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complexes were present in the sera of all patients withlepromatous leprosy, one would not be able to detectthose formed at equivalence or antibody excess.From our results it seems that lepromatous patients

with active E.N.L., whether or not they are receivingspecific anti-E.N.L. therapy at the time, are far morelikely to have circulating immune complexes in

antigen excess than those without E.N.L. Similar

preliminary results have been obtained by Dr. D. J.Drutz and Dr. R. H. Gelber at the University ofCalifornia School of Medicine, San Francisco (per-sonal communication). Whether this bears anyrelation to the aaiology of E.N.L. is as yet unclear.

Sequential studies are in progress to determine therelation between the presence of detectable circulatingimmune complexes and the incidence of episodes ofE.N.L. and their ultimate prognosis. Further, this

technique has for the first time made it possible toisolate the immune complexes present in the sera ofpatients with lepromatous leprosy so that their naturemay be more precisely determined.

C. J. M. and G. R. are in receipt of grants from the MedicalResearch Council. The Leprosy Research Unit, Sungei Buloh,is jointly sponsored by the Malaysian Ministry of Health and theBritish Medical Research Council.

Requests for reprints should be addressed to J. L. T., RoyalCollege of Surgeons, Lincoln’s Inn Fields, London W.C.2.

REFERENCES

1. Rees, R. J. W., Chaterjee, K. R., Pepys, J., Tee, R. R. Am. Rev.resp. Dis. 1965, 92, 139.

2. Wemambu, S. N. C., Turk, J. L., Waters, M. F. R., Rees, R. J. W.Lancet, 1969, ii, 933.

3. Agnello, V., Winchester, R. J., Kunkel, H. G. Immunology, 1970,19, 909.

4. Agnello, V., Koffler, D., Eisenberg, J. W., Winchester, R. J.,Kunkel, H. G.J. exp. Med. 1971, 134, 228.

Hypothesis

MODIFIED AMINE HYPOTHESIS FOR

THE ÆTIOLOGY OF AFFECTIVE ILLNESS

MEDICAL RESEARCH COUNCIL BRAIN METABOLISMUNIT*

University Department of Pharmacology,Edinburgh EH8 9JZ

REPORTS of low levels of 5-hydroxyindolacetic acid(5-H.I.A.A.) in cerebrospinal fluid (c.s.F.) in depressiveillness 1 have been confirmed,2-4 and low levels ofhomovanillic acid (H.V.A.) have also been reported-6However, there is no consistent relation between theseabnormal levels and mood state—e.g., low levels of5-H.I.A.A. found in depression and mania did not risewhen the patient recovered.7 If we accept that theselow metabolite levels reflect a fall in the activity andmetabolism of serotoninergic neurons, then these

experimental clinical studies are not consistent with theamine hypothesis as it was simply stated-namely " thatdepression can occur when the levels of biologicalamines at reactive sites within the brain are reducedand that anti-depressant drugs will be those whichincrease the levels of the amines at the reactivesites ".8 The object of this communication is, there-fore, to develop a modification of the amine hypothesiswhich will more closely fit the facts and which mayprove susceptible to further testing. In constructingthe new hypothesis, we will summarise the results oftwo of our studies on amine metabolism in the c.N.s.In making comparisons between affective disorders inman and the behavioural changes which accompanythe experimental manipulation of amine-mediatedsystems in animals, we have found it necessary to

emphasise behavioural aspects of mania and depres-sion : and in this paper more weight is given to a

* Dr. G. W. ASHCROFT, Dr. D. ECCLESTON, Dr. L. G. MURRAY,and Dr. A. I. M. GLEN (clinicians); Dr. T. B. B. CRAWFORD,Dr. I. A. PULLAR, Mr. P. J. SHIELDS, and Mr. D. S.WALTER (biochemists); Miss IVY M. BLACKBURN (psycholo-gist); J. CONNECHAN (charge nurse); and Miss MARYLONERGAN (dietitian).

discussion of these than to the description of the" feeling state " with which no ready parallel can bedrawn from animals.

C.S.F. STUDIES IN MAN

Amine Metabolites in Unipolar and Bipolar AffectiveIllnessIn most of the studies carried out on depression,

including our own,2 there has been no attempt todesignate specific diagnostic subgroups. We haverecently separated patients into unipolar(recurrent depressive) and bipolar (manic depressive)subgroups. 9 In the bipolar group all patients have ahistory of both manic and depressive attacks whereasthe unipolar group have a history only of previousdepressive episodes.The results (table I) show that the concentration of

5-H.I.A.A. and H.V.A. in lumbar C.S.F. in unipolardepression is significantly lower than in the controlgroup, but in the bipolar depressive group the levelof both these metabolites are within the normal rangeand significantly higher than in the unipolar group:

TABLE I—MEANS.D. CONCENTRATIONS (ng./ml.) OF 5-H.I.A.A.AND H.V.A. IN LUMBAR C.S.F. OF PSYCHIATRIC PATIENTS BOTH

BEFORE AND AFTER TREATMENT AND OF CONTROLS

Numbers of observations are shown in parentheses.

t . < Comparison with controls; Student’s t test.

574

TABLE II&mdash;MEAN&plusmn;S.D. CONCENTRATIONS OF 5-H.I.A.A. AND

TRYPTOPHAN IN THE LUMBAR C.S.F. OF PSYCHIATRIC PATIENTS

8 hr. AFTER THE ORAL ADMINISTRATION OF L-TRYPTOPHAN

(50 mg./kg.) AS COMPARED WITH CONTROLS TREATED SIMILARLY

The concentrations of 5-H.I.A.A. and tryptophan in any of the psychiatricgroups of patients do not differ significantly (r 0-05) from those ofthe control group.

c.s.F. levels are thus clearly not related to mood-e.g., in the unipolar depressed group, a change inmood state is not related to a change in level of themetabolites.

Synthesis of 5-H.T. in DepressionOne suggested explanation for low levels of 5-H.I.A.A.

in unipolar depression would be a defect in synthesisof the amine. Such a deficiency might be due to adefect in the activity of the rate-limiting enzyme,tryptophan-5-hydroxylase. 10The synthetic capacity for the formation of 5-H.T,

can be evaluated by administering a loading doseof tryptophan and later measuring the increased levelof 5-H.I.A.A. in c.s.F. The results (table n) seem tosuggest that there is no reduced potential synthesisof 5-H.T. in affective illness.The findings of these two investigations suggest

that in unipolar depressive illness there is a changein functional release of amine transmitters (at least for5-H.T.) without a change in the capacity for aminesynthesis. However, if we wish to formulate a generalhypothesis to acknowledge a central role of the amine-containing system in the different types of affectiveillness, then we must search for a modification of thesimple amine hypothesis normally put forward.

ANIMAL STUDIES

Structure and Function of Amine-containing Systems in theC.N.S.The presence of high concentrations of 5-H.T., noradrena-

line, and dopamine in brainstem, limbic structures, andbasal ganglia has been recognised for some time.12-14With the introduction of the techniques of fluorescencemicroscopy by Swedish workers,t5 specific amine-containingneuronal systems have been clearly delineated.16 In

general, cell bodies of the aminergic neurons are in brain-

Fig. I-Model of noradrenergic synapse.NA =Noradrenaline.MAO =Monoamine oxidase.COMT =CatechoI-0-niethyI transferase.

stem with projections to corpus striatum, to amygdalaand hippocampus, to cortex, and also, for some systems,downwards to the spinal cord.

Amine-mediated Synaptic TransmissionA schematic representation of transmission at a synapse

mediated by an amine transmitter is shown in fig. 1.The enzymatic machinery for the synthesis of amines is

transported down the axon, and at the nerve terminalvesicles of transmitter release their contents into the

synaptic cleft. Inactivation appears to be mainly by re-uptake into the presynaptic nerve terminal, although enzy-matic catabolism by monoamine oxidase and catechol-0-methyl transferase is also important. The active re-uptakemechanisms are ion dependent 17 and inhibited by thetricyclic group of antidepressant drugs.1.8 In this respect,dopamine may be the exception.19 Little is known of thereceptor, although there is evidence 20 that the synthesisof the biogenic amines in the presynaptic neuron is in-fluenced by receptor activity, possibly through an inhibitoryneuronal feedback mechanism.

Changes in Receptor Sensitivity and Feedback Control ofTransmitter Synthesis at SynapseIn animals the administration of haloperidol, a drug

Fig. 2-Diagram of possible inhibitory feedback mechanism.

which blocks cerebral dopamine receptors, results inan increase in the turnover of cerebral dopamine. 21 Theadministration of lysergide (L.S.D.), a compound which inlow dosage stimulates cerebral 5-H.T. receptors," is

accompanied by a decreased turnover of 5-H.T.22-23

Recording from the presynaptic 5-H.T.-containing neuronsshows that the administration of L.S.D. produces a fall infiring-rate,24 whilst the firing-rate in postsynaptic cells isincreased.20 The results are explained by the presence ofa neuronal inhibitory feedback mechanism (fig. 2). In-creased receptor activity in the postsynaptic neuron in someway feeds back to inhibit the firing of the presynapticaminergic neuron and in addition results in a simultaneousreduction in amine synthesis and turnover. Receptorblockade is thought to release the inhibition and result inan increased firing-rate in the presynaptic neuron and anincrease in amine synthesis. Amine turnover may thusshow an inverse relation to the activity of the postsynapticneuron. Activity in the postsynaptic neuron will be depen-dent on the events occurring in the synaptic cleft and inthe postsynaptic receptor membrane. Thus the factorsinvolved will include the level of presynaptic transmitterrelease, the efficiency of inactivation of released transmitterby re-uptake and/or enzymatic degradation, and the" sensitivity of the postsynaptic receptors ". That receptorsensitivity is capable of variation is shown in the peripheralautonomic nervous system, where denervation (e.g.,sympathectomy) increases the sensitivity of the postsynapticneurons to available transmitter. 25 In the central nervoussystem there is now evidence suggesting the presence of a

575

similar mechanism 26-e.g., lesions in the substantia nigrawhich destroy dopaminergic neurons have been shown tolead to an increase in the sensitivity of dopaminergicreceptors in postsynaptic neurons.

BEHAVIOUR AND THE AMINE-CONTAINING SYSTEMS

In AnimalsMany attempts have been made to draw inferences

regarding the functions of amine-containing systemsfrom a study of the behavioural effects of psychotropicdrugs known to be acting on these neurons (e.g.,reserpine 27). Lack of specificity of these drugs has,however, made it difficult to elucidate the role ofindividual systems.More recently, however, the use of stereotaxic

lesions 26 and electrical stimulation 28-30 via implantedelectrodes has been used to investigate function. Fromthese investigations certain general conclusions canbe drawn regarding the role of the systems in thecontrol of animal behaviour. The noradrenergicsystem has cell bodies lying in the brainstem projectingto many other areas, in particular, the locus coeruleusprojects ipsilaterally to the cortex in the rat.31 The

dopaminergic neurons arise primarily in the substantianigra and project to the corpus striatum.32 Stimula-tion of dopaminergic receptors by apomorphine leadsto stereotyped behaviour consisting of sniffmg, licking,and biting. 33 Dopaminergic activity also seems tocontrol gross motor activity. Lesions of the substantia

nigra result in profound hypokinesia in rats, presumablyanalogous to the symptoms of parkinsonism: " allanimals showed pronounced hypokinesia, loss of

exploratory behaviour and curiosity and an inabilityto initiate activity". 26 On the other hand, ablationof the striatum and cortex in rats 3 and monkeys 35leads to pronounced hyperactivity with a stereotypedcomponent. It would seem from these animal observa-tions that " it is more probable that the dopaminergicsystem and striatum control a general arousal or drivelevel that is necessary for performing a number ofactivities". 2 6

The noradrenergic system, on the other hand, hasbeen implicated in excitation and in exploratorybehaviour.36 A further facet of behaviour has beenstudied in self-stimulation experiments,28-30 whichhave shown that animals will self-stimulate whenelectrodes are placed either in the substantia nigra (thedopaminergic system) or in the locus coeruleus (anoradrenergic system). It therefore becomes appar-ent that both systems may be necessary for thisparticular pattern of behaviour. Similarly, we havealso found this to be true by studying the effect ofamphetamine in rats. This drug will give overactivityand stereotyped behaviour. Lesions of the substantianigra destroying dopaminergic neurons modify thiseffect. 37 In a preliminary study we have found thatbilateral lesions of the locus coeruleus also almostcompletely abolishes this response to amphetamine.Again it appears that both noradrenergic and dopa-minergic function are necessary for this particularbehavioural manifestation.

5-H.T. has been implicated in many forms ofbehaviour. The strongest evidence, however, is itsrole in the mediation of sleep. Cats with lesions in the

raphe nuclei-an area which contains many of thecell bodies of the 5-H.T. neurons-show prolongedinsomnia.3 a 5-H.T. neurons have also been postulatedto control sensory input into the brain; stimulationof the raphe nuclei reduces the normal habituation torepeated stimuli,39 which is a phenomenon also foundin animals treated with LoS.D.,40 a drug which in smalldoses stimulates 5-H.T. receptors. 20 It has been

suggested 36 that the 5-H.T. system antagonises thebehavioural effects of dopaminergic and noradrenergicsystems, reminding one of the earlier theories 41 oftrophotrophic and ergotrophic systems in brain withopposing functions. The results of these experimentallesions or stimulation of particular systems leadto the exhibition of fragments of behaviour and notto complex behaviour patterns which might beconsidered to be examples of adaptive behaviour

expected in the normal environment. However, thesefragments may be the building blocks ofmore complex adaptive reactions. McLean 42 hasreviewed the neuronal systems whose activity isassociated in animals with certain types of behayiour-namely, social behaviour, aggressive /submissive be-haviour, sexual behaviour, and oral behaviour. Theseneurons form, in particular, part of the lymbic systemand seem to be identical to the amine-mediated path-ways described above.

In ManWe can now attempt to examine the problems of

relating the activity of neuronal systems to what weunderstand as " mood " in man. In general, moodis regulated so that it is syntonic with environmentalevents and pressures, as they are assessed in terms ofprevious experience. In man, it seems that the label" mood change " is used to cover complex subjectiveand objectively observed changes in the organism.The components of mood response include a subjectivefeeling state, cognitive changes with appropriatecolouring of thought content, behavioural changes,and changes in the state of arousal. The feeling stateand cognitive aspects can only be examined in manbecause he is the only species to communicate feelingsby language. It seems likely, however, that certainof the behavioural and autonomic changes may havemuch in common in man and other species. In

animals, as we have seen above, there is evidence

linking behavioural components of the mood responsewith activity in specific subcortical and limbic neuronalsystems. If it is possible to make valid behaviouralcomparisons between the behaviour of animals sub-jected to stimulation or lesions in specific systems andhumans with affective illness, then we may be advanc-ing to a position where we can draw conclusions aboutthe basic mechanisms by which behavioural com-ponents of the affective disorders are mediated. Thisis not to claim that we would be any nearer the causeof depression and mania-we would merely be

examining the mechanisms by which some aspects ofmood are expressed.The development of complete mood response must

involve many stages and many neuronal systems. Wesuggest that the results of animal experiments relatingtransmission and metabolism in amine-containingneuronal systems may indicate the mechanisms by

576

which function may be disrupted in similar systems inman. Whilst experiments comparable to those donein animals are impossible in man, we believe thatcircumstantial evidence permits certain tentativeconclusions regarding the state of the aminergicsystems in affective illness.

EVIDENCE IN MAN FOR ROLE OF AMINE-

CONTAINING SYSTEMS IN AFFECTIVE ILLNESS

Exploratory and Stereotyped Behaviour in Depression andMania

We would postulate that changes in exploratory andstereotyped behaviour patterns are seen in both depressionand hypomania. Changes in exploratory behaviour areseen as a change in the overall activity level of these patients.Changes in the stream of mental activity can also be seenin these terms, thus in mania there is often a constantlychanging stream of mental activity. In depression, there isa lack of exploration both in motor and mental activity.Stereotyped motor activity and stereotyped thinking may,however, be accentuated in depression, particularly in so-called agitated depression.

In mania, stereotyped activity may also be an importantcomponent of the clinical picture-most psychiatrists willrecall a manic patient rummaging through drawers forhours or days at a time, apparently without purpose. Whilstin most manic patients a combination of exploratory andstereotyped activities make up the clinical state, in others,one or other can predominate. We are struck by thesimilarity between this situation and the effects noted onamphetamine administration to both animals and man.Here both increase in exploratory and stereotyped behaviourpatterns are reported. In animal studies it has been

postulated that the increase in exploration results fromstimulation of noradrenergic systems 36 whilst increase instereotyped behaviour patterns results from stimulation ofdopaminergic systems.33 If this difference were to operatealso in man, the varying proportions of exploratory andstereotyped activity in mania might be related to varyingactivities of these two systems.

In addition to complex stereotypes, other simpler stereo-types can also be observed in patients with affective illness.Chewing, mouthing, tongue-protruding movements are

seen in many patients with bipolar affective illness. Theyresemble the faciobuccal dyskinesias reported in otherconditions (e.g., some parkinsonian patients treated withlevodopa 43). The movements come and go at particulartimes in the cycle of affective illness, recurring at the samephase in subsequent cycles, and they seem unrelated todrug treatment. The movements are identical with thoseseen in amphetamine addicts 44 and similar to those seenin animals treated with large doses of this drug, where theyare attributed to stimulation of dopaminergic systems.26By analogy we might argue that stimulation of dopaminergicsystems occurs at certain stages in a bipolar affective illness.

Paradoxical Response to Drug TherapyIn the treatment of mania with haloperidol or pheno-

thiazines, we find that as long as the underlying maniapersists then motor side-effects of drug therapy do notdevelop and large doses of the drugs can be used becausetolerance is high. Suddenly during treatment patients maydevelop symptoms of parkinsonism and akathisia, and whenthey do so withdrawal of the drug or reduction of doseinvariably reveals a remission or alleviation of the mania.This suggests that a fundamental change in sensitivity ofthese motor systems is present in mania which disappearscoincidentally with remission of the mania. A change inpostsynaptic receptor sensitivity might be consistent withthese findings.

A basic change in receptor sensitivity might be invokedto explain variations in response to other drugs both inanimals and man. Ungerstedt 26 notes that the adminis-tration of 6-hydroxydopamine destroys the dopaminergicsystems in rat brain and this is followed by the developmentof supersensitivity of postsynaptic receptors to apomorphineand levodopa. He suggests that some parkinsonian patientsshow dyskinetic side-effects on levodopa because of asimilar type of receptor supersensitivity.Some hyperkinetic children show a reduction in hyper-

kinesia and an improvement in behaviour when treatedwith small doses of amphetamine.45 Paradoxically, insome patients single doses of amphetamine provoke anincrease in hyperkinesia 46 and the development of severefaciobuccal dyskinesias usually seen only with much higherdoses of the drug. These findings would be consistent withthe hypothesis that hyperkinesia in some children is dueto a specific overactivity of dopaminergic systems resultingfrom a supersensitivity of postsynaptic receptors. Thismight lead to a sensitivity to the administration of amphet-amine in a single dose, but continued administration of smalldoses might lead to a suppression of receptor sensitivity asa result of constant low-level stimulation.

If this type of therapy is considered logical in the hyper-kinetic child, then a similar reasoning might also be appliedto the management of rare cases of recurrent mania. Inthese patients we might postulate recurrent episodes ofincrease in receptor sensitivity in one or more amine-containing systems. If our hypothesis regarding the modeof action of amphetamine in hyperkinetic children is correct,then the administration of small doses of this drug to patientswith recurrent mania may suppress receptor sensitivity,at least in dopaminergic systems and control manic episodes.Suitable cases resistant to other treatments are rare. Thereis, however, a report of treatment of mania in this way,"and we can confirm the effect in one case.

Lithium TreatmentOne might also re-examine the role of lithium in bipolar

affective illness from the standpoint of it influencing,perhaps stabilising, the sensitivity of amine-containingsystems. U’Prichard and Steinberg 48 have reported thatlithium will block certain types of behaviour induced by amixture of chlordiazepoxide and amphetamines in rats

which they have advanced as an animal model for mania.This action is interesting in view of our suggestions aboutthe relation between certain aspects of animal behaviour,induced behaviour, and components of the manic response.Lithium might reduce the availability of amine at the recep-tor by promoting ion-mediated re-uptake into nerve

terminals.

CONCLUSIONS

We suggest that animal studies may give a lead tothe identification of neuronal systems which are

involved in the mediation of patterns of behaviourseen during " mood responses " and in affective illnessin man. These behaviour patterns include changesin motor behaviour, aggressive/submissive patterns ofbehaviour, and changes in social and sexual behaviourpatterns. The motor patterns seen in animal experi-ments during stimulation of amine-containing systemsmay represent non-adaptive " components " or " frag-ments " of these more complex behaviours. We haveattempted to equate the neuronal systems involvedwith the limbic and brainstem systems described byMcLean and others, in some of which transmission,in at least one synapse, may be mediated by one orother of the biogenic amines.We have argued that in depression and mania there

577

will be changes in one or more of these systems andthat the resulting behaviour modifications can beobserved. The change in function and activity in theneuronal systems may result from a changed appraisalof the environmental situation dependent on highercortical systems, in which case the changes are to befound in input and output into the aminergic systemswithout any primary change in their sensitivity. Inthe case of depressive illness, this may be reflected inlow output of amine transmitters and in low levels ofone or more amine metabolites in C.S.F.

Change in function in aminergic systems may, how-ever, result from a change in sensitivity or thresholdsetting, possibly as a result of a change in postsynapticreceptor sensitivity. In depression, this would involvea fall of sensitivity in one or more groups of amine-mediated synapses with, at least initially, normal trans-mitter output and normal C.S.F. amine metabolite levels.The conclusion we would draw in relation to

depression is that both low output of amine trans-mitters (low-output depression) and low sensitivity ofamine receptors (low-sensitivity depression) may giverise to a similar clinical picture. Our preliminaryresults suggest that the clinical division into unipolarand bipolar depression might parallel such a classi-fication.A similar subdivision into high output and high

sensitivity mania does not yet emerge from the clinicaldata, but certainly this is susceptible to further testing.A consideration of the interactions between trans-

mitter output and receptor sensitivity lead us to certainconclusions regarding recovery from depression andmania. Recovery from depression may involve a risein receptor sensitivity or a rise in transmitter output,or both. The possibility for an " overswing " infunctional activity is present both in low output andlow sensitivity depression, but we might postulatethat a normal functioning of control mechanisms forreceptor sensitivity would rapidly restore this in

unipolar cases. If the hom&oelig;ostatic mechanisms for thesetting of receptor sensitivity are at fault in bipolarcases, then overswing to mania may occur.Secondary changes in transmitter output may

follow the primary changes in receptor sensitivity inbipolar affective illness, making the interpretation ofc.s.F. metabolite levels difficult.We would state our modified amine hypothesis as

follows:

The activities of amine-mediated synapses in brain aremodified in affective illness either as a result of alteredinput into the neuronal systems from other centres or as aresult of altered sensitivity of the postsynaptic receptors.

It will be the balance between transmitter availability atthe receptor and receptor sensitivity which will determinethe functional state of the systems. We would also postulatethat one or more of the amine-mediated systems may beimplicated and that the pattern of involvement of thesystems will be important in determining the characteristicpattern of behaviour and autonomic components comprisingthe clinical picture.

Functional recovery of these systems in depression willfollow either a rise in receptor sensitivity or a rise intransmitter output or both. True functional restoration ofthe systems will however, occur only when both trans-mitter output and receptor sensitivity and the reactivity ofthe system to incoming stimuli are all restored to normal.

To test this hypothesis further we must develop tests ofneuronal sensitivity in man. In addition, we must re-examine our therapies to consider effects on postsynapticas well as presynaptic events. A search for methods of

influencing receptor sensitivity may be of value, in particular,methods for stabilising these mechanisms.

None of these techniques will provide a treatmentfor depression-a complex human reaction. All theymay be expected to do is to restore the integrity ofthe behavioural systems to respond to the environmentas assessed by the individual.

Requests for reprints should be addressed to G. W. A.

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