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Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal

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15 janvier 2010
Life Sciences
New evidence for a locus coeruleus
norepinephrine connection with anxiety
DE Redmond, YH Wang
Primate and Clinical Research Facilities Department of Psychiatry and Connecticut Mental Health Center Yale University School of Medicine New Haven, Connecticut USA


The hypothesis that brain noradrenergic systems have a broad biological function which is related to human fear or anxiety is reviewed. Data from studies of the function of the nucleus locus coeruleus in non-human primates are presented in the context of recent anatomical, physiological, pharmacological, and animal behavioral experiments. Implications are suggested for the treatment of anxiety, drug addictions, pain, and psychosomatic diseases.
The idea that fear, or the related emotion, anxiety, might be associated with the noradrenergic-sympathetic nervous system has a long history. Darwin's 1872 picture of fear merging into terror (1) provided the basis for this association, and his observations still provide a useful beginning and descriptive definition for a review of such emotions.
The identification of adrenalin (2) which stimulated many of the physiological changes described by Darwin supported the involvement of the sympathetic nervous system, but the fact that adrenalin infusion did not reliably induce the subjective emotions, in addition to other data, led Cannon to postulate essential central nervous system mechanisms in pain, fear, and rage (3). There is still no concensus as to what these central neural substrates of emotions might be, except that they involve the "limbic system" (4). The physiological changes associated with fear (5-7), in particular, are believed to result from interactions of the sympathetic and the parasympathetic nervous systems (8), which are thought to be non-specific components of arousal responses to "stresses" (9) and a number of emotions.
In addition to evidence implicating adrenergic systems, studies of anxietyreducing compounds also suggest the involvement of a number of neurotransmitters (10). Recently, the discovery of specific opiate receptors (11) and benzodiazepine receptors (12) has suggested endogenous aoxiolytic neurotransmitters which might provide evidence regarding the central mechanisms of anxiety. It is the purpose of this review to suggest that these and other anxiety-related neurotransmitters may interact with brain norepinephrine systems which mediate a biological function that at various levels might be described as surprise, alerting, astonishment, alarm, anxiety, fear, panic, or terror. Our hypothesis is based on studies of brain noradrenergic function in the stump-tailed monkey (Mscaca arctoides or spscioss) utilizing and combining electrical stimulation or lesions of the major noradrenergic nucleus locus coeruleus (LC) with the administration of pharmacologic agents which have relatively specific interactions with noradrenergic function. We will first describe the rationale for these studies, review the results briefly, and then review anatomical, pharmacological, and physiological evidence pointing to a connection of this system with human anxiety or fear.
Studies of the nucleus locus coerulsus in monkeys
Why study the locus coeruleus The dark blue (coeruleus) streak in the dorsolateral tegmentum of the pons is thought to have the highest density of norepioaphrine-containing neurons in the brain (13). It contains nearly half of the norepinephrine (NE) neurons (14) and produces over 70% of the total NE found in macaque brain (15). In M. arctoides the nucleus is compact and almost entirely composed of NE containing cells (16). Therefore, it is a convenient entry point for studying and altering NE function. The LC provides the principal NE innervation to the cerebral and cerebellsr cortices, the limbic system, and brain stem and spinal cord regions (17-19). Afferent projections to the LC come from almost as many areas including the reticular formation, adjacent central gray, some forebrain areas, other catecholamine nuclei in the brain stem (20), sensory brain stem nuclei, and pain-sensitive neurons in the dorsal horns of the spinal cord (21-23). Physiological and biochemical studies confirm the feasibility of discretely increasing or decreasing brain NE function by stimulating or lesioning this nucleus.
However, there are reminders that these methods have their limitations. Besides the obvious problem of lesioning or stimulating adjacent structures or fibers of passage, manipulations may alter other systems secondarily and may last for a limited period of time (29-31). It is also merely an inference that the presumed deficit after lesions will reveal the physiologic functions of the intact system throughout its range of activity. Some LC stimulation-associated effects are not blocked by 6-hydrozydopemine (6-OHM) destruction of the dorsal NE bundle (DB) (32) or of the LC itself (33). And, even NE-neuron mediated effects will alter other transmitter systems in a living -brain, leading to the confusion of primary and secondary effects. It is clear, therefore, that multiple approaches combining neurophysiologic and pharmacologic techniques are necessary to relate functional effects with specificity to the LC or to NE function end that this specificity is always elusive and potentially illusory. We have attempted, therefore, to look broadly for behavioral correlates of locus coeruleus activity in a higher old world primate species, by combining neurophysiologic and phermacologic techniques to achieve some degree of specificity.
Effects of increases or decreases of LC function in monkeys: Unilateral LC or DB aimed electrodes have been correctly placed (15) in 16 monkeys for studies of locus coeruleus activation. Low intensity stimulation of these electrodes produces alerting, manifested by widening of the palpebral fissures and increased body movements which are most obvious in a drowsy animal. With increasing intensity of stimulation, chewing mouth and tongue movements and teeth grinding appear along with grasping of the chair, scratching, selfmouthing, yawning, hair-pulling, hand wringing, escape-struggling, and spasmodic single body jerks. None of these behaviors are stimulus bound nor leterelized to the stimulated side. Vocalizations and facial grimaces, usually accompanying painful stimuli, were not seen. The behaviors are not unusual and might easily have been ignored since they occur frequently in chair-restrained monkeys at times unrelated to electrical stimulation. Similarities were noted originally between these behaviors and those following direct threatening confrontations by humans, leading to the suggestion that these behaviors were related to increased fear or anxiety (34). Some of these behaviors, in particular, opening and closing of the mouth, scratching, and yawning have been previously noted in field studies of this species to be associated with situations of conflict, uncertainty, or impending aggression (35). Bilateral LC lesions decreased the naturel occurrence of some of these behaviors in a social group situation (36), and all were decreased in response to similar direct threatening confrontation by humane (37). These experiments led to a preliminary grouping of the behaviors just described which were increased either by LC stimulation or by human threats, which we have labelled as Group I behaviors. Other behaviors which appeared to be independent of the changes in LC function are defined as Group II behaviors. These include: head and body turning, facial grimaces, vocalization, lipsmacking, moving the hands, manipulating objects or the chair, self-grooming, and threatening facial gestures. Group III behaviors appeared to be inversely related to LC activation: freezing without observable motion for 5 seconda, eyes partly closed for 5 seconda, or eyes fully closed for 5 seconds. The effects of low intensity electrical field stimulation of LC on these behaviors by 3 monkeys are compared in Fig. la. Group I behaviors are more strikingly affected than Group II or III.
Pharmacological agents with known single neuronal unit effects on LC neurons produced behavioral effects which were consistent with those of electrical stimulation or lesions. The alpha-2 adrenergic antagonist piperoxane is an example of the effects of an agent which activates the LC, probably by antagonizing NE or E-sensitive auto-receptors (38-42) without activating adjacent non-noradrenergic neurons. The quantitative and qualitative effects are similar to those produced by electrical stimulation of the LC (Fig. lb).
Other agents studied so far which have Group I behavioral effects consistent with their single unit effects are yohimbine (increase) (43), morphine (decrease) (44,45), enkephalin (decrease) (45), and clonidine (decrease) (46). D,Lpropranolol, which blocks NE systems at beta-adrenergic receptors (18,40), also decreases the saine group of behaviors and partially blocks the effects of electrical stimulation of the LC. Diazepam, which decreases NE turnover (47), decreases the saine group of behaviors in monkeys (Fig. le) in non-sedative doses comparable to those used clinically in humans. Diazepam also diminishes the effect of LC stimulation on the same behaviors (48). Other agents which decrease LC activity and have not yet been studied in monkeys are dopamine, glycine, GABA, and serotonin (40,44,45,49,50). Acetylcholine, glutamate, and substance p (49-51) excite LC neurons and would be predicted to increase the same behaviors.
Fear stimuli increase the same behaviors increased LC activation Since the original classification of behaviors was derived empirically from studies of LC stimulation, w have attempted to determine whether these behaviors were altered by a variety of stimuli which are associated with fear or anxiety, using increases in these behaviors as a kind of "operational" definition of anxiety. We previously noted the almost identical responses to human threat gestures and to LC stimulation. These monkeys also show increases in the same behaviors in response to threats by conspecifica, suggesting that they are not artefacts of conditioning or of chair-restraint. Natural fear-inducing stimuli, however, have the disadvantage that they are difficult to control in intensity and quality. We have, therefore, also looked at a Pavlovian conditioning method which has been supposed to induce fear (52-55). This procedure (56,57) was used to study behavioral effects of conditioning with a light stimulus paired with an unconditioned electrical leg shock (Fig. 2). After 5 days of 2 hours/day of training, there were clear-cut increases in Group I and Group II behaviors during the second condition (W), compared with the baseline-control level when no shocks ever occurred (B). There was a trend toward a further increase in Group I behaviors during the third condition (R) always preceding shock by two minutes, end a significant decrease occurred in both Groups I and II behaviors during the shock (S) when this period was adjusted to match the durations of (W) and (R). Group III behaviors decreased progressively during each period after baseline (B). The qualitative and quantitative increases in Group I behaviors were comparable to the effects of LC activation by field stimulation or by piperoxane (Figs. la, lb).
These results appear to support the association of an empirically determined group of behaviors (Group I) both with alterations in LC activity and with a situation supposed to induce fear. The same group of behaviors are affected by pharmacologic agents known to increase or diminish LC function, and to increase after natural threats, chair restraint, and a stimulus previously paired with a noxious electrical shock. It is our epistemological belief that this hypothesis can only be tested in humans, based on pharmacologic agents with identifiable effects on these emotions or tested by the accurate prediction of effects in humans based on pharmacologic actions on NE systems in experimental animals. Although our studies in this area are only beginning and many obvions experiments yet undone, the hypothesis seams already to have had some predictive velue in humans, and is consistent with an extensive animal experimental literature. In the remainder of our discussion we will attempt to examine this literature and further outline a postulated NE system function in its context.
Pharmacological physiological and behavioral evidence relevant to a locus coeruleus-anxiety hypothesis
Effects in humans The NE (and LC) neuronal "activators" piperoxane and yohimbine have been reported to cause anxiety in humans (58-60) as have a number of agents which interact somewhat more inconsistently with NE systems, particularly with beta-adrenergic receptors (61). Electrical stimulation in the region of the LC in humans produces feelings of fear and imminent death (62). In the other direction, heroin, morphine, and other opiates have powerful anti-fear and anti-anxiety effects (63) after acute administration, and both D, L propranolol (64) and diazepam (65) have clearly demonstrated anxiolytic properties. All of these have anti-NE effects. In addition ethanol and barbiturates are widely used by humans, at least in part, for their antianxiety effects; and both also decrease NE function (66,67). Several major classes of compounds which decrease anxiety in humans, therefore, have known mechanisms of interaction with the LC and presumably other brain NE nuclei. Based on the powerful effects of clonidine in suppressing LC activity in the rat (46) and LC stimulation effects in the monkey, we predicted that clonidine should have anxiolytic actions in humans (48).
Speculative functions of known structures In addition to the human pharmacologic evidence, there are confirming physiologic data based on anatomical projections of the LC which provide one-synapse innervation of neuroanatomical structures associated with specific physiologic correlates of anxiety or fear (68). Briefly, these include HYPOTHALAMIC, MEDULLARY, and SPINAL SYMPATHETIC AREAS (tachycardia, tmchypnea, hypertension (69,70), piloerection, gastrointestinal hypermotility, urination, defecation), the CEREBELLUM (tremor), the RETICULAR FORMATION (arousal-sleep) (71), OTHER HYPOTHALAMIC NUCLEI (neuroendocrine changes, such as increased ACTH secretion [72], and effects on appetite [73]) and LIMBIC and CORTICAL AREAS (which might subserve such functions as conscious awareness of the affect and or alterations in memory mechanisms (74,75). Interactions with PARASYMPATHETIC SYSTEMS (dry mouth, gastric acid secretion) and NUCLEI CONTAINING OTHER NEUROTRANSMITTERS provide the neuroanatomic basis for widespread effects on other systems. Similarly, the LC receives numerous afferents which might activate this system in response to stimuli or conditions which might be expected to elicit fear or anxiety. SPINAL CORD AFFERENTS come from large neurons in the dorsal horns, which are known to be sensitive to noxious stimuli (21) and which give rise to fibers which do not terminate in specific sensory areas of the thalamus (22) providing a direct pathway for activation by painful stimuli (41). Afferents from SOLITARY TRACT NUCLEI and from other NE and epinephrine containing cell groups in the MEDULLA (23) might provide enteroceptive information from peripheral sympathetic systems which are activated by the LC, consistent with clinical data suggesting that the perception of physiological manifestations of anxiety may increase it. The LIMBIC SYSTEM AFFERENTS described (23) may also activate the LC if cortical areas identify non-painful stimuli that were previously learned to be potentially noxious, or decrease LC activity if novel non-noxious stimuli are correctly identified (76).
These possible functions, associated with clearly-described neuroanstomy, are outlined to illustrate that the LC is uniquely situated to subserve almost all of the known physiological correlates of anxiety or fear, as well as to have direct pathways for activation under circumstances where activation would be predicted. Where the predicted physiological pathways have been studied, the effect is consistent with known correlates of anxiety or fear. These correlates of LC function also suggest that this nucleus may be necessary but not sufficient to subserve the emotions of fear or anxiety which also require other brain areas and the autonomic nervous system for their complete expression. In addition, the differences between the effects of lesions end pharmacological or electrical activation of the LC at various levels in monkeys suggest that, although anxiety or fear may be a part of LC function, its normal function is much wider and more complex - a broadly functioning "alarm system" rather than a neural "substrate" for anxiety or fear alone.
Evidence from animal "models of anxiety or fear: Many animal models have been proposed based on intuitive "operational" definitions of fear or anxiety, or on suppositions about the effects of fear on performance. One example of a classical animal model of fear may serve to illustrate some of the problems with these models. Since pain reliably induces both fear and avoidance (52), it has been suggested that fear is the prime motivator of avoidance (77). One might predict, therefore, that animals with drug-induced decreases in fear would not avoid aversively conditioned stimuli (53,54). However, phenothiazine compounds which decrease avoidance or escape in conditioned avoidance (e. g. "one-way active" or "two way" avoidance tests) and therefore would be predicted to have anti-fear or anti-anxiety properties (78) do not effectively reduce human anxiety (79) ; while the anxiolytic benzodiazepines facilitate rather than diminish performance on the same tests (80). The problem is complicated and confounded by drug-induced alterations in sensation, general alertness, and motor capacity on particular tests, making it uncertain whether any effect is due to fear-reduction. But, in retrospect, one might question the initial implicit assumption that fear is the ONLY motivator of avoidance. Would an animal or human without fear endure avoidable pain? Or under some circumstances might the physiology of fear even interfere with, rather than facilitate, avoidance? Bilateral LC lesioned monkeys threatened with an electrical shock device do not show increases in Group I behaviors, nor increase their heart rates (81), scream, struggle, urinate, or defecate as do normale, but will still avoid shock if given the opportunity (37).
Another prediction from the notion that fear is the motivator of avoidance would be that LC electrical stimulation would be avoided, or at least not selfactivated, if the LC were associated with fear. Studies in rodents and monkeys suggest that, contrary to this prediction, animals will self-stimulate electrodes implanted close enough to activate LC neurons (82), with one report indicating that only placements which activated LC neurons supported self stimulation (83). Most investigators agree that the rates and the pattern of stimulation are different from those seen in other brain areas such as the hypothalamus. Some evidence indicates that projections from the LC to other neurotransmitter systems or adjacent neuronal systems are responsible for the aspects of stimulation that are reinforcing, since neither destruction of the dorsal NE bundle or of the LC extinguishes self-stimulation (32,84) but DA blockers do (85). These studies suggest that, although the LC brain NE system may not be a necessary neural substrate for "reward" (82), it is at least not sufficiently aversive at the intensities studied to neutralize the "rewarding" aspects of self-stimulation in the region. Again, one might also question the assumption that fear is always aversive. Many humans engage repetitively in activities which are fear provoking, such as riding roller coasters, climbing high mountains, and jumping from airplanes with parachutes. Whether the fear generated in these activities becomes dysphoric and aversive seems to depend on the proximity of actual danger and, to some extent, on the intensity of the emotion. Whether animals or humans would prefer a reduction or an increase in the function of a brain "alarm system" seems also to depend on the current level of activity and the situation, with both extremes being avoided.
Effects of NE depletion in rats: NE deficits produced by the neurotoxin, 6-OHM, fail to have certain effects on a variety of behavioral tests (31,86-96) which have been interpreted as showing that ME systems are uninvolved in anxiety or fear (87-92). It is not clear what empirical or pharmacological support there is for many of these interpretations. With a few exceptions (92) the results reported with 6-OBDA are consistent with the effects of barbiturates (BTs), benzodiszepines (8Es), and ethanol (ET) on the same procedure. (JO). BTs, ET, or BZs have inconsistent effects on rewarded behavior and the conditioned suppression of behavior (80). They do not generally affect escape behavior from unconditioned aversive stimuli or one-way active avoidance (80). All of these drugs improve performance on two-way active avoidance presumably due to reduced freezing responses to footshock (80), as reported for 6-OHDA dorsal bundle treated rats by Mason and Fibiger, who also reported reduced freezing by NE depleted rats (87). The increases in aggressive behaviors after 6-ORnA treatment reported by Crow et al (91) and File et al (92) have also been reported with low doses of BT5, SZs, and ET (80) and are similar to the effects of LC lesions in monkeys. NE depletion in rats is reported by some (24,86,94) but not all investigators (95) to produce decreased running speeds for food reward in a "straight alley," consistent with an effect of 8Es (80). One might also interpret a number of the findings with DE lesioned rats as being consistent with reduction of an alarm system related to fear or anxiety. Increased exploratory activity (89), increased contact time with a novel object (89), and decreased disturbance of a licking behavior by a tone (91) might all be consistent with diminished function of an alarm system. LC lesioned (96) or 6-ORDA treated rats (31) which spent more time in the center of an open-field test ambulating (31) were described, somewhat anthropomorphically, as "inattentive and overconfident, walking all around the enclosure while making few observing responses" (31). The investigator also noted that these behaviors after 6-ORnA changed with time after treatment, with some significant recoveries by 40 days (31). This time period from 12 to 40 days after treatment, characterized by a variety of changes in NE turnover and alterations in NE-receptors, is precisely the period studied so extensively in rats after 6-ORDA. This produces uncertainty as to the functional consequences of lesions, which led us to shift our emphasis to stimulation and pharmacologic studies which could produce reversible effects at varying intensities.
Pharmacologic studies of NE function in rodents: Nearly all testing of a NEfear hypothesis in rats has been done with electrolytically or 6-ORnA lesioned animals. Our data suggest that the LC function is not monotonically related to anxiety or fear; and although fear-related effects can be interpreted in the deficit syndrome, these effects are more clearly identifiable during increased function. With the exception of the self-stimulation studies mentioned, we know of no other studies of behavioral effects of LC stimulation. Other animal "models" would also he more interpretable if opposite effects could he demonstrated with agents which increase fear or anxiety in humans from those effects obtained with various classes of human anxiolytics. Davis et al (97-99) have found effects of increased as well as decreased neuronal function of NE systems using amplitude measurements of a startle reflex that is augmented by the presentation of a loud tone in the presence of a light previously paired with a shock, known as "potentiated startle" (100). This response is also related to shock-Intensity in a non-monotonic fashion (101), and is reduced by the anxiolytics (cf 61) sodium amytal (100), diazepam (98), flurazepaa (98), morphine (99), and propranolol (97). The response is also decreased by clonidios, which decreases NE neuronal activity, and increased by piperoxane and yohimbine (97) which increase it. Since all of the pharmacologic effects on "potentiated startle" are consistent with those seen in our monkey studies with agents also affecting human anxiety, a specific study of the effects of electrolytic or 6-ORnA lesions of LC on this measurement would be of interest. Locus coeruleus lesions were reported by Geyer, et al, to decrease the magnitude of unconditioned startle responses to air puff stimuli (102), suggesting that results might be similar to the effects of anxiolytic drugs.
An operant procedure in which on-going lever pressing for food reward is inhibited by electrical shocks has been studied extensively because the anxiolytic drugs disinhibit the response suppression (103,104), while a second unpunished lever, which is rewarded at a lower density, serves to control for non-specific effects. This Geller-Seifter "conflict" test" (103) has successfully identified a number of new anxiolytic compounds, and is sensitive to the effects of BTa, ET in some tests, BZs (cf 80), and recently to clonidine (105). This test is sensitive to irrelevant changes in motor, appetitive, and sensory functions; and perhaps for these reasons, it fails to clearly identify the anxiolytic properties of propranolol (106,107), morphine (108) and haloperidol (109). Nonetheless, the effects on this procedure of agents which increase LC function, such as piperoxane, yohimbine, or substance P would also be of interest as would the effects of LC or DB lesions.
An empirical correlation has been reported between the effects of several classes of anxiolytics and a 7.7 Hz hippocampal theta rhythm (80), which provided the basis for Gray to identify the NE systems as involved in anxiolytic drug effects (110) since similar effects were also produced by NE synthesis inhibitors or lesions of the dorsal NE bundle with 6-OHDA. Because of the large noradrenergic innervation of the hippocampus from the LC (17,18), this phenomenon may be one effect of many LC projections that are relevant to anxiety mechanisms. A large thoroughly reviewed literature on the behavioral pharmacology of the catecholamines also suggests that NE depletion by synthesis inhibitors produces similar changes in behavioral tests to those produced by the anxiolytic drugs (111), but the agents used are less specific than those discussed above.
Does the LC or central NE function increase duriq fear? In the rat the LC system reponds with increased single unit firing to novel stimuli (41,76), although it rapidly decreases its response to non-noxious stimuli even in anesthetized animals, while noxious stimuli produce the same or incremented responses (41). In awake rats (76) and squirrel monkeys (112) this noveltydetecting function is maintained. These responses are consistent with the "alarm function" which has been suggested, but noxious stimuli or stimuli conditioned to noxious stimuli have yet to be studied. The biochemical corollary of increased NE neuronal function during noxious stimuli or anxiety provoking situations has been supported by considerable data, which shows that stress decreases static measures of brain NE (cf 113), most likely the result of increased activity in NE neurons (113,27). Recent studies have demonstrated increases in brain MG during conditioned fear in rodents (114). In depressed humans, urinary HIIPC (115) and CSF MHPG (116) correlate positively with anxiety ratings.
Implications of the thesis of an LC-alarm function for treatment of medical problems
Anxiety: The most obvious clinical implications relate to mechanisms and treatments to produce or relieve anxiety. Pharmacologic agents which increase brain NE function should produce fear or anxiety as the limited evidence so far suggests for piperoxane, yohimbine and beta-adrenergic agonists (61). Agents which decrease net NE function should have anxiolytic properties (61). Clonidine, and similar chemical analogs and alpha-2 adrenergic agonists, should have potent anxiolytic properties (48,117). Patients with the phobic anxiety syndrome, who do not usually respond well to benzodiszepines (79), should be improved by clonidine. New agents might be utilized which deliberately affect several modulatory receptors with similar actions on NE neurons, thereby improving effectiveness and perhaps decreasing undesirable effects. Or agents might be deliberately synthesized to have more specific effects for certain NE receptors.
Abstinence syndromes The recent clinical demonstration of suppression of signs and symptoms of opiate abstinence by clonidine (118,119) was based on interactions of clonidine, piperoxane, and morphine with LC stimulation in the monkey (120). The opiate abstinence syndrome resembles locus coeruleus stimulation in many respects, and reproduces many of the signs ad symptoms of anxiety or fear. Since clonidine was known to suppress these signs and behaviors associated with LC stimulation (48), and since a detailed neuronal circuitry (11,121,122) supports opiate (or endorphin) - NE interactions (119), clonidine was tested for effects directly against the opioid abstinence syndrome. Since the initial clinical study, the predicted increases in NE activity during opiate abstinence have been confirmed: increased neuronal activity in LC in rats (123), and increased MIII'S in monkey brain, CSF, and plasma and in human plasma (124). Clonidine might also be useful in other withdrawal syndromes in which anxiety-like changes are prominent-- those due to chronic benzodiazepines, barbiturates, ethanol, and nicotine.
Analgesia: The neuronal circuitry and recent specific data on analgesic effects of LC lesions (125) or clonidine (126-128) suggest that some "analgesic" effects of opioids, which suppress NE neuronal activity, may be mediated by decreased NE activity. Combinations of receptor agents having similar effects at different receptors might increase analgesia, as has been shown for the combination of amphetamine and morphine which was discovered empirically (129,130) with no understanding of its probable action via alpha-2 and opiate receptors.
Stress-anxiety exacerbated diseases A number of conditions which anxiety and "stress" factors are thought to exacerbate, such as burette's syndrome (131), "benign essential tremor," tardive dyskinesia, and functional bowel diseases such as duodenal ulcer, ulcerative colitis, irritable colon syndrome, and chronic nonspecific diarrhea (132), might benefit from treatment with agents designed to interact with specific NE receptors, similar to the effects of clonidine. Longterm blockade of aspects of LC activation may also have beneficial effects on arteriosclerotic cardiovascular disease and essential hypertension. The risk factors of "stress," type "A" personality, and chronic anxiety are well recognized in the etiology of hypertension, myocardial infarction, and cerebral thrombosis and infarction, as are the benefits of "stress" reduction. Many detailed anatomic and physiologic connections from LC activation (recently reviewed, cf 61) can be made to the pathophyaiclogy of arteriosclerosis, including increases in blood pressure, increased ACTH, increased circulating NE, gluconeogenoeia, impaired carbohydrate tolerance, hyper-beta-lipidemia, increased formation of triglycerides, effects on betalipoprotein release, activation of alpha-adrenoreceptora on platelets which may lead to increased thrombogenicity, as a basis for the known increased tendency for the blood to clot. The predicted benefits of blockade of these chronic and usually unnecessary effects of activation of an LC alarm system might be considerable, and provide an additional rationale for the clinical use ni clonidine, proprannlnl, or anti-nnradrenergic agents besides their effects on hypertension or or cardiac arrhythmiae.
We have summarized experiments in monkeys suggesting that a group of behaviors is affected almost identically by increases in LC activity produced either by electrical field stimulation or by alpha-2 NE antagonists. The same behaviors are increased by a variety of stimuli which might induce fear. Bilateral LC lesions reduce expression of these behaviors similar to the effects of clonidine, morphine, diazepam, and D, L propranolol. These agents are thought to reduce LC activity via alpha-2 adrenergic, opiate, or GABA aomatodendritic receptors or by post synaptic beta-adrenergic blockade respectively. Since the alpha-2 antagonists which increase LC activity have been reported to induce fear-anxiety syndromes in humane, and the agents which reduce net LC fonction all have anxiolytic activity in humane, we suggest that brain NE systems, such as the LC, are involved in the production of fear or anxiety, and that they are a major mechanism of action for auxiolytic drugs. Anatomical and functional evidence especially supports the unique location of the nucleus LC for being involved in the physiological manifestations of anxiety or fear. The same evidence, however, also suggests that the LC is not sufficient for the manifestation of these emotions which require numerous other systems in the central nervous system.
These studies also suggest that anxiety or fear is only a part of the function of the brain NE systems. LC lesions and LC stimulation at many levels reveal a wide range of functions. The system's absence or diminished function, perhaps anhedonic, eight produce certain liabilities- the failure to withdraw promptly in the face of danger or the inability to inhibit certain responses or to learn from certain kinds of new experience (95,88). At low levels, it might be a novelty detector, a stimulus enhancer, or an attention focuser. In a middle or normal range of function, such a system would generally be "cautionary," and would be associated with improved chances for survival. At higher levels the system continues to respond to all novel stimuli, differentially amplifies and distinguishes noxious from non-noxious stimuli, and helps to prepare for a survival struggle; but its non-monotonic and modulatory behavioral effects may range from freezing to flight. An "alarm system" might be a more adequate description of this function. The system has sensory nerve, spinal neuronal, and forebrain efferents which can modulate its function directly or in response to interpreted information, and has efferent connections to the anatomic structures known to mediate the "fight" or "flight" response. The term "alarm system" also conveys an adaptive nature, the deficit which would be present if the system were missing, and the unpleasantness of its ringing loudly or too long. In normal individuels, the emotions associated with increasing activation, therefore, might be called attention, carefulness, interest, surprise, alerting, astonishment, alarm, anxiety, fear, panic, or terror. Which was identified would depend on s number of situational, semantic, intensity, or personality factors. Clinical or "morbid" anxiety might be the result of alterations in the operation of this system. Pharmacologic agents aimed more specifically at this system might improve the treatment of anxiety, drug abstinence syndromes, pain, and some psychosomatic diseases.