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Br. J. clin. Pharmac. (1986), 22, 251-261
States of anxiety and their induction by drugs
MALCOLM LADER & MALCOLM BRUCE
Department of Pharmacology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF
1 Syndromes of anxiety include generalized anxiety states, various forms of phobic
disorder and panic attacks. It is unclear whether panic attacks are a separate syndrome
from anxiety states or a more severe form.
2 Drug-induced states of anxiety should provide useful models of the mechanisms of
anxiety and its treatment. High-risk populations might be identifiable.
3 Catecholamine infusions produce marked peripheral changes without fully reproducing
the central feelings. Lactate infusions also produce anxiety-like states lacking full credibility.
4 Experience with the benzodiazepine-receptor contragonists, the ,-carbolines, is limited
but panic states have been reproduced following their use. Caffeine produces an anxiety
state in high dose and some panic states have been induced.
5 The critical evaluation of drug-induced anxiety states is a promising way of elucidating
the mechanisms, psychological and physiological, associated with clinical anxiety.
Keywords anxiety panics yohimbine ,-carbolines caffeine
Introduction
Anxiety is a common human emotion, character- some act'. For example: 'I am anxious to keep
ized by a feeling of overwhelming apprehension your interest and attention'. The second meaning
and accompanied by many peripheral physio- is 'being troubled in mind about some uncertain
logical changes. The latter, being fairly easy toevent, being in disturbing suspense, being fraught
measure, have provided a deceptively simple way with worry'. The first type of anxiety is goal-
of studying anxiety but at the risk of oversimpli-
directed and controllable; the second type is dif-
fying the relationship between the central 'core'fuse, causing the person to feel passive and help-
properties of anxiety and the peripheral epiphen-less. The latter meaning includes the indescribable
omena. Attempts to induce anxiety have often feeling of foreboding that is the core of anxiety;
failed to address themselves to this problem. It is irreducible scientifically so one must rely on
Indeed, it is only partially soluble as use must be
subjective reports of this state.
made of subjective reports with inevitable scien- Anxiety as part of everyday experience is a
tific reservations. In addition, the clinical classi-
normal emotion, as is fear. If the cause is clear,
fication of anxiety states and related conditionsthe emotion induced is labelled 'fear'; if the cause
remain rudimentary despite attempts to develop is obscure, or although identifiable, its potential
rational schemata. impact is unpredictable, the more diffuse emotion
This brief review will first outline the various
experienced is termed 'anxiety'. However, anxiety
syndromes of anxiety. Then it will review models may also be an abnormal emotion, and distinc-
of anxiety which have been developed using tions between normality/abnormality and nor-
various pharmacological agents and evaluate them mal/clinical can be difficult. Clinical (morbid,
for their relevance to clinical syndromes. It will
pathological) anxiety can be defined operation-
not discuss animal models of anxiety (Lal & ally by the need of the sufferer to seek relief from
Emmett-Oglesby, 1983; Kandel, 1983). his anxiety. Such anxiety may be too severe, too
persistent or too pervasive for the person to
tolerate. He seeks medical advice, thereby be-
Definition of anxiety coming a 'patient' and the condition an 'anxiety
state'. Thus, a 'normal' subject may not seek
Anxiety has two main meanings. To be anxious help, although his anxiety levels might actually
can mean 'full of desire and endeavour to effect be 'greater' than those of the 'patient'.252 M. Lader & M. Bruce
Another distinction is between state and trait dyspnoea, palpitations, chest pain, choking sen-
anxiety. State anxiety refers to anxiety felt at one sations, dizziness, feeling of unreality, paraes-
particular time, the moment of enquiry. Trait thesiae, hot and cold flushes, sweating, faintness
anxiety is the habitual tendency to feel anxious. and trembling. Attacks usually last minutes but
Some individuals have such high levels of trait may persist for hours. Nervousness and appre-
anxiety that they are chronically in a condition of hension may develop between attacks. In gener-
state anxiety. alized anxiety disorder, the anxiety does not
come in attacks but is persistent and accompanied
by symptoms of motor tension, autonomic hyper-
Clinical aniety activity, apprehensive expectation, vigilance and
scanning of the environment. In the obsessive
Clinical anxiety can thus be defined operationally compulsive disorder, recurrent ideas, thoughts,
as an emotional state, disproportionate to any images or impulses incessantly invade conscious-
apparent cause, for which the sufferer seeks ness and seem senseless or repugnant to the
help. However, several syndromes have been person. The obsessions may be accompanied by
delineated since Freud's initial description in ritualistic stereotyped behaviours (compulsions):
1894 (Freud, 1894). The American Psychiatric The third main group are the post-traumatic
Association's Diagnostic and Statistical Manual, stress disorders, acute, chronic or delayed. Diag-
third edition, (DSM-III), has a new and rather nosis depends on recognizing the existence of a
complex classificatory scheme (Brown et al., stressor, such as accidents, natural disasters,
1984). The anxiety disorders are divided into combat or torture, that would evoke significant
four categories; phobic disorder, anxiety states, symptoms of distress in almost everyone. The
post-traumatic stress disorders and atypical post-traumatic stress disorders are pathological
anxiety disorder. Hypochondriacal, hysterical reactions to these events, with re-experiencing
and depressive disorders are placed elsewhere. of the trauma as evidenced by recurrent and
Phobic disorders are characterized by fear and intrusive recollections of the event, recurrent
avoidance of certain situations or objects with dreams of the event and suddenly feeling the
subsequent restriction of social or role function- event was happening again. Numbing of respon-
ing. The phobic disorders are subdivided into siveness to and reduced involvement with the
three types. In agoraphobia, the individual has external world ensues. Other symptoms include
marked fear of, and thus avoids, being alone or exaggerated startle response, sleep disturbance,
in public places from which escape might be guilt about surviving, and impairment of memory
difficult or help unavailable, such as crowded and concentration.
shops, tunnels and public transportation. The Finally, atypical anxiety disorder is a ragbag
individual's normal activities become increasingly residual category for individuals who cannot be
restricted. Agoraphobia may include discrete placed elsewhere.
panic attacks but can occur in their absence. The Of course, other diagnostic and taxonomic
essential feature of social phobia is that the systems are extant but none include such carefully
individual has a persistent, irrational fear of, and constructed diagnostic criteria as does the DSM-
compelling desire to avoid, situations in which III. Nevertheless, some question the utility of
he may be exposed to public scrutiny. He also the DSM-llI anxiety disorder categories in clinical
fears that he may behave in a manner that will usage, in particular noting that mixed syndromes
be humiliating or embarrassing. As with agora- are common both cross-sectionally and over the
phobia, anticipatory anxiety may be marked. natural history of the condition (Tyrer, 1984).
Examples include fears of speaking, performing These different syndromes reflect the recog-
or eating in public, and using public lavatories. nition by the clinicians of different types of
The third phobic disorder is simple phobia anxiety with respect to symptom patterns and
('specific phobia') in which the individual fears temporal relationships. Further support comes
and avoids animals such as dogs, snakes, birds, from differing pharmacological responses: phobic
mice and insects, or closed spaces (claustro- and panic disorders respond well to antidepres-
phobia), heights (acrophobia), elevators, etc. It sants, but not to benzodiazepines, and generalized
is a very common condition but only occasionally anxiety disorder conversely. These distinctions
leads to marked restriction or modification of should be borne in mind when considering the
activities. effects of drugs purporting to induce anxiety.
In anxiety states no specific phobic object or
situation is identified. The essential features of
panic disorder are recurrent attacks of intense The rationale of inducing anxiety with drugs
apprehension, fear or terror, often associated
with feelings of impending doom, and accom- As anxiety is such an unpleasant feeling, studies
panied by a range of bodily symptoms such as attempting to deliberately induce it need scien-States of anxiety and their induction by drugs 253
tific justification to balance against ethical reser- readily pass the blood-brain-barrier, such prob-
vations. Several benefits might accrue: lems are very germane to the interpretation of
The main reason is that the reliable and repro- the observations.
ducible induction of a clinical phenomenon is Maranion (1924), in a descriptive report, em-
usually very helpful in studying the pathological phasizes the 'as if ' nature of the anxiety engen-
mechanisms associated with that disorder. In dered in normal volunteers. Physiological
most branches of medicine animal models have changes such as palpitations and trembling are
been established but these are never convincing noted but the emotional feeling is 'cold', partial
in psychiatry because of the absence of subjective and lacks conviction to the subject. However,
reports (Crawley et al., 1984). Study of the some subjects developed full blown anxiety and
mental and bodily states induced by reserpine not just feeling 'as if I were anxious'. In another
has increased our understanding of mechanisms study (Cantril & Hunt, 1932) some of the reac-
in depression and psychomotor retardation, as tions to intramuscular adrenaline were described
has the use of amphetamine and L-dopa in schizo- by normal volunteers as quite pleasant but
phrenia-like syndromes. An anxiety-inducing others became anxious.
procedure should be even more heuristic because Basowitz and his co-workers (1956) interviewed
of the resemblance between anxiety states in 12 normal subjects (medical interns) to ascertain
normal and clinical contexts. any past history of stress and to note any specific
Such a model could be used to evaluate anti- reactions to it such as palpitations, apprehension,
anxiety medications and non-pharmacological tremor and perspiration. Using double-blind pro-
treatments. Much development work could take cedures and a cross-over design, adrenaline was
place in normal human volunteers before tackling infused intravenously in a dose of 5,ug kg-1 body
the greater problems of therapeutic trials in weight h-1 and its effects compared with those of
patients. Induction of anxiety may itself be saline. Adrenaline produced a distinct rise in
capable of exploitation as a therapeutic pro- pulse pressure, averaging 20 mm Hg, and a
cedure in that patients can be taught strategies to tachycardia, averaging 13 beats min-. Hand
deal with that anxiety, thereby gaining experience steadiness and physical persistence were impaired.
and confidence in coping with their naturally- The commonest subjective experience was pal-
occurring anxiety (Bonn et al., 1971). pitations. Symptoms were reported with the
High risk populations might be identified using saline testing as well as on the adrenaline
drug induction of anxiety as a challenge pro- occasions, but only half as frequently and usually
cedure (Wearn & Sturgis, 1919). Thus, indivi- when saline was the first treatment. Adrenaline
duals at risk of developing anxiety symptoms produced symptoms which generally resembled
could be identified. Similarly, particular indiv- those elicited at the initial interview as occurring
iduals might be especially sensitive to specific in the subjects in response to stress. In emotion-
compounds, such as caffeine which may induce ally labile subjects, excess symptoms but few
or exacerbate anxiety feeling (Greden, 1974). cardiovascular changes were noted; in rigid per-
Finally, insights might be gained into the tax- sonalities, no symptoms but marked physiological
onomy of anxiety disorders, as to whether the changes ensued.
subgroups outlined earlier are discrete entities. Similar studies have been conducted in Sweden.
Thus, if the administration of an anxiogenic In an initial experiment in six students, adrenaline
substance produced generalized anxiety but never i.v. led to a greater distress than did noradrena-
precipitated panics, whereas another compound line (Frankenhaeuser et al., 1961). An infusion
acted vice versa, this would support the indepen- of both adrenaline and noradrenaline (0.28 mg
dence of the two syndromes. of each over 26-41 min lowered systolic and
diastolic blood pressures without affecting pulse
rate (Frankenhaeuser & Jarpe, 1962). This
Adrenergic induction of anxiety suggests that the adrenaline's effects predom-
inated. Amongst the 11 subjects, palpitations,
Catecholamines have long been known to be tremor, and a general feeling of discomfort were
released in states of anxiety and suspected of reported by most subjects: restlessness, appre-
reinforcing the state (Kopin, 1984). Many hension, tenseness and dyspnoea by about half.
studies have used adrenaline and/or noradrena- In a similar experiment, an infusion of adrenaline
line to induce anxiety but suffer from a number produced a tachycardia, a rise in systolic and a
of drawbacks. Some reflect design problems but drop in diastolic blood pressure (Frankenhaeuser
many fail to address the complex scientific and & Jarpe, 1963). The intensities of the physio-
philosophical problems that beset the relation- logical and the subjective reactions were un-
ship between the central and peripheral mechan- related. Subjective estimates of effects declined
isms of anxiety. As the catecholamines do not steadily as each infusion proceeded. Males254 M. Lader & M. Bruce
seemed more aware of the body sensations follow- 4. False information about the injection may not
ing intramuscular injections of adrenaline than have prevented the 'misinformed' subjects from
did females (Fast & Fisher, 1971). inferring correctly that their bodily symptoms
The widely cited experiments of Schachter & were caused by the injection.
Singer (1962) highlight the interactions between These problems illustrate the difficulties in
cognitive factors and physiological arousal. They designing and executing informative experi-
injected small doses of adrenaline, some sub- ments in this area. Surprisingly, despite the
jects knowing what effects to expect, others pivotal importance of this theory in the area of
remaining in ignorance. The subjects were then emotions, replications have been few. Erdmann
placed with a stooge who acted either in a & Janke (1978) tried to obviate as many as
euphoric manner or angrily. Observation of the possible of the above objections. Drug admini-
subject and his self-report both indicated that stration (ephedrine) was disguised so the sub-
subjects ignorant of the effects of their injection jects were unaware they had been administered
showed and felt more emotional experience anything. Four situational conditions were used
(euphoria or anger) than informed subjects. In a - a neutral condition and 'anger', 'happiness'
second experiment, subjects given either adrena- and 'anxiety'. The subject read a report on his or
line, a placebo or chlorpromazine watched a her performance on a previously completed in-
comedy film. The adrenaline subjects showed telligence test and answered supplementary
more amusement than those given the cx- questions designed to elicit angry or happy
adrenoceptor blocking agent, chlorpromazine responses, or was threatened with electric shocks.
(Schachter & Wheeler, 1962). Thus awareness Even so, the four conditions differed in respects
of physiological arousal seemed to be the sub- other than the emotion to be induced. Mood was
strate on which cognitive clues induced a specific assessed using an adjective checklist which
emotion. yielded a scale of general well-being, an anxiety
Schachter (1966) presented a new theory of scale, and an excitement scale.
emotions based on this work. According to this The results were only partly in accord with
theory, emotions arise from an interaction Schachter's theory. The effects of the 'happiness'
between a state of physiological arousal and and 'anger' situations were consistent with the
cognitive information derived from the situation. theory and the ephedrine increased the emotional
Three assumptions underlie the theory: ratings. With the 'anxiety' situation, which is our
1. An individual labels an inexplicable state of present concern, the results were unexpected.
physiological arousal according to situational Differences between anxiety scale ratings with
cognitive clues. the anxiety and the neutral situations were found
2. If an immediate and totally congruent explan- after placebo administration but not following
ation is forthcoming, the person will not feel an ephedrine, when the two states were indistin-
emotion. guishable. This is contrary to Schachter's theory
3. Even if cognitive clues are forthcoming, an but the authors were at a loss to explain their
emotion will result only insofar as the underlying findings. It could be speculated that anxiety was
physiological arousal is raised. already maximal under the placebo condition.
However, several problems of method include: In a further experiment, Erdmann & van
1. The placebo and adrenaline groups did not Lindem (1980) administered the 3-adrenoceptor
differ in the degree of emotional reaction, antagonist, oxprenolol, or placebo, or the ,1-
whether euphoria or anger was induced. Thus, adrenoceptor agonist, orciprenaline, to students
clear evidence was lacking that the degree of in one of two situations; one designed to induce
emotional reaction depends on the level of evoked anger, the other neutral. The expected physio-
arousal. Against this must be set the limitation logical changes were induced by the drugs, and
that adrenaline does not induce a credible the 'anger' situation led to a significant rise in
arousal state; as many studies have shown, sub- blood pressure, especially diastolic. The 'anger'
jects report only feeling 'as if ' they were anxious. situation led to an increase in self-reports of
2. The emotional situations were poorly stan- anger only in the placebo subjects but to increases
dardized in that the confederate's behaviour was in anxiety ratings both in the placebo and the
not strictly controlled, and varied with the sub- orciprenaline subjects.
ject's reactions, possibly confounding effects. The circulatory effects of the 3-adrenoceptor
3. The emotional situations were also poorly stimulant, orciprenaline, more closely resem-
matched. The euphoria-inducing situation and bled those accompanying anxiety than those
the anger-inducing situation differed with respect associated with anger. This implies that self-
to duration, the type of subject's activity and the perception of the physiological pattern out-
type of behaviour rating as well as the intended weighed the cognitive prompting provided by
affective differences. the anger-inducing situation as anxiety, notStates of anxiety and their induction by drugs 255
anger, ratings were increased. caused patients to feel uncomfortable, restless,
A recent study exemplifies the current interest and irritable, and to appear tense and anxious;
in the biological basis of panic states. Nesse et al. and heart rate and systolic blood pressure were
(1984), used increasing bolus doses of i.v. iso- elevated. Yohimbine produced more physio-
prenaline in eight patients with panic attacks and logical hallmarks of anxiety (13/13) than did
six normal control subjects. Patients had higher adrenaline (6/13). The second infusion of saline
resting heart rates and increased plasma con- produced considerable anxiety implying rapid
centrations of adrenaline, cortisol and growth conditioning to the test room situation.
hormone than did controls. Plasma noradrenaline As the pharmacological properties of yohim-
levels were only marginally increased and the bine became clearer, namely, that it was primarily
heart rate response to the infusions were de- an a2-adrenoceptor antagonist, yohimbine
creased relative to the normals. It was suggested administration was used as an index of such
that the 1-adrenoceptor response may actually autoreceptor function. A 20 mg dose had signi-
be diminished in patients with panic attacks. If ficant anxiogenic effects in eight normal volun-
this is so, it might reflect a down-regulation of teers (Charney et al., 1982). A 30 mg challenge
these receptors consequent on the repeated in 10 volunteers produced in addition increases
release of catecholamines during states of anxiety in systolic blood pressure and autonomic symp-
and panic. toms such as piloerection and rhinorrhea. Plasma
free MHPG (3-methoxy 4-methoxy phenylethy-
lene glycol), a noradrenaline metabolite, con-
Yohimbine centrations were substantially increased. Both
diazepam and clonidine antagonized yohimbine-
As mentioned above, catecholamines are not induced anxiety but only clonidine attenuated
ideal as anxiogenic substances because they act the increase in plasma MHPG, blood pressure
peripherally and the anxiety induced is secondary and autonomic symptoms (Charney et al., 1983).
to those physiological changes. Yohimbine is a Yohimbine can precipitate panic attacks in
more satisfactory sympathomimetic agent but patients diagnosed as suffering from panic dis-
with complex actions. At low dose it appears to orders (Uhde et al., 1983). The effects of
block ct2-adrenoceptors thereby enhancing yohimbine were assessed in 39 drug-free patients
neural release of noradrenaline; at higher doses with agoraphobia and panic attacks, as compared
it blocks a1-adrenoceptors producing an with 20 normal controls (Charney et al., 1984a).
adrenolytic action. It was used extensively by Yohimbine (20 mg orally) was associated with
Gershon's group. In the first study, 51 male greater self-ratings of anxiety, nervousness,
mental hospital subjects and 9 normal volunteers palpitations, hot and cold flushes, restlessness,
were given 0.5 mg kg-' (Holmberg & Gershon, tremors, piloerection, and sitting systolic blood
1959). Psychological changes were noted pressure in the patients than in the normals.
'simulating an anxiety state': the subjects MHPG plasma concentrations were higher in
became tense, anxious, restless, irritable and the patients, especially those with frequent panic
tremulous. The degree of autonomic response attacks. It was suggested that panicky patients
correlated highly with the subject's initial anxiety have heightened brain noradrenergic activity.
level. Imipramine (1 mg kg-1) was given three Thus, yohimbine is more effective than adrena-
times daily for 3 weeks to some of the sub- line which in turn is more effective than nor-
jects. Marked potentiation of yohimbine effects adrenaline in inducing both central and peripheral
ensued with tremor and restlessness amounting anxiety-like symptoms.
to an acute panic. Ingram (1962) used a Other drugs acting on the adrenergic system
yohimbine challenge (0.5 mg kg-' infused over 5 used as anxiomimetic agents are isoprenaline
min) to evaluate the effectiveness of anti-anxiety (Frohlich et al., 1969) and piperoxane (Bunney,
drugs. Reserpine and amylobarbitone reduced 1981). Often, however, the emotion is a cold and
the psychological and autonomic effects of unconvincing feeling. Where anxious patients
yohimbine whereas atropine decreased the are involved or other subjects have had extensive
pressor response. Paradoxically, chlorproma- experience of anxiogenic substances, secondary
zine enhanced the responses to yohimbine. conditioning is believed to occur linking drug-
In a direct appraisal of how much yohimbine- induced peripheral changes to central feelings of
and adrenaline-induced states resemble clinical anxiety (Tyrer, 1976).
anxiety, Garfield and his colleagues (1967)
presented a battery of behavioural tests to 12
psychiatric patients before and after infusing Lactate infusions
these compounds and saline, two administrations
of each. Both yohimbine (0.5 mg kg-' over 6 Patients with anxiety states have a less efficient
min), and adrenaline (0.2 ,ug kg-' over 20 min exercise response than normal controls256 M. Lader & M. Bruce
(McFarland & Huddleson, 1936; Jones & original findings of Pitts & McClure (1967) have
Mellersh, 1946; Holmgren & Strom, 1961). In a been replicated several times, with EEG changes
standard exercise task, the patients show greater (Fink et al., 1969) and alterations in forearm
rises in heart rate and blood lactate level, and blood flow (Kelly et al., 1971), providing objec-
following the exercise they take up oxygen more tive support. The data from these and other
than normals, suggesting the repayment of a studies are quite consistent (Haslam, 1974;
larger oxygen debt. Gorman et al., 1981; Bonn et al., 1971; Liebowitz
From this, Pitts & McClure (1967) developed et al., 1984). Over 80% of patients with panic
the idea that perhaps the lactate ion itself could disorder but less than 20% of normal subjects
produce anxiety attacks in susceptible persons. experience a panic attack when given lactate.
To test this hypothesis, the following were intra- Propranolol does not block all the effects
venously infused double-blind in random order (Arbab et al., 1971), but the lactate-induced
into 14 patients with anxiety neurosis and 10 panic in patients is prevented by prior successful
normal controls: 500 mmol sodium (±) lactate, treatment with an antidepressant such as imipra-
500 mmol sodium (±) lactate with 20 mmol mine (Rifkin et al., 1981). Plasma adrenaline
calcium chloride and 555 mmol glucose in 167 concentrations, but not plasma prolactin, tes-
mmol sodium chloride. These solutions, of simi- tosterone, noradrenaline or cortisol, are higher
lar osmolarities, were given as 20 ml kg-1 body among panickers than non-panickers (Fink et
weight over 20 min to each subject. al., 1969).
Symptoms were rated. However, the mechanism of induction of
Sodium lactate produced symptoms which symptoms may be related to adrenaline release.
'were markedly similar or identical' to those In the accounts of lactate-induced symptoms,
experienced in their 'worst attacks' by the one is struck by the similarity of the symptoms
anxious patients. Such reports were fewer from produced to those following the infusion of
normal subjects. Symptoms were much less adrenaline (Hawkins et al., 1960). Animal studies
frequent when lactate plus calcium chloride was show that lactic acid releases adrenaline and
infused, and the glucose in saline infusion noradrenaline from the adrenal medulla (Cannon
produced almost no symptoms in either patients etal., 1924; Woods etal., 1956), and preliminary
or controls. The authors suggested that anxiety reports suggest the same in humans for adrenaline
symptoms were related to hypocalcaemia pro- (Appleby et al., 1981). Anxious patients may
duced by lactate infusion. have learned to associate such symptoms with
Grosz & Farmer (1969) pointed out how anxiety and these subjects might be more stressed
tenuous the link was between anxiety symptoms by the non-specific aspects of the experimental
and hypocalcaemia. Anxiety can occur without situation anyway. Also, the relationship between
high blood lactate concentrations and high blood anxiety, lactate, glucose and adrenaline release
lactate levels without anxiety. An infusion of would appear to be a fruitful area of research
sodium lactate produces a metabolic alkalosis (Stanaway & Hullin, 1973).
whereas the endogenously produced lactate ion
shifts the acid-base balance of the body towards Pentylenetetrazol
metabolic acidosis. Sodium bicarbonate levels
rise with sodium lactate infusion and the com- This drug was first found to be anxiogenic in man
pensatory respiratory acidosis (adaptive hypo- during research into its proconvulsant effects
ventilation) could be accompanied by feelings of (Rodin, 1958; Rodin & Calhoun, 1970). How-
discomfort. Grosz & Farmer (1969) add that the ever, no systematic work has been done in
rise in lactate produced by the infusion would humans despite much animal work (Lal &
cause only a trivial change in the ionized calcium Enmett-Oglesby, 1983).
concentration in the blood.
In a further study, Grosz & Farmer (1972)
repeated Pitts & McClure's (1967) experiment Carbon dioxide
but included a control infusion of sodium bicarb-
onate. Symptoms produced by the bicarbonate Carbon dioxide was initially used as an anxiolytic
and the lactate infusions were the same, and (Wolpe, 1958), but replication attempts more
were not associated with a rise in blood lactate recently have not confirmed this. Indeed, it has
concentrations. Thus, the association of lactate instead produced anxiomimetic effects (Van den
production and anxiety was not upheld by the Hout & Griez, 1984; Griez, 1984). Further work
evidence. implies that carbon dioxide-induced sensations
Nevertheless the infusion of alkalinizing solu- are labelled as either pleasant or unpleasant,
tions does seem to induce feelings of anxiety, depending on prior expectations (Van den Hout
especially in patients with anxiety states. The & Griez, 1982). Thus, the increased respirationStates of anxiety and their induction by drugs 257
rate and rise in catecholamines (Lambertsen, all blocked by prior administration of the benzo-
1965), cause peripheral symptoms which in diazepine antagonist, Ro 15-1788. More graded
patients with panic disorder are associated with responses were obtained with lower doses (25-
their panic thereby creating a positive feedback 500 ,ug kg-') (Insel et al., 1984), with behavioural
loop. There is no evidence, as yet, of central effects similar to those seen in monkeys facing a
effects. threat such as the approach of an unfamiliar
investigator.
One study in man used N-methyl-,B-3-carbox-
,-carbolines amide (FG 7142) (Dorow et al., 1983). Five
healthy male volunteers received increasing oral
The development of adrenaline and yohimbine- doses, 100-200 mg and in one case 400 mg. On
induced models of anxiety stemmed from the two occasions (out of 12) severe anxiety was
well-known sympathomimetic concomitants of observed and in both instances the plasma con-
anxiety such as tachycardia and tremor. Another centration of FG 7142 was over 150 ng ml-'. One
starting point has been the benzodiazepines and volunteer reported severe anxiety with intense
the discovery of specific high-affinity receptors inner strain and excitation with inability to speak.
in the brain for these and related drugs (Petersen Flushes of the face and the extremities were
et al., 1986). In the search for endogenous sub- accompanied by a feeling of warmth. Blood
stances binding to these receptors with physio- pressure and pulse rate rose. Agitation increased
logical effects, a class of 13-carboline compounds and the subject paced around the ward with the
was studied. These substances are related to feeling of precordial pressure and palpitations.
plant alkaloids and derivatives such as harmine Muscle tension and reflexes increased. These
and harmol with well-studied psychotropic prop- effects peaked 1 h after administration and lasted
erties (Ho, 1977). Braestrup and his coworkers for 2 h. The second volunteer was given 400 mg
isolated and identified the methyl and ethyl of FG 7142 after taking doses of up to 200 mg
esters of ,B-carboline-3-carboxylic acid from without incident. After 10 min, he developed
human urine and showed that they bound to facial flushes, tremor and cold sweat. Fifteen
benzodiazepine binding sites (Nielsen et al., minutes later a stronger attack started. He felt a
1979; Braestrup et al., 1981). Although these sense of impending doom. Yet a third attack
particular compounds were artefacts of extraction started which was terminated by an intravenous
(Squires, 1981), the 3-carbolines in general are benzodiazepine.
proving to be useful tools in our elucidation of On the basis of two such fragmentary accounts
neurochemical mechanisms involved in anxiety. it is not clear whether a true anxiety syndrome
In animals, ,-carbolines antagonize the anti- was induced. A slow infusion with an attempt to
convulsant actions of the benzodiazepines measure sustained anxiety levels would be more
(Tenen & Hirsch, 1980; Cowen et al., 1981). convincing. The waves of anxiety experienced
They also reduce the dose of a convulsant such as by the second subject are not typical of panic
pentylenetetrazol needed to induce convulsions attacks which, although they can be repeated,
without producing convulsions themselves, a tend not to be in waves. They are more reminis-
proconvulsant effect (Oakley & Jones, 1980). cent of hallucinogens such as LSD. The relation-
The sedative/antianxiety properties (as inferred ship between ,B-carbolines and harmaline alka-
from animal models) of benzodiazepines are loids cannot be overlooked. Nevertheless, the
antagonized by substituted ,B-carbolines (Cowen interactions, biochemical and clinical, with the
et al., 1981; Petersen et al., 1982; Mendelson et benzodiazepines suggest that this model of anxiety
al., 1983). ,-carbolines also possess intrinsic is useful.
actions opposite in nature to the benzodia-
zepines. For example, they significantly increase
sleep latency (Mendelson et al., 1983). These Caffeine
compounds have been termed 'inverse agonists'
or 'contragonists'. Caffeine, a methylxanthine, is so well-known
In primates, several P-carbolines induce syn- and widely used that its anxiogenic properties
dromes resembling anxiety. Following a large are often overlooked. It has been studied in the
dose of drug (2.5 mg kg-1 of ,B-carboline-3- laboratory since the last century (Hoch &
carboxylic acid ethyl ester, 13-CCE), Rhesus Kraepelin, 1895; Mosso, 1893), and a monu-
monkeys rapidly became agitated and struggled mental study was published by Hollingsworth
in the restraining chair, vocalization increased, (1912). Case reports indicate that caffeine either
they urinated and defecated (Ninan et al., 1982). in high dose or in withdrawal may produce symp-
Heart rate, blood pressure, plasma cortisol and toms of anxiety (Greden, 1974; MacCallum,
catecholamines were elevated. These effects were 1979), such as insomnia, tremor (Wharrad et al.,258 M. Lader & M. Bruce
1985), irritability, palpitations, nausea and taining beverages, especially late at night. This
diarrhoea. area of research is probably the most useful at the
One controlled double-blind study yielded moment involving, as it does, a widely used drug.
complex results (Goldstein et al., 1965).
Caffeine, 300 mg, made subjects feel more alert Conclusions
mentally, more active physically, and more
nervous than did placebo. However, reports of Guttmacher et al. (1983) set out the require-
increased arousal and of nervousness tended to ments for an ideal model of anxiety:
occur in different individuals. The lower dose 1. It should mimic naturally occurring anxiety
(150 mg) gave similar but non-significant results. but pharmacologic models engender 'as if' or
Another study showed quite consistently that 'cold' anxiety.
caffeine citrate in doses of 300 and 600 mg 2. It should therefore produce not only the
increased ratings of alertness, elation and feeling physical signs of motor tension and autonomic
of quickness (Lader, 1969}. A recently completed hyperactivity but also the dysphoria, worry,
study (Bruce et al., 1986) on nine normal subjects fear, hypervigilance, irritability, and dread of
given placebo, 250 and 500 mg of anhydrous which anxious patients complain.
caffeine, in a double-blind balanced design, 3. It should be replicable.
showed that caffeine significantly increased skin 4. The phenomena should be either short lived
conductance, mood ratings of alertness and or readily reversible.
bodily symptom ratings of severe shaking and 5. It should differentiate between normal and
trembling. These results indicate increased those with pathology, e.g. reflect the potential of
arousal in normal subjects, but not the induction a trait response.
of clinical anxiety, at the doses of caffeine used. 6. It should reflect the potential for a state
A previous study produced similar findings response. Those who have been successfully
(Charney et al., 1984b), but found that MHPG treated clinically should not respond or respond
levels were not altered in a consistent fashion by far less than those who have had no treatment.
caffeine and that there was no correlation with As argued above, catecholamines, lactate
anxiety rating scales. infusions and carbon dioxide, fail the second
A preliminary survey comparing patients with requirement of the model. They have no specific
panic disorder and normal controls found that central manifestations, but rather induce periph-
the patients had increased sensitivity to caffeine eral changes which, in anxiety disorder subjects,
(Boulenger & Uhde, 1982). Other evidence sets up a cognitive positive feed back loop leading
suggests that patients with anxiety disorders have to the development of the central manifestations
increased caffeine sensitivity which leads to de- of anxiety. Caffeine has yet to be tested so as to
creased consumption (Lee et al., 1985). At high satisfy item 6, but otherwise fits the model. The
dose (720 mg orally), panic attacks were induced a2-adrenoceptor antagonist, yohimbine, meets
in two normal volunteers (Uhde et al., 1983,) a all the criteria of the model and is the best
finding of great relevance to the controversy as current pharmac logical model of anxiety. The
to whether panic attacks and generalized anxiety 1-carbolines havJ not been adequately tested in
are separate syndromes or whether panic attacks man although anipal data have much promise.
are a severe variant of anxiety. Of the anxiety disorders defined in DSM III,
Caffeine and its related compounds interact drug induction of panic disorder and generalized
weakly with the benzodiazepine receptor site anxiety disorder has been achieved. Clinical
(Boulenger et al., 1982). They also stimulate dispute concerns categorization of panic disorder
central noradrenergic activity (Berkowitz et al., as a separate condition from generalized anxiety
1970). In caffeine-naive subjects they produce a disorder or as a more severe form. However,
dose related increase in plasma noradrenaline inferences can be made from the pharmacological
(Robertson et al., 1978), although not in habitual induction of anxiety. The drugs which satisfy
caffeine users (Robertson et al., 1984). How- Guttmacher's model for anxiety, that is yohim-
ever, the most potent central effect is at the bine, caffeine and 3-carbolines, suggest that
adenosine receptor site (Boulenger et al., 1982). both generalized anxiety disorder and panic dis-
To date caffeine provides a fairly convincing order can be induced in a dose related manner.
model of generalized anxiety. Literally thous- The implication therefore is that panic disorder
ands of people are aware that caffeine produces is a more severe form of generalized anxiety
anxiety and insomnia and avoid caffeine con- disorder.States of anxiety and their induction by drugs 259
References
(1984a). Noradrenergic function in panic anxiety,
American Psychiatric Association (1980). Diagnostic effects of yohimbine in healthy subjects and
and Statistical Manual of Mental Disorders. 3rd ed. patients with agoraphobia and panic disorder.
Washington, D. C. Arch. gen. Psychiat., 41, 751-763.
Appleby, I. L., Klein, D. F., Sachar, E. J. et al. Charney, D. S., Galloway, M. P. & Heninger, G. R.
(1981). Biochemical indices of lactate-induced (1984b). The effects of caffeine on plasma MHPG,
panic: A preliminary report. In Anxiety: New subjective anxiety, autonomic symptoms and
research and changing concepts, eds Klein, D. F. & blood pressure in healthy humans. Life Sci., 35,
Rabkin, J. pp. 411-423. New York: Raven Press. 135-144.
Arbab, A. G., Bonn, J. A. & Hicks, D. C. (1971). Cowen, P., Green, A., Nutt; D. & Martin, I. (1981).
Effect of propranolol on lactate induced phenom- Ethyl-beta-carboline-carboxylate lowers seizure
ena in normal subjects. Br. J. Pharmac., 41, 430. threshold and antagonizes flurazepam-induced
Basowitz, H., Korchin, S. J., Oken, D., sedation in rats. Nature, 290, 54-55.
Goldstein, M. S. & Gussack, H. (1956). Anxiety and Crawley, J. N., Skolnick, P. & Paul, S. M. (1984).
performance changes with a minimal dose of epine- Absence of intrinsic antagonist actions of benzo-
phrine. AMA Arch. Neurol. Psychiat., 76, 98- 105. diazepine antagonists on an exploratory model of
Berkowitz, B. A., Travers, J. H. & Spector, S. (1970). anxiety in the mouse. Neuropharmacology, 23,
Release of norepinephrine in the CNS by theo- 531-537.
phylline and caffeine. Eur. J. Pharmac., 10, 64-71. Dorow, R., Horowski, R., Paschelke, G., Amin, M.
Bonn, J. A. Harrison, J. & Rees, W. L. (1971). & Braestrup, C. (1983). Severe anxiety induced by
Lactate induced anxiety; therapeutic application. FG 7142, a beta-carboline ligand for benzodi-
Br. J. Psychiat., 119, 468-471. azepine receptors. Lancet, H, 98-99.
Boulenger, J. P. & Uhde, T. W. (1982). Caffeine Erdmann, G. & Janke, W. (1978). Interaction
consumption and anxiety: preliminary results of a between physiological and cognitive determinants
survey comparing patients with anxiety disorders of emotion: Experimental studies of Schachter's
and normal controls. Psychopharmac. Bull., 18, theory of emotion. Biol. Psychol., 6, 61-74.
53-57. Erdmann, G. & van Lindern, B. (1980). The effects of
Boulenger, J. P., Patel, J. & Marangos, P. J. (1982). beta-adrenergic stimulation and beta-adrenergic
Effects of caffeine and theophylline on adenosine blockade on emotional reactions. Psychophysi-
and benzodiazepine receptors in human brain. ology, 17, 332-338.
Neurosci. Lett., 30, 161-66. Fast, G. J. & Fisher, S. (1971). The role of body
Braestrup, C., Nielsen, M., Skovbjerg, H. et al. attitudes and acquiescence in epinephrine and
(1981). Beta-carboline-3-carboxylates and benzo- placebo effects. Psychosom. Med., 33, 63-84.
diazepine receptors. In GABA and benzodiaze- Fink, M., Taylor, M. A. & Volavka, J. (1969).
pine receptors, Costa, E. et al. New York: Raven Anxiety precipitated by lactate. New Engl. J.
Press. Med., 281, 1429.
Brown, J. T., Mulrow, C. D. & Stoudemire, G. A. Frankenhaeuser, M., Jarpe, G. & Matell, G. (1961).
(1984). The anxiety disorders. Ann. int. Med., 100, Effects of intravenous infusions of adrenaline and
558-564. noradrenaline on certain psychological and physio-
Bruce, M., Scott, N., Lader, M. & Marks, V. (1986). logical functions. Acta Physiol. Scand., 51, 175-
The psychopharmacological and electrophysio- 186.
logical effects of single doses of caffeine in healthy Frankenhaeuser, M. & Jarpe, G. (1962). Psycho-
human subjects. Br. J. clin. Pharmac., 22, 81-87. physiological reactions to infusions of a mixture of
Bunney, W. E. (1981). Current biological strategies adrenaline and noradrenaline. Scand. J. Psychol.,
for anxiety. Psychiatric Annals, 11, 11-15. 3, 21-29.
Cannon, W. B., Linton, J. R. & Linton, R. R. (1924). Frankenhaeuser, M. & Jarpe, G. (1963). Psycho-
Conditions of activity in endocrine glands. IV. physiological changes during infusions of adrenaline
The effects of muscle metabolites on adrenal in various doses. Psychopharmacologia, 4, 424-
secretion. Am. J. Physiol., 71, 153-162. 432.
Cantril, H. & Hunt, W. A. (1932). Emotional effects Freud, S. (1894). The justification for detaching from
produced by the injection of adrenaline. Am. J. neurasthenia a particular syndrome: The anxiety
Psychol., 44, 300-307. neurosis. Collected works, 1, 76-109. London:
Carr, D. B. & Sheehan, D. V. (1984). Panic anxiety: A Hogarth Press and Institute of Psychoanalysis.
new biological model. J. clin. Psychiat., 45, 323- Frohlich, E. D., Tarazi, R. C. & Dustan, H. P. (1969).
330. Hyperdynamic beta-adrenergic circulatory state.
Charney, D. S., Heninger, G. R. & Sternberg, D. E. Increased beta-receptor responsiveness. Arch.
(1982). Assessment of the alpha-2 adrenergic auto- intern. Med., 123, 1-7.
receptor function in human: effects of oral Garfield, S. L., Gershon, S., Sletten, I. et al. (1967).
yohimbine. Life Sci., 30, 2033-2041. Chemically induced anxiety. Int. J. Neuro-
Charney, D. S., Heninger, G. R. & Redmond, D. E. psychiatry, 3, 426-433.
(1983). Yohimbine induced anxiety and increased Goldstein, A., Karzer, S. & Warren, R. (1965).
noradrenergic function in humans: effects of Psychotropic effects of caffeine in man. II Alert-
diazepam and clonidine. Life Sci., 33, 19-26. ness, psychomotor coordination and mood. J.
Charney, D. S., Heninger, G. R. & Breier, A. Pharmac. exp. Ther., 150, 146-151.260 M. Lader & M. Bruce
Gorman, X M., Fyer, A. F., Gliklick, J., King, D. & Kopin, I. J. (1984). Avenues of investigation for the
Klein, D. F. (1981). Effect of sodium lactate on role of catecholamines in anxiety. Psycho-
patients with panic disorder and mitral valve pro- pathology, 17, Suppl 1, 83-97.
lapse. Am. J. Psychiatry, 138, 247-249 Lader, M. (1969). Comparison of amphetamine
Greden, J. F. (1974). Anxiety or caffeinism: A sulphate and caffeine citrate in man. Psycho-
diagnostic dilemma. Am. J. Psychiatry, 131, 1089- pharmacologia, 14, 83-94.
1092 Lal, H. & Emmett-Oglesby, M. W. (1983) Be-
Griez, E. (1984). Experimental models of anxiety. havioural analogues of anxiety: Animal models.
Problems and perspectives. Acta Psychiatr. Belg., Neuropharmacology, 22, 1423-1441.
84, 511-532. Lambertsen, C. J. (1965). Theraputic gases, oxygen,
Grosz, H. J. & Farmer, B. B. (1969). Blood lactate in carbon dioxide, helium. In Drill's pharmacology in
the development of anxiety symptoms. A critical medicine, ed. Dipalma, J. R. New York: McGraw
examination of Pitts and McClure's hypothesis and Hull.
experimental study. Arch. gen. Psychiatry, 21, Lee, M. A., Cameron, 0. G. & Greden, J. F. (1985).
611-619. Anxiety and caffeine consumption in people with
Grosz, H. J. & Farmer, B. B. (1972). Pitts and anxiety disorders. Psychiatric Research, 15, 211-
McClure's lactate-anxiety study revisited. Br. J. 217.
Psychiatry, 120, 115-118. Liebowitz, M. R., Fyer, A. F., Gorman, J. M., Dillon,
Guttmacher, L. B., Murphy, D. L. & Insel, T. R. D. & Appleby, G. (1984). Lactate provocative of
(1983). Pharmacologic models of anxiety. Comp. panic attacks. I. Clinical and behavioral findings.
Psychiatry, 24, 312-326. Arch. gen. Psychiatry, 41, 764-770
Haslam, M. T. (1974). The relationship between the Marafion, G. (1924). Contribution a l'etude de l'action
effect of lactate infusion on anxiety states, and emotive de l'adrenaline. Rev. Fr. Endocrinol., 2,
their amelioration by carbon dioxide inhalation. 301-325.
Br. J. Psychiatry, 125, 88-90. MacCallum, W. A. G. (1979). Excess coffee and
Hawkins, D. R., Monroe, J. D., Sandifer, M. G. & anxiety states. Int. J. Soc. Psychiatry, 25, 209-210.
Vernon, C. R. (1960). Psychological and physio- McFarland, R. A. & Huddleson, J. H. (1936). Neuro-
logical responses to continuous epinephrine circulatory reactions in psychoneuroses: studies by
infusion. Psychiatric Research Reports of the the Schneider method. Am. J. Psychiatry, 93, 567-
American Psychiatric Association, 12, 40-52. 599.
Ho, B. (1977). In Current developments in psycho- Mendelson, W. B., Cain, M., Cook, J. M., Paul, S. M.
pharmacology, 4, 153-175, ed. Essman, W. New & Skolnick, P. (1983). A benzodiazepine receptor
York: Spectrum. antagonist decreases sleep and reverses the hypnotic
Hoch, A. & Kraepelin, E. (1895). Uber die Wirkung actions of flurazepam. Science, 219, 414-416,
der Theebestandtheile auf korperliche und geistige Mosso, U. (1893). Action des principes actifs de la
Arbeit. Psychologische Arbeiten, 1, 379-488. noix de kola sur la contraction musculaire. Arch.
Hollingsworth, H. L. (1912). The influence of caffeine Ital. Biol., 19, 241-256.
on mental and motor efficiency. Arch. Psychol., Nesse, R. M., Cameron, 0. G., Curtis, G. C.,
22, 1-166. McCann, D. S. & Huber-Smith, M. J. (1984).
Holmberg, G. & Gershon, S. (1961). Autonomic and Adrenergic function in patients with panic anxiety.
psychic effects of yohimbine hydrochloride. Arch. gen. Psychiatry, 41, 771-776.
Psychopharmacologia, 2, 93-106. Nielsen, M., Gredal, 0. & Braestrup, C. (1979). Some
Holmgren, A. & Strom, G. (1959). Blood lactate properties of 3-H-diazepam displacing activity with
concentration in relation to absolute and relative human urine. Life Sci., 25, 679-86.
work load in normal men, and in mitral stenosis, Ninan, P. T., Insel, T. R., Cohen, R. M., Cook, J. M.,
atrial septal defect and vasoregulatory asthenia. Skolnick, P. & Paul, S. M. (1982). Benzodiazepine
Acta med. Scand., 163, 185-193. receptor-mediated experimental 'anxiety' in
Ingram, C. G. (1962). Some pharmacologic actions of primates. Science, 218, 1332-1334.
yohimbine and chlorpromazine in man. Clin. Oakley, N. R. & Jones, B. J. (1980). The procon-
Pharmac. Ther., 3, 345-352. vulsant and diazepam reversing effects of ethyl-
Insel, T. R., Ninan, P. T., Aloi, J., Jimerson, D. C., beta-carboline-3-carboxylate. Eur. J. Pharmac.,
Skolnick, P. & Paul, S. M. (1984). A benzodiaze- 68, 381-382.
pine receptor-mediated model of anxiety. Studies Petersen, E. N., Pschelke, G., Kehr, W., Neilsen, M.
in nonhuman primates and clinical implications. & Braestrup, C. (1982). Does the reversal of the
Arch. gen. Psychiatry, 41, 741-750. anticonffict effect of phenobarbital by beta-CCE
Jones, M. & Mellersh, V. (1946). A comparison of the and FG 7142 indicate benzodiazepine receptor
exercise response in anxiety states and normal mediated anxiogenic properties? Eur. J. Pharmac.
controls. Psychosom. Med., 8, 180-187. 82, 217-221.
Kandel, E. R. (1983). From metapsychology to mole- Petersen, E. N., Jensen, L. H., Drejer, J. & Honore,
cular biography: Explorations into the nature of T. (1986). New perspectives in benzodiazepine
anxiety. Am. J. Psychiatry, 140, 1277-1293. receptor pharmacology. Pharmacopsychiat., 19,
Kelly, D. H. W., Mitchell-Heggs, N. & Sherman, J. 4-6.
(1971). Anxiety and the effects of sodium lactate Pitts, F. N. & McClure, J. N. (1967). Lactate meta-
assessed clinically and physiologically. Br. J. bolism in anxiety neurosis. New Engl. J. Med., 277,
Psychiatry, 119, 129-141. 1329-1336.States of anxiety and their induction by drugs 261
Rifkin, A., Klein, D. F., Dillon, D & Levitt, M. Med., 3, 343-349.
(1981). Blockade by imipramine or desipramine of Tenen, S. S. & Hirsch, J. D. (1980). Beta-carboline-3-
panic induced by sodium lactate. Am. J. Psychiatry, carboxylic acid ethyl ester antagonizes diazepam
138, 676-677. activity. Nature, 288, 609-610.
Robertson, D., Frolich, J. C., Carr, R. K., Watson, Tyrer, P. (1976). The role of bodily feelings in anxiety.
J. T., Hollifield, J. W., Shand, D. G. & London: Oxford University Press.
Oates, J. A. (1978). Effects of caffeine on plasma Tyrer, P. (1984). Classification of anxiety. Br. J.
renin activity, catecholamines and blood pressure. Psychiatry, 144, 78-83.
New Engl. J. Med., 298, 181-186. Uhde, T. W., Boulenger, J. P., Vittone, B., Siever,
Robertson, D., Hollister, A. S., Kincaid, D., L. J. & Post, R. M. (1983). Human anxiety and
Workman, R., Goldberg, M. R., Tung, C. & noradrenergic function: Preliminary studies with
Smith, B. (1984). Caffeine and hypertension. Am. caffeine, clonidine and yohimbine. In Proceedings
J. Med., 77, 54-60. of the 7th world congress ofpsychiatry, Vienna, 2,
Rodin, E. A. (1958). Metrazol tolerance in a 'normal' 693-698. New York: Plenum Press.
and volunteer population. Electroencephalogr. Van den Hout, M. A. & Griez, E. (1982). Cognitive
clin. Neurophysiol., 10, 433-446. factors in carbon dioxide therapy. J. psychosom.
Rodin, E. A. & Calhoun, (1970). Metrazol in a Res., 26, 209-214.
'normal' volunteer population. J. nerv. ment. Van den Hout, M. A. & Griez, E. (1984). Panic
Dis., 150, 438-450. symptoms after inhalation of carbon dioxide. Br. J.
Schachter, S. & Singer, J. E. (1962). Cognitive, social Psychiatry, 144, 503-307.
and physiological determinants of emotional state. Wearn, J. T. & Sturgis, C. C. (1919). Studies on
Psychol. Rev., 69, 379-399. epinephrine. Effects of the injection of epinephrine
Schachter, S. & Wheeler, L. (1962). Epinephrine, in soldiers with irritable heart. Arch. intern. Med.,
chlorpromazine, and amusement. J. abnorm. soc. 24, 247-268.
Psychol., 65, 121-128. Wharrad, H. J., Birmingham, A. T., MacDonald,
Schachter, S. (1966). The interaction of cognitive and I. A., Inch, P. J. & Mead, J. L. (1985). The
physiological determinants of emotional states. In influence of fasting and of caffeine intake on finger
Anxiety and Behavior, ed. Spielberger, C. D. New tremor. Eur. J. clin. Pharmac., 29, 37-43.
York: Academic Press. Wolpe, J. (1958). Psychotherapy by reciprocal
Squires, R. F. (1981). GABA receptors regulate the inhibition. Stanford, California: University Press.
affinities of anions required for brain specific Woods, E. F., Richardson, J. A., Richardson, A. K.
benzodiazepine binding. Adv. biochem. Psycho- & Bozeman, R. F. (1956). Plasma concentrations
pharmac., 26, 129-138. of epinephrine and arterenol following the action
Stanaway, R. G. & Hullin, R. P. (1973). The relation- of various agents on the adrenals. J. Pharmac. exp.
ship of exercise response to personality. Psychol. Ther., 116, 351-355.
(Received 27 January 1986,
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