Brain dopamine and behaviour

J. psychiat.Res., 1974,Vol. 11.pp. 163-172. PergamonPress.Printedin GreatBritain.

BRAIN DOPAMINE A CRITICAL ANALYSIS DOPAMINE

AND BEHAVIOUR

OF THE RELATIONSHIP BETWEEN

ANTAGONISM

AND THERAPEUTIC

EFFICACY

OF NEUROLEPTIC DRUGS* T. J. CROW and C. GILLBE Division of Psychiatry, M.R.C. Clinical Research Centre, Northwick Park Hospital, Watford Road Harrow, London, HA1 3uj, England THE VALUE of phenothiazine medication in schizophrenia is well established, both in acute illness (COLE et ~~1.3and in relapse prevention (ENGELHARDTet d2; LEFF and WINGS: HIRSCH et aZ.*). Some phenothiazines, e.g., promazine and mepazine, are generally reported as less effective than others (DAVIS?, and neither barbiturate (CASEY et al.? nor lithium (JOHNSON et aZ.7) administration can reproduce the beneficial effects of the most commonly-used compounds. The wide range of symptoms ameliorated by these drugs suggests that they do more than merely suppress abnormal behaviours, and may in some way modify the underlying pathological process (GOLDBERG et aL3), Therefore the therapeutic efficacy of the phenothiazines may be an important lead toward the pathophysiology of these diseases. Following the observation that phenothiazines can cause Parkinsonism (DELAY and DENIKER~), the hypothesis was advanced that this peculiarity is an essential concomitant lo; DENIKER~~; HAASE~~). The clinical evidence for and of therapeutic efficacy (FL~~GEL against this hypothesis has been reviewed (COLE and CLYDE~~; BISHOP et aZ.14; CHIEN and DI MASCIO~~; SIMPSON and ANGUS~~).More recently with increasing evidence for an impairment of dopaminergic transmission in Parkinson’s disease it has been proposed that the extrapyramidal effects of the phenothiazines are related to the ability of these drugs to block dopamine receptors (HORNYKIEWICZ~~). Thus it appears possible that the therapeutic efficacy of these drugs in schizophrenia may also be attributable to dopamine receptor blockade (VANRossu~~s; HORN and SNYDER~~).

DOPAMINE AND BEHAVIOUB A conceptual obstacle to this hypothesis may have been the feeling that extrapyramidal effects lie in the field of motor control and therefore are unlikely to be related to the complex mental functions which bear the main impact of the schizophrenic process. However, there is much evidence from animal studies to suggest that the dopamine-containing neurones play a more subtle and pervasive role in behavioural control than might be predicted from observations

of the akinesia

of Parkinson’s

disease.

* Supported by Grant No.-968/301/R from the U.K. Medical Research Council and a grant from the Mental Health Research Fund. 163

164

T. J. CROW and C. GILLBE

Three separate behavioural findings bear on the function of cerebral dopamine: (1) Repetitive sniffing, licking and gnawing results from administration of relatively large (2 mg/kg. or more) doses of amphetamine, and can be abolished by administration of a-methyl-p-tyrosine, which inhibits catecholamine synthesis, but not by drugs which inhibit dopamine+hydroxylase, and deplete noradrenaline alone (MUNKVAD et ~~1.20). Such stereotyped behaviours are also abolished by extensive destruction of the nigr-striatal dopamine pathway produced by injections of 6-OH-dopamine into the substantia nigra (CREESEand IICERSEN~~). These observations support the contention (RANDRUP and SCHBEL-KR~IGER~~; S~HEEL-KRUGER and RANDRUP23 that the syndrome of repetitive sniffing, licking and gnawing behaviour reflects overactivity of central dopaminergic mechanisms. (2) Interruption of the nigro-striatal pathway, either by electro-coagulative or ~-OHdopamine-induced lesions, if extensive and bilateral, results in a syndrome of akinesia, aphagia and adipsia (UNGERSTEDT~~).This constellation of behavioural changes closely resembles the well-known “lateral hypothalamic syndrome” (ANAND and BROBECK~~ ; TEITELBAUMand EPSTEIN~~),and it is likely that many of the earlier lesions interrupted nigro-striatal

fibres in their course through the lateral hypothalamus

the

(UNGERSTEDT~~).

(3) Electrical stimulation through electrode tips implanted close to the cell-bodies of the dopamine-containing neurones in the ventral mesencephalon (A9 and A10 areas of DAHLSTRSM and FI_I~E~~)causes increased the sniffing, licking, gnawing syndrome

forward

described

locomotor

activity

and elements

of

by RANDRUP and MUNKVAD (ANLEZARK

et cd.,28 CROWER). Such electrodes will also support self-stimulation responding

and it has been argued (CROW~O) that the dopamine-containing

neurones

(CROWER),

arising from

the ventral mesencephalon are one of two catecholamine systems involved in this behaviour, the other being the coerulo-cortical norepinephrine pathway. Dopaminergic involvement is supported

by recent observations

and on the association nigro-striatal

on electrode

of self-stimulation

sites in the A10 region (ANLEZARK et ~1.31)

with behaviours

resulting from activation

of the

pathway (CHRISTIE et ak32).

On the basis of these three pieces of evidence of the role of dopaminergic

mechanisms

one can attempt to synthesise a concept

in overall behavioural

control.

Firstly, whatever

may be happening at a cellular level, it is clear that the gross effects of the system on motor behaviour are facilitatory. Decreased function, as in Parkinson’s disease, results in hypokinesis,

and when extreme,

as in the case of complete

bilateral

nigro-striatal

lesions in

animals, in akinesia with aphagia and adipsia. Conversely increased dopaminergic activity, whether induced by amphetamine or electrical stimulation, is associated with increased motor activity, although the range of the activities engaged in becomes increasingly circumscribed as the activity of the system increases beyond normal levels.

more

Secondly, the specific behaviours which do appear are those which might be described as “appetitive” in the sense that they are directly concerned with searching-out and ingesting food. Thirdly, to judge from the evidence of the self-stimulation experiments, activity of dopaminergic

mechanisms

is “rewarding”

in the sense that, given the choice,

the animal will choose more rather than less. Thus it appears that the ventral mesencephalic dopamine system functions as a mechanism facilitating motor, particularly appetitive, behaviours, and may mediate some effects of rewarding stimuli on performance. Some behavioural theorists have suggested the existence

DOP~MINERGIC HYPERACTIVI~V AND SCHIZOPHRENIA of such a mechanism. MILLER~~ speaks of “a ‘go’ or ‘activating’

165

mechanism . . . which act.5

to intensify ongoing responses to cues . . . , producing a stronger intensification the more strongly the ‘go mechanism’ is activated.” SHEFFIELD~~postulates a ‘drive induction’ system whereby the motivating

effects of reward get channeled into instrumental acts, a

system which “increases skeletal tonicity and feeds into whatever skeletal responses are being executed at the moment.”

What we know of the dopamine

system might fit well

with these hypotheses. An important question is whether or not it is correct to speak of a single dopaminergic system arising from the ventral mesencephalon. It is true that whereas fibres from the A8 and A9 areas are distributed to the corpus striatum, those from the A10 area (the mid-line region

over the interpeduncular

olfactorium,

nucleus) innervate the nucleus accumbens, tuberculum

and nucleus interstitialis of the stria terminalis (UNGERSTEDT~~). However,

it is clear from histochemical

studies of the cell body areas (DAHLSTX~M and FuxE~‘;

UNGERSTEDT~~;ARBUTHNOTT, unpublished) that the AX, A9 and A10 areas are not discrete nuclei but a continuous sheet of cells extending across the midline at the level of the interpeduncular nucleus out into the pars compacta of the substantia nigra (A9 area) and beyond this caudally (A8 area). Moreover the effects of electrical stimulation in the A9 and A10 areas, at least, are closely related, with the single and obvious exception that contraversive

turning cannot

be elicited from the mid-line A10 area. It seems entirely possible, therefore, that although the terminals are distributed to a number of prosencephalic structures, the system functions as a single unit. The afferent connexions of the dopamine neurones pose a problem which as yet has attracted little attention. Although there is no known direct connection between the interpeduncular nucleus and the ventral mesencephalic dopamine cell bodies, there is a striking anatomical relationship between these structures, the latter encircling the former. HERRICK~~ emphasised the olfactory connexions of the interpeduncular nucleus and conceived this structure as a centre for integrating various visceral and somatic afferent influences, particularly

those concerned with feeding reactions, and transmitting their effects to the

strio-penduncular-bulbar

motor systems. Both HERRICK~’ and SWERRINGTON~~have drawn

attention to the singular position of the olfactory teroceptor

concerned with the environment,

modality,

as, on the one hand an ex-

and, on the other hand, as a modality

con-

cerned primarily with the ingestion of food, with some of the characteristics of a visceroceptor. The primary function of olfaction,

according to these authors, is to activate the

organism toward possible environmental sources of food, and, from the evidence reviewed, it seems entirely conceivable that this function is performed by activation of the mesencephalic dopamine system. The hypothesis has been proposed therefore that the dopamine neurones are phylogenetically

related to olfactory

pathways but have developed

mechanism whereby diverse sensory stimuli exert their activating effects on behaviour (CROWER). DOPAMINERGIC The view that dopaminergic

OVERACTIVITY overactivity

into a

or “drive-inducing”

AND SCIIIZOPHRENIA

might underly some phenomena of the schizo-

phrenias has been based upon similarities between the features of amphetamine psychosis

T. J. CROW and C. GILLBE

166

(CONNELL40; GRIFFITH et ai43 and observations and paranoid schizophrenia that some, at least, of the behavioural actions of the amphetamines are dependent upon central dopamine release (RANDRUP and SCHEEL-KR‘~~GER~~; RANDRUP and JoNAs~~). Much of the work relevant to this hypothesis has been conducted by RANDRuP et al., (see reviews by RANDRUP and MUNKVAD~~; MUNKVAD et aZ.20 and FAURBYE,~~). The hypothesis has been elaborated by RANDRUP and MUNKVAD~~ and other authors (e.g. see KETY and MATTHWSE~~; SNYDER~?). One might suppose that this hypothesis would encounter perimental work relevant to the behavioural role of cerebral and

“drive”

are unusual

features

of schizophrenic

problems in some of the exdopamine. Increased activity

behaviour

and their

opposites

are

commonplace. The schizophrenic experience is seldom reported as pleasurable. As against this one need not interpret self-stimulation behaviour as indicating that pleasurable subjective

sensations

have been elicited,

that the organism itself is common

but merely that the systems involved

will repeat the behaviour in some schizophrenic

that an inappropriate

increase

becomes

illnesses.

increasingly

activity

actually

doses of amphetamine,

stereotyped,

have the effect

Repetitive

One must also consider

in dopaminergic

directed motor activity. With increasing behaviour

leading to the stimulus.

and other

results

in a decrease

for instance,

adaptive

behaviour

the possibility in

the organism’s

behaviours

may be ex-

cluded (LYON and RANDRUP~~). It is not inconceivable system

might

In this

context

account

therefore for

it is also

some

that

excessively

behavioural

interesting

that

some

KORNETSKY and MIRSKY~O) have formulated dysfunction. VENABLES and WING measured indices

of “arousal”

and degree

of social

MIRSKY ascribed subjects

and found a positive withdrawal

certain

differences

to phenothiazine

authors

(e.g.

VENABLES and

between increasing

schizophrenic

in the susceptibility

and barbiturate

of the dopaminergic

of schizophrenic

illnesses. WINGED;

“over-arousal” theories of schizophrenic two-flash threshold and skin potential as

correlation

in long-stay

high activity

characteristics

administration

patients;

levels of arousal KORNETSKY and

of schizophrenic

and normal

to a high level of arousal

in the

patients. The concept of physiological “arousal” is somewhat ill-defined, particularly in behavioural terms. Much earlier theorising no doubt will be replaced by more precise concepts to account

for the functions

to exist within the general that many particularly

region

of the neurohumorally of the brainstem

reticular

specific

systems

formation.

now known

It. seems possible

of the behavioural effects previously attributed to the reticular formation, those which can be antagonised by the phenothiazines (e.g. KORNETSKY and

ELIA~SON~~)have been due to activity induced in the dopaminergic

system.

DRUG ACTION ON DOPAMINE NEURONES Rats with unilateral lesions of the nigro-striatal pathway (ANDI?N~~) can be used to provide a direct behavioural index of drug action on central dopamine neurones. After recovering from the lesioning operation such rats show normal locomotion and have no striking asymmetries. towards the lesioned explanation

If given amphetamine side, and this turning

put forward

1 mg/kg or more they begin to turn in circles persists for the duration of drug action. The

is that this behaviour

reflects the unopposed

release of dopamine

DOPAMINERGIC HYPERACTIVITY ANDSC~~OPHRENIA

167

from terminals of the nigro-striatal pathway on the intact side. This hypothesis is supported by the following observations : (i) Turning occurs only in those cases where the lesion is so sited that nigro-striatal fibres are interrupted (CROW53). (ii) Turning after amphetamine administration is seen not only following electrolytic lesions but also when nigro-striatal degeneration is induced by intracerebral injections of 6-OH dopamine (UNGERSTEDT~~). (iii) Somewhat similar turning behaviour can be induced by stimulation through electrodes implanted in the region of the nigro-striatal fibres (ARBUTHNOTTand CROWER).Such stimulation presumably causes increased activity in one nigro-striatal tract and thus an imbalance in dopamine release on the two sides. (iv) Such electrically-induced turning occurs awayfrom the stimulated side. When electrolytic lesions are made through these implanted electrodes, turning is no longer elicited by stimulation, but after amphetamine the animals turn towards the lesioned side. Subsequent histochemical examination reveals dopamine depletion in the ipsilateral corpus striatum (ARBUTHNOTT and (30~~~). (v) Turning behaviour can be abolished by administration of tyrosine hydroxylase, but not of dopamine-&oxidase, inhibitors (UNGERSTEDT~~;CHRISTIEand CROWER). These observations strongly support the hypothesis that turning reflects unilateral release of dopamine from the terminals of the nigro-striatal pathway. Like the sniffing, licking and gnawing behaviours turning can be inhibited by neuroleptic administration, and this inhibition can be distinguished from a general reduction of motor activity (CHRISTIEand CROWER). DOPAMINE ANTAGONISM AND ANTISCHIZOPHRENIC POTENCY Using turning behaviour as an index of dopaminergic activity we attempted to assess the hypothesis that dopamine receptor blockade underlies the therapeutic efficacy of the phenothiazines in schizophrenia. We selected two drugs, chlorpromazine and thioridazine, which in a large comparative trial (COLEet al.l) were shown to be equipotent in diminishing a wide range of schizophrenic symptoms. Thioridazine, nonetheless, has a reputation for producing fewer extra-pyramidal side effects (COLE and CLYDE~~;DAVIS~) and in biochemical studies (LAVERTYand SHARMAN 57; O’KEEFE et ~1.~~)has less influence on cerebral dopamine turnover than has chlorpromazine. We examined the effects of chlorpromazine and thioridazine in doses of 1, 2, 4 and 8 mg/kg on the turning induced by methylamphetamine sulphate 5 mg/kg, and on spontaneous motor activity, assessed directly before methylamphetamine administration in an open field apparatus (squares 40 x 40 cm). The phenothiazines were administered 180 min before methylamphetamine in a balanced experimental design in which sessions were separated by at least a week. Spontaneous motor activity was reduced following chlorpromazine 4 and 8 mg/kg, and even more following thioridazine (Fig. 1). The situation was reversed in the case of turning behaviour (Fig. 2). Chlorpromazine 4 and 8 mg/kg significantly reduced turning but the same doses of thioridazine had no such effect.

T. J. CROW and C. GILLBE

168

Exploratory I-

_-

activity

-------------__--

*

1 h

.E

20

-

‘3

I

”

<-

2

4

Thioridozine,

8

I

mglkg

2

4

Chlorpromazine,

8 mg/kg

BIG. 1. Spontaneous motor activity, measured as number of entries into squares of an open field apparatus 180 min after neuroleptic administration expressed as a percentage of activity before drug administration. (*p < 0.005: t p < @OOl) Modified from CROW, T. J. and GILLBE, C. Nature 245,27,1973. 30 -

A Saline .e CPZ 4 m CPZ 8

mg/kg mg/kg

6

.E f 20 .

E

3

0

1802iO 270 I

CPZ Thio or Saline

420 min

MA

FIG. 2. Turning behaviour induced in rats with unilateral nigrostriatal lesions by methylamphetamine HCl (MA) 5 mg/kg administered 180 min after pre-treatment with 4 or 8 mg/kg of chlorpromazine. (a) or thioridazine (b), compared to saline. Bars & S.E.M. Modified from CROW, T. J. and GILLBE, C. Nature 245,27, 1973.

DOPAMINERGIC HY~ERACITVITY ANII SCHIZOPHRENIA

169

These results showed a marked discrepancy between the dopamine receptor blocking activities of these two drugs. Since thioridazine reduced spontaneous motor activity to at least as great an extent as chlorpromazine at the time (180 min after administration) when dopamine blockade was absent it can hardly be argued that differences in timecourse of action account for the discrepancy. On the contrary it appears that there must be a genuine and quantitatively significant difference in the ability of these two drugs to antagonise dopaminergic activity. When these results are taken in conjunction with the clinical evidence (COLE et cdl; DAVIS~) that chlorpromazine and thioridazine are equipotent in their therapeutic effects in schizophrenic illnesses, the conclusion appears probable that dopamine receptor blockade cannot account for the efficacy of the neuroleptic drugs. A possible escape from this conclusion is to postulate that in chronic administration in man a metabolite of thioridazine accumulates which has greater dopamine receptor blocking potency and lesser effects on motor activity than the parent compound. It should be noted however that in the experiments of LAVERTYand SHARMAN~’and O’KEEFE,58et al., the differences between the actions of chlorpromazine and thioridazine on dopamine turnover in the corpus striatum were greater after repeated administration over a period of 14 days than after single doses. SUMMARY

Recent evidence is summarised concerning the functional role of the system of dopaminecontaining neurones arising from the ventral mesencephalon. On the basis of the histochemical evidence and the effects of electrical stimulation it is suggested that the entire system of fibres arising from the A8, A9 and A10 areas of DAHLSTR~M and FUXE may function as a single unit. In rats increased activity in this system, induced by amphetamine-like drugs or by electrical stimulation, results in the inappropriate emergence, and stereotyped repetitive performance, of “appetitive” behaviours. Decreased activity of the same system, caused by electrolytic or 6-OH dopamine-induced lesions, is associated with a syndrome of severe akinesia, aphagia and adipsia (similar, if not identical, to the previously described “lateral hypothalamic syndrome”). Some evidence from self-stimulation experiments suggests that in certain circumstances the organism will act to increase its own level of dopaminergic activity. The hypothesis is proposed that the dopamine system functions as a mechanism which mediates some of the effects of positively-rewarding stimuli on the organism’s behaviour, particularly, in iower mammals at least, those effects concerned directly with obtaining and ingesting food. It is suggested that the system transmits to the motor apparatus those aspects of teloreceptor stimulation which orientate and energise the organism’s responses toward, and thereby maximise the probability of, consummatory reward. The hypothesis that dopaminergic overactivity or “hyper-arousal” underlies some components of schizophrenic dysfunction provides a possible explanation of the mode of action of neuroleptic drugs. However using amphetamine-induced turning in rats with nigro-striatal lesions as an index of dopaminergic activity it has been shown that there is a wide quantitative discrepancy between the ability of chlorpromazine and thioridazine, 13

170

T. J. CROW and C. GILLBE

drugs which are equally efficacious in schizophrenia, to antagonise central dopaminergic transmission. It is suggested that comparisons of the effects of these two drugs on central dopaminergic mechanisms provide a critical test of the dopamine receptor blockade hypothesis of neuroleptic action, and that the behavioural and biochemical evidence at present available is inconsistent with this hypothesis. REFERENCES

1. COLE, J. 0. et. al. Phenothiazine treatment in acute schizophrenia. Archs gen. Psychiat. 10,246, 1964. 2. ENGELHARDT,D. M., FREEDMAN,N., GLICK, B. S., HANKOFF, L. D., MANN, D. and MARGOLIS,R. Prevention of psychiatric hospitalisation with use of psychopharmacological agents. J. Am. Med. Ass. 173, 147, 1960. 3. LEFF, J. P. and WING, J. K. Trial of maintenance therapy in schizophrenia. Br. Med. J. 3, 599, 1971. 4. HIRSCH, S. R., GAIND, R., ROHDE, P. D., STEVENS,B. C. and WING, J. K. Outpatient maintenance of chronic schizophrenic patients with long-acting fluphenazine: double-blind placebo trial. Br. Med. J. i, 633, 1973. DAVIS, J. M. Efficacy of tranquillizing and antidepressant drugs. Archsgen. Psychiat. 13, 552, 1965. CASEY,J. F., LASKY,J. J., KLETT, 6. J. and HOLLISTER,L. E. Treatment of schizophrenic reactions with phenothiazine derivatives : a comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazine, perphenazine and phenobarbital. Am. J. Psychiat. 117,97, 1960. 7. JOHNSON,G., GERSHON,S., and HEKIMIAN,L. J. Controlled evaluation of lithium and chlorpromazine in the treatment of manic states: an interim report. Camp. Psychiat. 9, 563, 1968. 8. GOLDBERG,S. C., KL.ERMAN,G. L. and COLE, J. 0. Changes in schizophrenic psychopathology and ward behaviour as a function of phenothiazine treatment. Br. J. Psychiat. 111, 120, 1965. 9. DELAY,J. F. and DENIKER,P. Trente-huit cas de psychoses trait&es par la cure prolong&e et continue de 4560 R.P. In: C.R. due Congres des Al. et Mew-01de Langue Fr., Masson et Cie, Paris, 1952. 10. FL~GEL, F. Therapeutique par medication neuroleptiques obtenue en realisant systematiquement des etats Parkinsoniformes. L’Enc&phale 45, 1090, 1956. 11. DENIKER, P. Experimental neurological syndromes and the new drug therapies in psychiatry. Comp. Psychiat. 1, 92, 1960. 12. HAASE,J. H. Extrapyramidal modification of fine movements-a “conditio sine qua non” of fundamental therapeutic action of neuroleptic drugs. Rev. Can. Biol. 20,425, 1961. 13. COLE, J. 0. and CLYDE,D. J. Extrapyramidal side effects and clinical response to the phenothiazines. Rev. Can. Biol. 20, 565, 1961. 14. BISHOP,M. P., GALLANT,D. M. and SYKES,T. F. Extrapyramidal side effects and therapeutic response Archs gen. Fsychiat. 13, 155, 1965. 15. CHIEN, C. P. and DI MASCIO,A. Drug-induced extrapyramidal symptoms and their relations to clinical efficacy. Am. J. Psychiat. 123, 1490, 1967. 16. SIMPSON,6. M. and ANGUS, J. W. S. Drug induced extrapyramidal disorders. Acta. psychiat. stand. suppl. 212, 1, 1970. and brain function. Pharmac. Rev. I&, 925, 1966. 17. HORNYKIEWICZ,0. Dopamine (3-hydroxytyramine) blockade for the mechanism of action of 18. VAN ROSSUM,J. M. The significance of dopamine-receptor neuroleptic drugs. Archs int. Pharmacodyn. Ther. 160,492, 1966. 19. HORN, A. S. and SNYDER,S. H. Chlorpromazine and dopamine: conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs. Proc. natn. Acad. Sci., U.S.A. 68,2325,1971. 20. MUNKVAD,I., PAKKENEZRG,H. and RAND~U~, A. Aminergic systems in basal ganglia associated with stereotyped hyperactive behaviour and catalepsy. Brain, Behav. Evol. 1, 89, 1968. 21. CHEESE, I. and IVERSEN,S. D. Amphetamine response in rat after dopamine neurone destruction. Nature. 238,247, 1972. and amphetamine stereotyped behaviour. 22. RANDRW, A. and SCHEEL-KRUGER,J. Diethyldithiocarbamate J. Fharm. Pharmac. 18,752,1966. J. and RANDRUP, A. Stereotype hyperactive behaviour produced by dopamine in 23. SCHEEL-KRUEGER, the absence of noradrenaline. Life Sci. 6, 1389, 1967. induced degeneration of the nigro24. UNGERSTEDT,U. Adipsia and aphagia after 6-hydroxydopamine striatal dopamine system. Acid. physiol. stand. 82 (suppl. 367) 95, 1971c. 25. ANAND, B. K.and BROBECK,J. R. Hypothalamic control of food intake in rats and cats. Yale J. biol. Med. 24, 123, 1951.

DOPAMMERGICHYPERACTIVITY AND SCHIZOPHRENIA

171

26. TEITELBAUM, P. and EPSTEIN,A. N. The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Physiol. Rev. 69, 74, 1962. 27. DAHLSTR~M,A. and FUXE, K. Evidence for the existence of mono-amine containing neurones in the central nervous system-I. Demonstration of mono-amines in the cell bodies of brain stem neurones. Acta. physiol stand. 62 (suppl. 232) 1, 1965. 28. ANLEZARK,G. M., A~BUTHNO’IT,G. W., CHRISTIE,J. E. and CROW, T. J. Role of cerebral dopamine in the action of psychotropic drugs. Br. J. Pharmac. 41,406 P, 1971. 29. CROW. T. J. A man of the rat mesencephalon for electrical self-stimulation. Brain Res. 36, 265, 1972a. neurones and electrical self-stimulation-I. A review of some 30. CROW; T. J. Catecholamine-containing data. Psychol. Med. 2,414,1972. 31. ANLEZARK,G. M., ARBUTHNOTT,G. W., CHRISTIE,J. E. and CROW, T. J. Electrical self-stimulation with electrodes in the region of the interpeduncular nucleus. J. Physiol. 234, 103 P, 1973. 32. CHRISTIE,J. E., UNGERSTEDT,U. and LJUNGBERG,T. Dopamine neurones and electrical self-stimulation in the lateral hypothalamus. J. Physiol. 234, 80 P, 1973. 33. MILLER, N. E. Some reflections on the law of effect produce a new alternative to drive reduction. In: Nebraska Symp. on Motivation, JONESM. R. (Editor) pp. 65-112. University of Nebraska Press, Lincoln.. 1963. 34. SHEFFIELD,‘F.D. New evidence on the drive-induction theory of reinforcement. In: Current Research in Motivation. HAEZR, R. N. (Editor) pp. 111-122, Holt, Rhinehart and Winston, New York, 1966. 35. UNGERSTEDT,U. Stereotaxic mapping of the monoamine pathways in the rat brain. Actu physiol. stand. 82, (suppl. 367) 1, 1971a. 36. HERRICK, C. J. The Brain of the Tiger Salamander. Ambystoma Tigrinum. University of Chicago Press, Chicago, 1948. 37. HIERRICK, C. J. On the phybgenetic differentiation of the organs of smell and taste. J. camp. Neural. 18,157, 1908. C. S. The Integrative Action of the Nervous System. Yale University Press, New Haven, 38. SHERRINGTON, 1906. neurones and electrical self-stimulation-II. A theoretical 39. CROW, T. J. Catecholamine-containing interpretation and some psychiatric implications. Psychol. Med. 3, 66, 1973. 40. CONNELL,P. H. Amphetamine Psychosis. Chapman & Hall, London, 1958. evaluation of psychoto41. GRIFFITH,J. D., CAVANAUGH,J. HELD, J. and OATES,J. A. Dextroamphetamine: mimetic wroverties in man. Archs pen. Psvchiat. 26.97, 1972. interaction. J. Phurm. 42. RANDRUP,‘A. &d JONAS, W. Brain”dopamine and the amphetamine-reserpine Pharmac. 19,483,1967. 43. RANDRUP, A. and MUNKVAD, I. Stereotyped activities produced by amphetamine in several animal species and man. Psychopharmacologia. 11,300,1967. 44.FAURBYE,A. The role of amines in the etiology of schizophrenia. Comp. Psychiat. 9,155, 1968. 45. RANDRUP. A. and MUNKVAD. I. Evidence indicatine an association between schizovhrenia and donaI I minergic hyperactivity in the brain. Orthomol. Ps$hiat. 1,2,1972. 46. KETY, S. S. and MATTHYSSE, S. (Editors). Prospects for research on schizophrenia. Neurosci. Res. Prog. Bull. 10,370, 1972. 47. SNYDER,S. H. Amphetamine psychosis: a “model” schizophrenia mediated by catecholamines. Am. J. Psych&. 130, 61, 1973. 48. LYON, M. and RANDRUP, A. The dose-response effect of amphetamine upon avoidance behaviour in the rat seen as a function of increasing stereotypy. Psychopharmacologia, 23, 334, 1972. 49.VENABLKS,P. H. and WING, J. K. Level of arousal and the subclassification of schizophrenia. Archs gen. Psychiat. 7, 114, 1962. 50. KORNETSKY,C. and M~RSKY,A. F. On certain psychopharmacological differences between schizophrenic and normal persons. Psychopharmacologia, 8, 309, 1966. 51. KORNETSKY,C. and ELIASSON,M. Reticular stimulation and chlorpromazine: an animal model of schizophrenic overarousal. Science, 165,1273, 1969. 52.ANDBN, N. E. On the function of the nigro-striatal dopamine pathway. In: Mechanisms of Release of Biogenic Amines. von EULER, U. S., ROSELLS. and UVNAS B. (Editors) pp. 357-359. Pergamon Press, Oxford, 1966. 53. CROW, T. J. The relationship between lesion site, dopamine neurones, and turning behaviour in the rat. Exp. Neurol. 32,247,1971. 54.UNGERSTEDT,U. Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour. Acta. physiol. scund. 82 (suppl. 367) 49, 1971b.

172

T. J. CROW and C.

GILLBE

55. ARBUTHNO~, G. W. and CROW, T. J. The relationship between turning behaviour and unilateral release of dopamine in the rat. Exp. Neurol. 30,484, 1971. 56. CHRISTIE,J. E. and CROW, T. J. Turning behaviour as an index of the action of amphetamines and ephedrines on central dopamine neurones. Er. J. Pharmac. 43,658,1971. 57. LAVERTY,R. and SHARMAN,D. F. Moditkation by drugs of the metabolism of 3,4_dihydroxyphenylethylamine, noradrenaline and 5-hydroxytryptamine in the brain. Br. J. Pharmac. 24, 759, 1965. 58. O’KEEFE, R., SHARMAN,D. F. and VOGT, M. Effect of drugs used in psychoses on cerebral dopamine metabolism. Br. J. Pharmac. 38, 287, 1970.