaneously hypertensive rats. a A significant reduction in Pace, occurred during immobilization, which would decrease cerebral blood flow (CBF). b Change in extracellular lactate of hippocampus using in vivo dialysis. An increase in lactate is indicative of increased glucose utilization. ’ CBF was estimated from CMRGlu and arteriovenous glucose. d For hypoxic hypoxia, Pao,s were 108, 36, 26, and 18 Torr for corresponding O2 contents of 18 (control), 14, 8, and 4 ~01%. Pao, was not changed during carbon monoxide hypoxia. e The two increases represent different experiments using rats from different breeding colonies. f Data were analyzed by a 2 x 2 (intact/locus ceruleus lesion x silence/noise stress) analysis of variance for 109 regions. Noise was a significant main effect in 99 regions and was a significant simple effect in intact rats in 31 regions.
is used to power biochemical reactions in cells. The rate of ATP hydrolysis defines the cerebral metabolic rate for en.ergy metabolism or cerebral energy metabolism (CEM). Under normal aerobic conditions, glucose is the sole substrate for brain energy metabolism (89). The process requires oxygen and the net result is the production of ATP. Under these aerobic conditions glucose is almost completely oxidized to CO2 and H,O; very little lactate is produced. A stoichiometric relationship exists where 1 mole of glucose is oxidized utilizing 6 moles of oxygen to produce approximately 38 moles of ATP (89). During certain pathological conditions, this stoichiometric relation between glucose and oxygen may be altered. For example, during hypoxic conditions, the end product of glucose metabolism is not only CO2 and Hz0
but also lactate (89). The molar ratio of glucose utilization to oxygen consumed would therefore increase. During starvation and hypoglycemia, glucose is no longer the sole substrate for energy metabolism (89). During this condition the molar ratio between glucose utilization and oxygen consumption is decreased. When the stoichiometry breaks down as described above, CMR02 is a better measure of energy metabolism than CMRGlu. During most conditions there is a tight coupling between CEM and CBF. It is thought that flow increases in the brain or in a specific brain region as the metabolic demand increases. In other words, CBF increases linearly as CMRGlu or CMR02 increases. However, a strict coupling between flow and metabolism has been recently questioned (33). A number of conditions have been
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shown where, although a relationship between CEM and CBF still exists, it is, nevertheless, altered (57, 97). Furthermore, it has been shown that while flow and energy metabolism are usually regulated together, CBF can be regulated independently (70). For this reason, flow and metabolism will be discussed separately in this review, although their regulation is not entirely separate or independent. CEREBRALBLOODFLOWANDENERGYMETABOLISM DURING STRESSFULEVENTS
Cerebral Blood Flow Stressful events associated with increases in CBF in laboratory animals include pharmacological paralysis (19, 60, 78), ethanol withdrawal (43, 72), hypercapnia (7, 44), hypoxia (6, 96), hemorrhagic hypotension (ZO), conditioned fear (62), and moderate hypoglycemia (1, 11,46, 74) (Table 1). During tactile or spontaneously induced stress in pharmacologically paralyzed rabbits, the increase in CBF occurred very rapidly with the onset of the stress and was accompanied by desynchronization of the ECoG (78). Although it is well documented that CBF increases during hypercapnia and hypoxia (for reviews see Refs. 16 and 89), the mechanisms involved in the increase are not fully understood. Some studies indicate that local mechanisms can totally account for the increase in CBF during hypoxia and hypercapnia (see Ref. 16). However, other studies provide evidence that the increases in CBF during hypercapnia (7, 44, 64) and hypoxia (6) are due not only to the local mechanisms but also to a catecholaminergic mechanism acting through P-adrenoreceptors. Species difference, anesthetics used, and the level and duration of hypoxia in different studies could add to the confusion of the mechanisms involved. It is not the purpose of this review to sort out the discrepancies in the various studies but rather to make the reader aware that catecholaminergic mechanisms could be involved with the increases in CBF during hypoxia and hypercapnia. This catecholaminergic mechanism may be a stress response accompanying the hypoxic or hypercapnic episode (see MECHANISMS FOR INCREASING CEREBRAL ENERGY METABOLISM FULEVENTS).
AND BLOOD
FLOW
DURING
STRESS-
It is reasonably clear that moderate hypoglycemia (plasma glucose -1.5-2.5 pmol/ml) increases CBF in the rat (1, 11, 46, 74), although one study reported that hypoglycemia did not alter CBF (34). In the rat, at least part of the increase in CBF during moderate hypoglycemia appears to be due to a stress response (46). For humans and laboratory animals other than the rat, an increase in CBF caused by hypoglycemia has not been consistently reported (23, 31, 71, 88). Anesthetic effects and the level of hypoglycemia may account for the lack of effect in some studies but not in others. The effects of restraint stress on CBF are confusing and difficult to interpret. In one study four-limb restraint in rats appeared to decrease CBF (75). In spontaneously hypertensive rats, four-limb restraint had no effect except in the frontal cortex where CBF increased 21% (76). The stress of the restraint in these two studies produced
REVIEW
a significant decrease in arterial PCO~ (Pace,) caused by hyperventilation. The decrease in Pace, would act to decrease CBF by constricting vessels (89) and thus offset or mask any increase in CBF caused by the stress. In fact, when Ohata et al. (75) corrected for the change in Pco~, CBF was reported to have increased as much as 20% depending on the correction factor used. Lasbennes et al. (61) reported that hindlimb restraint, a method often used to immobilize the hindquarters of rats for studying CBF, had no effect on CBF for most regions and decreased it in the frontal and parietal cortices. In humans, intense shock and possibly ethanol w ithdrawal and hypoglycemia are associated with increases in CBF (23, 45, 48, 71) (Table 2). CBF was not affected during “apprehension” and during animal phobia (69, 83). Anxiety was associated with alterations in blood flow resembling an inverted “U” (38). For lower anxiety levels, CBF increased linearly with anxiety, whereas there was a negative lin .ear decli ne for high-anx iety levels. Cerebral Energy Metabolism Stressful events associated with increases in CEM in laboratory animals include pharmacological paralysis (10, 19), ethanol withdrawal (27, 43, 72), hypoxia (4, 6, 95, 96), hypotension (20, 37), conditioned fear (12), footshock (13), cold (82), hypoventilation (3), noise (51), handling (82), and possibly hypercapnia (7,44,67) (Table I) . CMRGlu did not change during either hindlimb or four-limb restraint stress (9, 84, 91). However, tissue lactate was reported to increase in the hippocampus during restraint (82); tissue lactate was not measured in other brain regions. The increase in lactate was interpreted to mean that the glycolytic rate was increased. It could be that the tissue lactate m.ethod, termed lactography, is more sensitive than the tracer methods for measuring CMRGlu. On the other hand, the increase in CMRGlu during restraint may be a transient phenomenon (82) that could go undetected by tracer techniques that require steady-state conditions. Handling animals transiently increased CMRGlu in the hippocampus as measured by lactography (82); however, CMRGlu measured using [14C]glucose immediately after handling was not different from the control rate, even though plasma catecholamines were increased (12). Hypercapnia (Pace, = 70-80 Torr) was reported to increase CMRO, in three studies (7, 44, 67) even when glycolysis was inhibited by 30-50% (67, 89). Two other studies reported that hypercapnia had no effect on CMR02 (32, 73). Hypoxia in laboratory animals has been reported to either have no effect on CMROz (50) or to increase CMR02 (6, 96). Traystman et al. (96) reported that CMROz increased in dogs when oxygen content decreased from control (18 vol/lOO ml) to 14 vol/lOO ml during hypoxic hypoxia [arterial PO, (Pao,) of 36 Torr] but not anemic hypoxia (Pao, of 113 Torr). At more severe levels of hypoxia CMROZ was “fairly well maintained,” although it did decrease. The effect of hypoxia on CMR02 may depend on the level and the duration of
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INVITED
TABLE
2. Cerebral energy metabolism (CMRGlu and CMR02) and blood flow during stressful conditions in humans Condition
Assessment
Apprehension Grave
apprehension
In tense shock thumb
Severe
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to
anxiety
Anxiety
of Stress
K/S
NzO
K/S
NzO
Discomfort reported by subject
133Xe clearance av O2
Visual
K/S
observation
Energy
Metabolism
with
with
18Fluorodeoxyglucose ‘8Fluorodeoxyglucose; ‘““Xe inhalation
Decrease in CMRGlu increasing anxiety”
H, “0
Alcohol
withdrawal
Visual
observation
av O2
Approximately 36% increase in CMRO, in a single subject 12% increase in CMRO,
Visual observation distress STAI
and SUDS
with
av 0,
“Fluorodeoxyglucose
STAI
with
PET
133Xe inhalation
Elevated blood pressure
K/S
N20 with
av O2
No change
K/S K/S K/S
N20 with “Kr with N20 with
av O2 av 0, av O2
Sweating, anxiety, hunger, tachycardia, tremulousness Perspiration and somnolence
K/S
N20 with
av 0,
K/S
N20 with
av O2
No change in CMROz No change in CMRO, Plasma glucose 1.06 and 0.44b pmol/ml accompanied by 24 and 45% decrease in CMRO, Plasma glucose 1.7 pmol/ml accompanied by 16% increase in CMRO, 26% decrease in CMRO, with plasma glucose of 1.89 pmol/ml, 21% decrease in CMRO, with plasma glucose of 1.56 pmol/mlb but NS
Blood
13”Xe clearance
Elevated heart Elevated heart Not stated
pressure
rate rate
Cerebral
Blood
Flow
No change
STAI
phobia
N20
Cerebral
Increased CMR02 in some, but not all, “severely anxious” subjects Frontocortical increase in CMRGlu with increasing anxiety up to a point then decrease (inverted “U” ) No change in CMRGlu
Animal
Hypercapnia Pace, (52 Torr) Hypoxia 10% 02 Pao, (34 Torr) Hypoglycemia
Method
Rapid pulse, elevated systolic pressure Visual observation
in CMROz
Reference
83 54
Increase in mean hemispheric gray matter, no change in white matter, frontal cortex most affected (13% increase)
48
90
80
24 Increased with increasing anxiety then decrease (inverted “U”) No change after correcting for CO, 24% increase in patients with hallucinations and agitation; other patients no change in CBF 75 % increase
38
35% increase 71% increase No change
55 21 56
Increase CBF patients
10 of 16
69 45
55
31
No change with plasma glucose of 1.89 pmol/ml; 38% increase with plasma glucose of 1.56 ,umol/mlb
23
21% increase with plasma glucose of 1.1 pmol/ml
71
K/S, Kety/Schmidt technique; STAI, State-Trait Anxiety Inventory; SUDS, Subjective Unit of Distress Scale; NS, not statistically significant. a The relationship between CMRGlu and anxiety is likely to be an inverted “U” as is the case for CBF. Subjects in the CMRGlu study showed higher levels of anxiety due to the procedure. The authors felt that only the higher anxiety portion of the curve is observed for the CMRGlu measurement. ’ Coma.
the hypoxic episode. In humans, CMRO, was not altered during hypoxia (21, 55). Although CMR02 did not increase in many of the studies, it did not decrease either. The fact that CMROz did not decrease during hypoxia may be looked on as a relative increase in CMROz given the Oz limitation. CMRGlu has been reported to transiently increase (lo-30%) during mild hypoxia (Pao, -40 Torr) (65) and increase globally (40-95% increase) during more severe hypoxia (Pao, -30 Torr) (4, 95). As stated in the introduction, CMRGlu may not be stoichiometrically related to CMR02 during hypoxia. Conditioned fear in rats increased CMRGlu in what
appeared to be a global effect (12). The increase in CMRGlu was superimposed on a decrease in CMRGlu, which was due to conditioning the rats with mild footshock. In humans, CMR02 increased during the stresses of “grave apprehension” and intense shock to the thumb (48, 54). Anxiety was reported to increase CMROz in certain individuals (go), to have no effect on CMRGlu (24), or to increase CMRGlu up to a point after which greater anxiety decreased it (80) (Table 2). In one study, anxiety was associated with a negative linear decline in CMRGlu (38). It was thought that CMRGlu did not show the “inverted-U” relationship as did CBF (38) or
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CMRGlu in another report (80), because the CMRGlu technique was anxiety producing and therefore no subjects were studied at the lower anxiety level (38). Hypoglycemia in humans was reported to increase, decrease, or have no effect on CMROZ (23, 31, 56). Neither hypercapnia nor hypoxia altered CMR02 in humans (21, 55). The study reported by Sokoloff (90) dealing with “severe anxiety” is worthy of more discussion. CMR02 was measured in 60 subjects. Five of the 60 subjects had elevated rates of CMROa, and each one of these subjects was determined to be “severely anxious.” Only the subjects that were determined to be anxious had elevated rates of CMRO,; however, some subjects were determined to be “severely anxious” but did not have an elevated CMRO,. Stress or anxiousness can be associated with increased CMROa, but it does not always have this effect. These studies show that stress or stress-related events can affect CMROz, but not all subjects respond in the same manner. Alternatively, these results point out that another means of assessing stress may be more appropriate when attempting to correlate stress with changes in CMR02. Summary
of Effects of Stress on CBF and CEM
There are several problems with the current data on the effects of stressful events on CBF and CEM. The results are at times confusing. Many stressful events appear to increase CBF and CEM, whereas other events have no effect. Furthermore, there is often no consensus as to the response of CBF and CEM to a given stressful event. However, the point to be made is not that stress unequivocally increases CBF and CEM but rather that these stressful events can in some circumstances and in some individuals produce increases in CBF and CEM. Several of the studies already discussed attest to this fact. For example, Berntman et al. (6) reported differences in the magnitude of the increase in CBF and CMR02 in rats during hypoxia by different breeding colonies. In humans, the response to “severe anxiety” and intense shock to the thumb varied with the individual being studied (48, 90). Furthermore, the state of the control measurement of CBF and CEM is questionable in many of the studies reported above. In some of the studies, anesthesia was used in either the controls or in both the controls and experimental animals. This is of concern, since many anesthetics are known to alter CBF and CEM (89). In some studies awake restrained animals were used as control conditions. In these studies the effects of a stressful condition were compared with those of a more stressful condition. In the human studies, the procedure of the measurement could be stress producing. Any of the above situations could complicate the interpretation of the results. Several conclusions can be drawn even when the above problems are considered. 1) Stress can increase CBF and CEM, although it does not always do so. The response may depend on the stressful event, the level of stress, and the individual. 2) The increases in CBF and CEM that do occur as a result of stressful events often are global in that all brain regions appear to be affected.
REVIEW MECHANISMS FOR ENERGY METABOLISM DURING STRESSFUL
Adrenergic
INCREASING CEREBRAL AND BLOOD FLOW EVENTS
Mechanisms
The control of CBF and CEM during stressful events is complex. During some stressful events, there is apparently a single mechanism responsible for increasing CEM and CBF, whereas during other stressful events there appear to be multiple mechanisms at work. Regardless of whether a single mechanism or multiple mechanisms are involved, the stimulation of ,@-adrenergic receptors seems to be a common aspect of many diverse stressful conditions. Evidence for the involvement of the ,&adrenergic receptors includes the following: 1) the increase in CBF and CEM that occurs during a number of stressful events can be completely abolished or attenuated by blocking the ,&receptors; 2) pharmacological stimulation of ,& receptors in brain increases CEM and CBF; and 3) removal of the adrenal medulla, the source for catecholamines that are ,&receptor agonists, often abolishes or attenuates the increase in CBF and CEM. Each of the above will be discussed separately. Pharmacological blockade of ,&adrenergic receptors during stressful euents. Increases in CBF and CEM have been either abolished or attenuated during stressful events by blocking the ,&receptors. During pharmacological paralysis, pretreatment with propranolol, a @-antagonist, abolished the increase in CMROz and CBF in the rat and attenuated the CBF increase in the rabbit (see Fig. 1 and Refs. 19 and 78). ,&Receptor blockade abolished the increase in CMR02 that occurred during ethanol withdrawal and hypercapnia (7, 43, 44). The CBF increase during hypercapnia was attenuated with propranolol (7, 44, 64). Attempts to show ,&receptor involvement during severe hypoxia (Pao, of 26-28 Torr) in the rat were unsuccessful because of cardiovascular failure during the hypoxic episode with ,&receptors blocked (6). During mild hypoxia, propranolol can be successfully used. MacNeill and Bryan (65) demonstrated that ,&receptor stimulation was not involved with the transient increase in CMRGlu that occurs during I I EXY EB3
0 c-l %
200
17 al 0
100
b a
N20 Control Stress Stress + Adrenalectomy Stress + Propranolol
150
50
0 CBF
CMR02
FIG. 1. Effects of stress (pharmacological paralysis), stress with prior adrenalectomy, and stress after blocking ,&adrenergic receptors with propranolol on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen ( CMR02). Control measurements were made in paralyzed rats ventilated with 70% N,O and 30% 0,; stress conditions were 30 min after N2 was substituted for the N20 (figure adapted from Ref. 19). * P < 0.05.
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INVITED
mild hypoxia (Pa o2 of 40 Torr). The increase in CBF during insulin-induced hypoglycemia was abolished in the hypothalamus, pyramidal tract, and cerebellum when rats were pretreated with propranolol. In all other brain regions, the increase was attenuated 3570% (46). It is concluded from the above studies that ,&receptor stimulation is responsible for at least part of the increase in CEM and CBF during many stressful events. Pharmacological stimulation of ,&receptors in brain. CEM and CBF are increased when the agonists for ,@receptors, norepinephrine and epinephrine, gain access to the brain. Elevated plasma catecholamines alone do not increase CEM or CBF if the blood-brain barrier is intact (22,28, 63,64); however, if the blood-brain barrier permeability is increased by elevated blood pressure or osmotic insult, then catecholamines enter the brain and increase CEM and CBF (2, 22, 28, 63, 64). When the blood-brain barrier was circumvented by directly injecting norepinephrine into the ventricles, CBF and CEM were increased (63). The increase in CEM and CBF produced by catecholamines was blocked with propran0101(28). The fact that CEM and CBF can be increased by stimulating ,&receptors in brain is consistent with and adds support to the idea that ,&receptor stimulation can increase CEM and CBF during stressful events. Agonist and its source for stimulation of ,&receptors during stressful events. The agonists for ,&adrenergic receptors are norepinephrine and epinephrine. The sources for these catecholamines are 1) epinephrine and norepinephrine secreted from the adrenal medulla [in the rat primarily epinephrine is secreted (66)]; 2) epinephrine and norepinephrine endogenous to the central nervous system, primarily the locus ceruleus in addition to other cell groups originating in the brain stem (8); and 3) norepinephrine secreted from nerve terminals whose cell bodies lie in sympathetic ganglia, primarily the superior cervical ganglia (16). INVOLVEMENT OF CATECHOLAMINES FROM ADRENAL MEDULLA. Catecholamines secreted from the adrenal
medulla are responsible for the increase in CEM and CBF during some stressful events but not others. Adrenalectomy abolished the increase in CMROa and CBF during immobilization stress in the rat (19) and attenuated the increase in CBF in the rabbit during immobilization stress (58). Adrenalectomy attenuated the increase in CMROs and CBF during severe hypoxia in one strain of rats, whereas it did not affect the increase in another strain (6). In a related study Iadecola et al. (47) showed that stimulation of the dorsal medial reticular formation increased both CMRGlu and CBF globally. The increase in CBF could be substantially reduced or abolished depending on the brain region by propranolol, adrenalectomy, or adrenal demedullation (Fig. 2). The mechanism for increasing CBF and CEM during stimulation of the dorsal medial reticular formation is apparently identical or quite similar to the mechanism for increasing CBF and CEM during some stressful events. EPINEPHRINEANDNOREPINEPHRINEENDOGENOUSTO CENTRALNERVOUS SYSTEM. Adrenalectomydidnotalter
the increase CMROZ and CBF during hypercapnia and did not alter the increase in CMROZ during ethanol withdrawal (7, 43). Furthermore, adrenalectomy did not
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2252 -b : 0
175-
s
EO-
x LL
125
-
100
-.-.*
m 0 L
75 Med
HYPO
Thai
Hippo
FC
2. Effects of dorsal medullary reticular formation stimulation on regional cerebral blood flow in intact (unfilled columns), acutely adrenalectomized (filled columns), and adrenal demedullated (columns with diagonals) rats. Regional cerebral blood flow (rCBF) is expressed as a percent of rCBF forunstimulated intact rats or unstimulated rats after adrenalectomy. * P < 0.05 compared with respective control. With the exception of hypothalamus, rCBF is significantly (P < 0.05) lower than in stimulated intact group. Med, medulla; Hypo, hypothalamus; Thal, thalamus; Hippo, Hippocampus; FC, frontal cortex. Figure adapted from Ref. 47. FIG.
affect the increase in CMR02 and CBF during hypoxia in one strain of rats (6). It was proposed that the source of the catecholamine for stimulating the ,&receptors was endogenous to the central nervous system and was most likely norepinephrine from the locus ceruleus (6, 7, 43). This conclusion is based on the following. First, benzodiazepines, which decrease the turnover of central nervous system norepinephrine, either abolished or attenuated the increase in CMROz and CBF during pharmacological paralysis, hypercapnia, ethanol withdrawal, and hypoxia (6, 7, 18,43, 72). Second, during stressful events release of norepinephrine from nerve terminals whose cell bodies lie in the locus ceruleus is increased (92) and the released norepinephrine is known to stimulate ,& receptors (93). Therefore, it was hypothesized that the locus ceruleus was the source for the centrally released norepinephrine that stimulates the ,&receptors. Although the administration of benzodiazepines during the above stressful events is consistent with the involvement of central norepinephrine neurons, presumably the locus ceruleus, it must be pointed out that the action of benzodiazepines is complex. Systems other than the norepinephrine system are affected and, therefore, cannot be ruled out. Furthermore, more recent studies provide evidence that the locus ceruleus does not increase CBF but actually decreases it (35, 36); the decrease in CBF may be secondary to changes in CEM (15). The role of endogenous catecholamines in the stimulation of ,&adrenergic receptors during stress remains to be resolved. NOREPINEPHRINE NERVOUS SYSTEM.
RELEASED
FROM
SYMPATHETIC
The sympathetic nervous system has extensive innervation throughout the brain. Neurons originating in the superior cervical ganglia are the primary source for sympathetic innervation in brain; however, other sympathetic ganglia also innervate caudal regions (16, 29). Stimulation of sympathetic nerves is associated with cerebral vasoconstriction that acts to attenuate CBF during stressful events such as hypertension, hypercapnia, and hypoxia ( 16, 29). There is no experimental evidence linking the sympathetic nervous
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system with an increase in CEM and CBF during stressful events. Location and type of ,&receptors. The location of the P-receptors responsible for increasing CEM and CBF during stressful events is not known. ,&Receptors are found throughout the body in vascular and nonvascular tissue alike (68). In the brain, ,&receptors receptors are found in all components including endothelial cells, glia, and neurons (25, 26, 40, 41). Both ,& and ,& type are found throughout the brain, with the relative percent of each varying with the brain region (79). Generally the ,& type of receptors predominate in forebrain regions; however, the relative percent of each can vary considerably depending on the specific brain region. The ,& type of receptors predominate in the cerebellum. In the endothelial cells isolated from the cerebral cortex, 84% of the total P-receptors are of the ,& type with the remainder being ,& type (52). An increase in CBF by the selective P-agonist, isoproterenol, can be blocked with propranolol, a ,&- and ,&antagonist, and practolol, a selective ,&-antagonist (29, 86). Terbutaline, a ,&-agonist, had no effect on CBF (86). Results consistent with the above come from studies of isolated brain vessels. Dilation produced by isoproterenol was blocked by propranolol and practolol (30, 86). The above studies indicate that ,&-type receptors are responsible for the increase in CEM and CBF during pharmacological stimulation and possibly stressful events. However, selective p-antagonists have not been used in studies during stressful events. Although the subtype and location of the P-receptors that are responsible for increasing CEM and CBF during stressful events are not known, the pharmacological studies described above would suggest that 1) the ,8receptors responsible for increasing CEM and CBF are located in the brain behind the blood-brain barrier and 2) the subtype of ,&receptor responsible for the increase in CEM and CBF is the ,& subtype. However, neither the location of the ,&receptors nor the subtype has been studied during stressful events. Caution must be applied when extrapolating from the pharmacological studies to stressful events. Unanswered
Questions
Regarding
Involvement
of Adrenal Medulla
The fact that plasma catecholamines secreted by the adrenal medulla play a role in increasing CBF and CEM during several stressful events and during stimulation of the dorsal medial reticular formation (6,19,47,58) raises several questions as to exactly how plasma catecholamines stimulate P-receptors. Elevated plasma catecholamines alone are not sufficient to increase CEM and CBF during stressful events. As previously stated, plasma catecholamines do not increase CEM and CBF if the blood-brain barrier is intact (22, 28, 63, 64). This is consistent with studies showing that plasma catecholamines do not readily penetrate the blood-brain barrier (39, 77) and thus have limited access to the brain parenchyma. The blood-brain barrier, for the most part, appears to remain intact during immobilization, hypoxia, and stimulation of the dorsal medial
REVIEW
reticular formation (4, 5, 47, 59, 76, 78). Therefore, elevation of plasma catecholamines alone is not sufficient to produce the increase in CEM and CBF. Something must occur during stressful events, in addition to the elevated plasma catecholamines, to produce an increased CEM and CBF. There are several possible interactions between plasma catecholamines and P-receptors to account for the above enigma. First, if the P-receptors responsible for increasing CEM and CBF during stressful events are located behind the blood-brain barrier, as pharmacological studies would suggest (22, 28, 63, 64), then plasma catecholamines must somehow cross the barrier. As stated above, the blood-brain barrier, for the most part, remains intact during several stressful conditions and stimulation of the dorsal medial reticular formation (4, 5, 47, 59, 76, 78). However, if stress produced a selective increase in the permeability of the blood-brain barrier to catecholamines, then the methods described above for measuring blood-brain barrier permeability that utilized sucrose, aminoisobutyric acid, Evans blue, and trypan blue as markers (4, 5, 47, 76, 78) would not be accurate for catecholamines. On the other hand, Lacombe et al. (59) studied epinephrine directly and did not find any permeability change during the stress of pharmacological paralysis. However, only a limited number of brain regions were used for the latter study. A few regional changes in the blood-brain barrier were noted during stressful events. Ohata et al. (76) reported an increase in the permeability of the blood-brain barrier in the frontal lobe, in the gray matter of the parietal lobe, and in the corpus collosum in spontaneously hypertensive rats during four-limb immobilization; Belova and Johnsson (5) reported that several brain regions have an increased blood-brain barrier permeability during immobilization, most notably the reticular formation of the brain stem, the rostra1 part of the mesencephalon, and the medulla oblongata. Perhaps plasma catecholamines only have to stimulate a single region or group of neurons to produce the increase in CEM and CBF during stress. If the P-receptors responsible for increasing CEM and CBF are located outside the blood-brain barrier (in the lumen of the cerebral vessels, in circumventricular organs of the brain that lack a blood-brain barrier, or somewhere in the periphery), then the P-receptors would not be sensitive to the plasma catecholamines under normal conditions, since elevated plasma catecholamines alone do not increase CEM and CBF (22, 28, 63, 64). Stress would have to sensitize the ,&receptors to plasma catecholamines. One possible peripheral site that has been suggested for the location of P-receptors that could increase CBF and CEM is the carotid body (49); however, most evidence indicates that the carotid body does not affect CBF and CEM (42, 96). Other Mechanisms Stimulatory mechanisms. Nonadrenergic mechanisms that increase CBF and/or CEM have been demonstrated. Pinard et al. (78) showed that the cholinergic system may be important for increasing CBF during stressful
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INVITED
events. Atropine, a cholinergic muscarinic antagonist, attenuated the CBF increase occurring during pharmacological paralysis. Schasfoort et al. (82) showed that an N-methyl-D-aspartic acid receptor antagonist attenuated the increase in tissue lactate during cold, handling, and restraint, indicating that excitatory amino acids stimulate glycolysis. It is not known if the cholinergic mechanism (78) is specific only to the particular stress described above; however, it appears that excitatory amino acid stimulation is common to different stressful conditions (82). Inhibitory mechanisms. There is evidence that in addition to the mechanisms for increasing CEM and CBF, there are also mechanisms at work that act to decrease CEM and CBF. The net change in CEM and CBF during stress would therefore be dependent on the relative effects of the stimulatory (increase CBF and CEM) and inhibitory (decrease CBF and CEM) mechanisms acting simultaneously. During most stressful events, therefore, the stimulatory mechanisms predominate over the inhibitory mechanisms leading to an increase in CEM and CBF. Ingvar et al. (48) reported that, during electrical stimulation of the thumb, CBF and CMROZ increased for the majority of the subjects studied. Occasionally, however, CBF decreased in individuals during the electrical stimulation. The authors interpreted these findings as the presence of more than one mechanism acting on CBF. At least one of these mechanisms would be vasoconstrictory and at least one vasodilatory. In most individuals during electrical stimulation the vasodilation mechanism(s) dominated, producing an overall increase in CBF. Pinard et al. (78) reported that phentolamine, an cyadrenergic antagonist, enhanced the CBF increase during pharmacological paralysis. Therefore, stimulation of aadrenergic receptors acted to decrease CBF. Justice et al. (51) reported that the locus ceruleus was responsible for limiting or inhibiting an increase in CMRGlu during noise stress. Other studies where it was demonstrated that the locus ceruleus decreased CBF (35, see Ref. 36 for a review) are consistent with the inhibitory effects of the locus ceruleus during noise stress. Furthermore, sympathetic vasoconstrictor processes working through aadrenoreceptors limit vasodilation during hypoxia and hypercapnia (16). The competing inhibitory and stimulatory mechanisms could confound the interpretations of changes in CEM and CBF that are measured during stressful events. The relative importance of the various stimulatory and inhibitory mechanisms that are involved during stress could produce different responses for individuals, species, or strains, depending on the predominant mechanism (6, 48) Summary of mechanisms. The mechanisms that regulate CEM and CBF during stressful events are undoubtedly complicated. For example, ,&receptor stimulation can totally account for the increase in CEM and CBF produced by some stressful events but not all stressful events. Therefore, other mechanisms, mostly unknown, must be involved in addition to ,&receptor stimulation. Other stimulatorv mechanisms involve the cholinergic
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system and excitatory amino acids (78, 82). In addition, other neurotransmitters and hormonal systems that are altered during stress could have profound effects of CEM and CBF. These other systems remain to be investigated as to their influence on CEM and CBF during stress. EFFECTS CEREBRAL
OF REPEATED BLOOD FLOW
OR CHRONIC AND ENERGY
STRESS ON METABOLISM
Up to this point this review has considered the effects of acute stress on CEM and CBF; a possible exception is anxiety in some of the human studies. This section will discuss the effects of repeated or chronic stress. The significance of chronic or repeated stress is that it is a model for depression in laboratory animals (53). Chronic or repeated stress produced by immobilization or pain is associated with a decrease in CMRGlu and CBF. Bryan and Lehman (12) reported that CMRGlu in rats decreased in all brain regions studied (21 of 30 regions statistically significant) after repeated footshock. Overall CMRGlu decreased 13% compared with the unshocked control rats. Caldecott-Hazard et al. (17) reported that forebrain global glucose metabolism decreased 16% from controls in a rat model for depression. The model consisted of a number of stressors including footshock, cold, heat, and shaking with each administered semirandomly over 20 days. Sharma and Dey (87) reported that in rats CBF decreased 2-37% depending on the brain region (mean decrease 17%) after 8 h of immobilization. Schasfoort et al. (82) reported that extracellular lactate in the hippocampus, indicative of an increased glycolytic rate, in previously immobilized rats was attenuated compared with naive rats during immobilization stress. Bryan and Pelligrino (14) reported that CBF increased significantly in 15 of 17 brain regions after 6-7 days of chronic hypoglycemia (plasma glucose 1.97 pmol/ml or 35 mg/dl). The increase in CBF ranged from 22 to 83% depending on the brain region. The control of CBF and CEM during chronic hypoglycemia is most likely unique and probably bears very little relationship to the other chronic studies where pain or immobilization were incorporated. It is not known why CMRGlu and CBF decrease in the above studies involving repeated or prolonged pain or immobilization. At the present there are two possible explanations for the above phenomenon. First, the decrease in CMRGlu, and thus CBF, could be a result of chronically elevated glucocorticoids. Sapolsky (81) has shown that elevated glucocorticoids disrupt CEM, most likely by inhibiting glucose metabolism. In addition to the direct effect on CEM, glucocorticoids cause a selective desensitization of the al subtype of the a-adrenoreceptors (94). These a-receptors potentiate the effect of ,&receptor stimulation, and their desensitization would effectively reduce the sensitivity of the ,&receptors to norepinephrine (94). Second, repeated stress not only reduces the ,&receptor sensitivity but it also decreases the ,&receptor density (92, 93). If P-receptor tone is partially responsible for determining the resting rates of CEM and CBF, then a decrease in density or sensitivity could be responsible for decreasing CEM and CBF after repeated stress. However, at this time the idea that ,&
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receptor downregulation is responsible in CMRGlu is only speculation. SIGNIFICANCE OF INCREASE METABOLISM
AND POTENTIAL CLINICAL IN CEREBRAL BLOOD FLOW DURING STRESSFUL EVENTS
for the decrease
RELEVANCE AND ENERGY
What is the significance, consequence, and strategy for increasing CBF and CEM during stressful events? One hypothesis is that the increase in CBF and CEM during stressful events is an overcompensation of a homeostatic mechanism that is responsible for maintaining CEM and CBF during stressful events. A mechanism that would maintain an unchanged cerebral metabolic rate when substrate (glucose or oxygen) supply to the brain is reduced would preserve cellular processes and neural communications in the face of adverse conditions. The mechanism could act in two ways. First, increased CBF would deliver more oxygen and/or glucose to the brain and thus maintain higher concentrations of the substrates in capillary blood. Second, the extraction of oxygen by the brain would be increased. This homeostatic mechanism would maintain CEM unchanged when there is a reduced supply of substrates for energy metabolism. When working properly the mechanism would maintain a metabolic homeostasis. However, if the homeostatic mechanism overcompensates for substrate limitation during the stressful event, then the rate of cerebral energy metabolism would be increased. This overcompensation may or may not occur and would depend on how well the response matched the insult of substrate limitation. Whether an increase did or did not occur would depend on the relative strength of the competing stimulatory and inhibitory mechanisms for the individual, strain, or species (6, 48, 90). There is no doubt that homeostatic mechanisms exist, since increases in CBF (1, 11, 21, 46, 55) and extraction of oxygen (20, 37) do occur. The above hypothesis would explain why some investigators do not find any change in CEM during the insult and others find an increase. Examples of stressful events where investigators found either no change or an increase in CMR02 consist of hypoxia (6, 21, 50, 55), hypotension (20, 37), and hypoglycemia (31, 74). The above hypothesis cannot account for other stressful events such as pharmacological paralysis and conditioned fear where the oxygen and glucose supply to the brain is not limited. The need for such a homeostatic mechanism is therefore not readily apparent. Possibly the increase in CBF and CEM is a nonspecific mechanism activated during many conditions of actual or perceived danger to prepare the brain for the worst possible outcome. If the hypothesis regarding the overcompensation of a homeostatic mechanism is correct, then the increase in CEM and CBF may not be an appropriate response for some stressful events. In those stressful events, such as hypotension and hypoxia, where delivery of oxygen is compromised, it may not be appropriate to respond to the stressful event by increasing the amount of oxygen required by the brain. An increased oxygen demand at a time when the oxygen supply is limiting would make the
REVIEW
brain even more hypoxic and put it in a more vulnerable position to be damaged. Stressful events where oxygen becomes limiting to the brain could lead to more severe brain damage if CMRO, is increased. In conclusion, many, but not all, stressful events are accompanied by an increase in cerebral energy metabolism and/or cerebral blood flow. The stimulation of ,& adrenergic receptors is responsible for increasing CEM and CBF during a number of diverse stressful conditions. The agonist for stimulating the ,&receptors during several stressful events appears to be catecholamines secreted by the adrenal medulla; the agonist for stimulating the ,&receptors for other stressful events is not presently known, but catecholamines endogenous to the brain remain a possibility. Although ,&receptor stimulation is responsible for at least part of the increase in CEM and CBF during all of the stressful events studied thus far, it is not known if it is involved in other stressful events where it remains to be studied. There appear to be stimulatory mechanisms, other than ,&adrenergic receptors, responsible for increasing CEM and CBF. It is not presently known if these stimulatory mechanisms, like the ,&receptor mechanism, are common to different and diverse stresses. In addition to the stimulatory mechanisms there are also inhibitory mechanisms acting during stress. The net change in CEM and CBF during stressful events is therefore dependent on the relative effects of the stimulatory and inhibitory mechanisms acting simultaneously. Since most stressful events are accompanied by an increase in CEM and CBF, the stimulatory mechanisms predominate over the inhibitory mechanism leading to an increase in CEM and CBF. However, dominance of the inhibitory or stimulatory mechanism depends on the individual, species, or strain and the stressful event involved. Address for reprint requests: R. M. Bryan, Jr., Dept. of Surgery, Division of Neurosurgery, The Milton S. Hershey Medical Center, The Pennsylvania State University, PO Box 850, Hershey, PA 17033. REFERENCES 1. ABDUL-RAHMAN, A., C. D. AGARDH, AND B. K. SIESJO. Local cerebral blood flow in the rat during severe hypoglycemia, and in the recovery period following glucose injection. Acta Physiol. Stand. 109: 307-314,198O. 2. ABDUL-RAHMAN, A., N. DAHLGREN, B. B. JOHANSSON, AND B. K. SIESJO. Increase in local cerebral blood flow induced by circulating adrenaline: involvement of blood-brain barrier dysfunction. Acta Physiol. Stand. 107: 227-232, 1979. 3. ANDERSEN, B. J., A. W. UNTERBERG, G. D. CLARKE, AND A. MARMAROU. Effect of postraumatic hypoventilation on cerebral energy metabolism. J. Neurosurg. 68: 601-607, 1988. 4. BECK, T., AND J. KRIEGLSTEIN. Cerebral circulation, metabolism, and blood-brain barrier of rats in hypocapnic hypoxia. Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H504-H512, 1987. 5. BELOVA, T. I., AND G. JOHNSSON. Blood-brain barrier permeability and immobilization stress. Acta PhysioZ. Stand. 116: 21-29, 1982. 6. BERNTMAN, I,., C. CARLSSON, AND B. K. SIESJO. Cerebral oxygen consumpt,ion and blood flow in hypoxia: influence of sympathoadrenal activation. Stroke 10: 20-25, 1979. 7. BERNTMAN, L., N. DAHLGREN, AND B. K. SIESJO. Cerebral blood flow and oxygen consumption in the rat brain during extreme hypercarbia. Anesthesiology 50: 299-305, 1979. 8. BJORKLUND, A., AND 0. LINDVALL. Catecholaminergic brain stem regulatory systems. In: Handbook of Physiology. The Nervous System. Intrinsic Regulatory Systems of the Brain. Bethesda, MD: Am.
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INVITED Physiol. Sot., 1986, sect. 1, vol. IV, chapt. 3, p. 155-235. 9. BRYAN, R. M., JR. Regional cerebral glucose utilization in freelyranging and restrained rats. Sot. Neuorsci. Abstr. 15: 858, 1989. 10. BRYAN, R. M., JR., R. A. HAWKINS, A. M. MANS, D. W. DAVIS, AND R. B. PAGE. Cerebral glucose utilization in awake unstressed rats. Am. J. PhysioZ. 244 (Cell Physiol. 13): C270-C275, 1983. 11. BRYAN, R. M., B. R. HOLLINGER, K. A. KEEFER, AND R. B. PAGE. Regional cerebral and neural lobe blood flow during insulin-induced hypoglycemia in unanesthetized rats. J. Cereb. BZood FLOW Metab. 7: 96-102, 1987. 12. BRYAN, R. M., JR., AND R. A. W. LEHMAN. Cerebral glucose utilization after aversive conditioning and during conditioned fear in the rat. Brain Res. 444: 17-24, 1988. 13. BRYAN, R. M., AND R. B. PAGE. The effect of stress on regional cerebral glucose utilization in rats. Stroke 15: 193, 1984. 14. BRYAN, R. M., AND D. A. PELLIGRINO. Cerebral blood flow during chronic hypoglycemia in the rat. Brain Res. 475: 397-400, 1988. 15. BUCHWEITZ, E., N. H. EDELMAN, AND H. R. WEISS. Effect of locus coeruleus stimulation on regional cerebral oxygen consumption in the cat. Brain Res. 325: 107-114, 1985. 16. BUSIJA, D. W., AND D. D. HEISTAD. Factors involved in the physiological regulation of cerebral circulation. Reu. Physiol. Biochem. PharmacoZ. 101: 162-211, 1984. 17. CALDECOTT-HAZARD, S., J. MAZZIOTTA, AND M. PHELPS. Cerebral correlates of depressed behavior in rats, visualized using 14C-2deoxyglucose autoradiography. J. Neurosci. 8: 1951-1961, 1988. 18. CARLSSON, C., M. HAGERDAL, A. E. KAASIK, AND B. K. SIESJO. The effect of diazepam on cerebral blood flow and oxygen consumption in rats and its synergistic interaction with nitrous oxide. Anesthesiology 45: 319-325, 1976. 19. CARLSSON, C., M. HAGERDAL, A. E. KAASIK, AND B. K. SIESJO. A catecholamine mediated increase in cerebral oxygen uptake during immobilisation stress in rats. Brain Res. 119: 223-231, 1977. 20. CHEN, R. Y. Z., F. C. FAN, G. B. SCHEUSSLER, S. SIMCHON, S. KIM, AND S. CHIEN. Regional cerebral blood flow and oxygen consumption of the canine brain during hemorrhagic hypotension. Stroke 15: 343-350, 1984. 21. COHEN, P. J., S. C. ALEXANDER, T. C. SMITH, M. REIVICH, AND H. WOLLMAN. Effects of hypoxia and normocarbia on cerebral blood flow and metabolism in conscious man. J. AppZ. Physiol. 23: 183-189, 1967. 22. DAHLGREN, N., I. ROSEN, T. SAKABE, AND B. K. SIESJO. Cerebral functional, metabolic and circulatory effects of intravenous infusion of adrenaline in the rat. Brain Res. 184: 143-152, 1980. 23. DELLA PORTA, P., A. T. MAIOLO, V. U. NEGRI, AND E. ROSSELLA. Cerebral blood flow and metabolism in therapeutic insulin coma. MetaboZism 13: 131-140, 1964. 24. DUARA, R., C. GRADY, J. HAXBY, D. INGVAR, L. SOKOLOFF, R. A. MARGOLIN, R. G. MANNING, N. R. CUTLER, AND S. I. RAPOPORT. Human brain glucose utilization and cognitive function in relation to age. Ann. Neural. 16: 702-713, 1984. 25. EBERSOLT, C., M. PEREZ, AND J. BOCKAERT. Neuronal, glial, and meningeal localizations of neurotransmitter-sensitive adenylate cyclases in cerebral cortex of mice. Brain Res. 213: 139-150, 1981. 26. EBERSOLT, C., M. PEREZ, G. VASSENT, AND J. BOCKAERT. Characteristics of the ,&- and ,&-adrenergic-sensitive adenylate cyclases in glial cell primary cultures and their comparison with ,&-adrenergic-sensitive adenylate cyclase of meningeal cells. Brain Res. 213: 151-161, 1981. 27. ECKARDT, M. J., G. A. CAMPBELL, C. A. MARIETTA, E. MAJCHROWICZ, H. N. WIXON, AND F. F. WEIGHT. Cerebral 2-deoxyglucose uptake in rats during ethanol withdrawal and postwithdrawal. Brain Res. 366: l-9, 1986. 28. EDVINSSON, L., J. E. HARDEBO, E. T. MACKENZIE, AND CH. OWMAN. Effect of exogenous noradrenaline on local cerebral blood flow after osmotic opening of the blood-brain barrier in the rat. J. Physiol. Lond. 274: 149-156, 1978. 29. EDVINSSON, L., AND E. T. MACKENZIE. Amine mechanisms in the cerebral circulation. Pharmacol. Rev. 28: 275-348, 1977. 30. EDVINSSON, L., AND CH. OWMAN. Pharmacological characterization of adrenergic alpha and beta receptors mediating the vasomotor responses of cerebral arteries in vitro. Circ. Res. 35: 835849, 1974. 31. EISENBERG, S., AND H. S. SELTZER. The cerebral metabolic effects of acutely induced hypoglycemia in human subjects. MetaboZism
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