The Dextroamphetamine Response In

TITE DEXTROA}IPHElAMTNE RESPONSE IN EUMAN STIBJECTS: A

PSYCHot0GICAt, PSYCHOPLYSI0t0GICAL AND NEUROENDOCR INE STUDY.

by

David Jacobs, M.8., BS. F.R.A.N.Z.C.P

Department of PsychlaEry.

Unlversity of Adelaide.

September 1985

û.,¿c.t¿€¿ eL 2'{ - f -'-( 6 PART I

An lnvestlgatlon of the roles of the dopamlne and noradrenal fne pa thway s 1n dexÈroamphetamfne lnduced arou sa1 .

PART II.

The response of the neuroendocrfne syslem to dextroamphetamlne: effects of dopamlnerglc or noradrenerglc

b1 ockade .

PART III.

Dextroamphetamine lnduced arousal as a pharmacological model for nfld nania. TABLE OF CONTENTS

page General Introduction 1 PART 1 An Investígatfon of the Roles of the Dopamine and Noradrenallne Pathways in DextroampheEamlne Induced Arousal 6

Introduction 7

1. I. Introductlon 9

L.2. Amphetamine Arousal ln Humans 10

1.3. Central Catecholamíne Pathways 20 I,4 Prevlous Attempts Eo Eludídate the Role of the Dopamine and Noradrenallne Pathways in Arnphetamine Arousal 57

1.5. Receptor Blocking Drugs 62

Me thod s 67

1.6. InÈroduc t I on 68

t.7 . Subjects 70

1.8. Measurenent s 73 'to L.). Drugs Used 80

1.10. Statlstíca1 Analysis 83

1.11. EEhical Approval and Informed ConsenÈ 84

Results 85 1.12. Dextroamphetanine Induced Arousal: Psychological and Psychophysiological Aspects 86

I . I3 . The Role of the Dopamine Palhr¡rays in Dextroamphe camíne Induced Arousal 96 1.14. The Role of t.he Noradrenergie Pathways in Dextroamphe tamine Induced Arousal I20 Part II The Response of the Neuroendocrine System to Dextroamphetamfne: Effects of Doparninerglc or Noradrenerglc Blockade 151

2 1 General Introductlon 153

2 2 Met,hodology 158

2 3 The Response of Èhe Neuroendocrlne system to Dextroamphetamlne 163 2,4 Effects of Dopamlnerglc and Noradrenerglc Blockade on the Response of the Neuroendocrfne System to Dextroamphetamfne 183 2.5. General Discusslon 264

Part III Dextroamphetamfne Induced Arousal as a Pharnacologlcal Model for Mtld Mania 267

3 1. InEroductfon 269

3 2. Me thod s 287

3 3. Results 289

3 4. Discussion 301 Bibllography 317 SUMMARY

Noradrenallne and dopamlne have been lmpllcated in the pathogenesis of affectlve dlsorders. Our understandlng of these di sorders should therefore be enhanced by clarificaEion of the roles of the noradrenallne and dopamine pathways within the central nervous system. An ldeal agent for such research ls dextroampheta¡nlne sulphate as 1t acts by the release of noradrenallne and dopamine at specific sltes in the CNS. Dextroamphetamine alters psychological and blological functloning ín normal subj ects in a nanner that resembles affect.ive 111ness. Its effects on neuroendocrine responses have been used ín research on affective t11ness.

The ains of thi s st.udy r¡rere to examine: ( I ) the psychological, psychophysiologieal and neuroendocrine responses to dextroamphetamine; and (2) the roles of central noradrenallne and doparnlne pathh¡ays in these responses by using specific centrally acting blocking drugs. These have been achleved by examlning the changes indueed in normal human volunteers by a slngle oral 20 mg dose of dextroamphetamíne and by observing the effects on these responses by pretreaEment with either the selective alpha-1-noradrenergic receptor blocker thymoxamíne or the selective doparnine receptor blocker pimozíde,

Experiments r^/ere randomi sed, placebo controlled and double b1ind. Subjective changes were measured using visual analogue rating scales. Psychophysiological measures lncluded pulse rate, blood pressure and skln conductarice. The neuroendocrine responses measured ütere: plasma cort.isol and serum prolactin, growth hormone ( GH) , thyroid stinulatlng hormone (TSH), luteinf zf ng hormone (l,tt) and fo111c1e stlmulattng hormone ( fSn¡ . Plasma dextroamphetamlne 1eve1s hrere assayed to conffrm that. changes observed hlere not the result of pharmacokfnetic effects of the blocking drugs.

Dextroârnphetamine lncreased subjective arousal and pulse blood pressure produced a concomitant rise in rate ' and skln conductance. These responses h¡ere aEtenuated by dopamine blockade ( pimozide ) and enhanced by noradrenerglc blockade (thyrnoxarnlne). These ftndlngs lrnply that dopamlne pathways are ínvolved 1n the promotion of arousal, wlth noradrenergic pathways exerting a modulatory role.

Dextroamphetanine r¡ras f ound to s tímulate the release of cortisol, prolacÈin TSH, LH and FSH buE not GH. The ínteractlon of the blocking drugs on the neuroendocrine response to dextroamphetamine imply thaE dopamine pathhrays are stimulaEory 1n the release of LIÌ and FSH, are lnhibitory in the release of prolactln and TSH, and have no effect on cortisol release. They may play a dual role in the regulation of GH release. Noradrenaline pathways may be stimulatory in LH release, inhibítory in the releas,e of cortisol GII and TSH, and noE involved in prolactin and FSIl release. The complexí ty of control of secretion of these hormones mean that the signlficance of dextroamphetamlne fnduced ehanges ln neuroendocrLne functloning ln patlents wlth affective dl sorder must be interpreted with care.

The response to a sfngle dose of 2Omg of dextroâmPhetamlne 1n nornal volunteers would appear to be a useful model for manfa since: ( 1 ) the range of subJecÈlve resPonses Eo dextroamphetamf.ne whlch hrere observed, ürere slmllar to the symptoms whfch are commonly seen ln manla; (2) both Èhe physlologlcal and neuroendocrine effects of dextroamphetamine vrere the same as t,hose reported to occur tn manla; (3) Èhe response to Ehe dopamlne receptor blocking drug pimo zíde 1s slrn{1ar ln the two condlElons. This thesls contains no materlal whfch has been accepted for the award of any other degree or diploma ln any universlty. To the best of my knowledge and belfef, the thesfs contalns no materlal Prevlously publlshed or wrlEten by another person, except where due reference 1s made ln the text. ACKNOI.¡L EDGEMENT S

I wish to thank the following people for their valuable assistance 1n the preparatlon of thls thesls:

Professor Trevor Sllverstone whose stimulus and ongofng support and guidance as a supervi sor has been fnvaluable throughout the whole proj ect; from organl sing the Research Grant, dfscusslng ldeas generated by the study to assisting 1n Èhe preparation of the manuscripE;

Professor Lesley Rees and Dr Bruce Carnpbell whose laboraEorles performed the large number s of hormone and dextroamphetamine assaYS ;

Dr [.Jayne Hal1 for hís tireless asslstance ln readlng and editing the different drafts;

Professor Issy Pilowsky as 1ocal supervl sor for h1 s encouragement. and practical advice;

Ms ELIzabeth Jacobsen who typed the orlginal draft;

Suzanne Jacobs for considerable asslsEance 1n proof reading the thesls. t

GENERAL INTRODUCTION

The series of lnvestlgatfons to be described were undertaken with the aim of furthering our understanding of the pathogenesls of affective disorder. Noradrenallne

( Sc¡ildkraut, I965) and dopamlne ( Sflverstone , I978) have both been tmpllcated in the blology of affectlve dlsorder but t.helr precise roles remaln unclear. The fírst objecEive was to invest,igate Èhe relative contributlons of the dopamine and noradrenallne pathways to the psychological, psychophysiologlcal and neuroendocrine resPonse to dextroamphetamlne in human subj ec Es. the second q¡as to determine how similar the arousal response to oral dextroamphetamine in nornal subjects 1s to mild mania ln terms of clinlcal pieture, psychoblological proffle and pharmacology. In ot,her words could amphetamlne induced arousal in normals be used as a pharmacologlcal model for manla?

The response to the anphetamine group of drugs has been well documented slnce their Lntroductlon earlíer this century. They inftuence psychologíca1 state and behavlour 1n hurnan subject,s; they elevate mood, heighLen arousal and increase actlvity ín hrays that resernble some f orms of psychiatric disease, especía11y manla. Their effect on the neuroendocrine system has not been so closely studíed' lievertheless the neuroendocrine response to amphetamine has been studíed in order to examine the activity of the catecholarnine paEh\^Iays in af f ective disorder. 2

1. The catecholamine pathways.

Pharmacological experimentatlon is a PotenÈia11y valuable tool for lnvestlgating the function of the central nervous system ln intact subjects and for examlnlng the roles of the lndfvldual neurotransmitter pathLrays 1n various types of psychologfcal and biologíca1 activtty. Dextroarnphetamfne ls particularly suited to examine the catecholamlne pathways ln thls contexE as 1t acts as an lndirect, agonist ín both the dopamine and noradrenallne pathways ( Carlsson, I970;

Scheel-Kruger, I97 2; Groves and Rebee, I97 6) .

As fat as pharmacological experimentatlon is concerned, the admlnistration of a pharnacological agonist or antagonist alone 1n the resting state, may provoke such sma11 changes that they are dtfficult to measure. Further lnformation about a neurotransmltter syst.ern can be gained by studying the lnteract,ions between the effects of. the agonlst and speclflc pharrnacologlcal antagonísLs. In the present series of studíes, the effects on the responses to dextroamphe Earnine of specific blockíng drugs have been examlned. The underlying assumption is thaL if a response Eo dextroamphetamine I s attenuated by a blocker, that response is probably lnitiated in the flrst place through activat.ion of Ehe particular pathway the blocker is thought to inhibit. Conversely, if the blocker enhances the amphetamine response, then Ehe original response rnay be due Eo suppression of the neurotransmitter in lhe pat.hway the blocker is thoughr to b1ock. 3

As far as psychopharmacologfcal investlgatlon of the catecholamine pathways are concerned, whlle there are a number of specific pharmacologfcal agonlsts and antagonist of dopamine that are avallable, there are few noradrenerglc agonist drugs. Amphetamlne derlvatives remain one of the few centrally actlng agents known to stlmulate, Posf synaptic noradrenergic receptors.

Although there is conslderable evidence that the catecholamines dopamlne and noradrenallne are lnvolved in psychobtologíca1 function, uûcertainty exists about their partícu1ar roles in humans. Recent evidence from animal experiments, has demonstrated t,hat the dopamine pathways play an important role in mof-or functlon, motlvation and arousal, sensory - motor lntegratíon and the control of neuroendocrine functlon ( Iversen, 1980; Checkley, 1981; UngersEedt et aL, Ig82; Iversen and Alpert, 1983)' In humans, dopamine pathways are involved in mood and arou sal in normal subjects (Jonsson, I972 Sllverstorie eÈ ãI , 1980) and ín Parklnson-s disease t{ornykiewicz, 1978; Ungerstedt et aI, 1983), schlzophrenia (Snyder et al, 1974) and mania (Sitverstone and Cookson, 1982).

Earller investigaEors proposed that noradrenallne pathL¡ays r¡Iere responsible for the a1ert. lng ínfluences of the reticular acEivatíng systea and r¡¡ere direct. ly involved in conditions of altered mood ( SchildkrauE and Kety , I967; Fuxe et a1, 197O; Snyder, L975). Schildkraut (1965) proposed that a relative lack of catecholarnines, particul arLy 4

noradrenaline, wâs correlated wlth depression and an excess wit.h mania. Intenslve studies of the noradrenergfc pathways over the past decade in experimental animals has falled to confirm that the noradrenerglc pathways play these ro1es. I,lhat thls research has suggested is that the noradrenerglc pathways are lnvolved ín the control of hypothalamic sysÈem in learning, and ln functíon and the neuroendocrlne ' the animal-s response to stimull (Mason, 1980, 1981, 1983; Clark , 1979; Robblns, 1984) . The role of the noradrenergic pathways in human psychoblological functioning remains less c1ear.

i i . A model for mania .

Research fnto the neurological aspecÈs of psychologíca1 functionlng and behaviour is 1ímiÈed by the innaccessíb111ty and complexl ty of the braín. Mo s t of our knowledge of the actlon of central catecholamine Patht,tays comes from studies using experfmenEal aníma1s. These experiments are frequently invasive in nature. Extrapolatíon of behaviour from one speeíes to another is difflcult, and one cannot assume Ehat the central neurotransmitter sysEens have the same functíon ln different anirnal specíes. Animal studies are also limited because ooe cannot direct.ly lnvestlgate the mental state. The development of a non-lnvasive technlque for the s tudy of catecholaníne func tion in normal human beings where experimental conditions can be controlled, would provlde a slgnlf lcant advance in research.

Pharmacological models have provided a useful avenue of 5

sclentlfic fnvestlgatlon 1n psychiatry, 1u' partlcular by provldtng a stfmulus for the generation of neür hypotheses which cal1, 1n turn, be tesÈed 1n the dlsease state. If a human model of psychlatrlc 111ness fulfll1s the necessary criterla for valldftyr lt would act as â valuable tool for further psychobtologlcal research lnto mania. PART I

AN TNVESTIGATION OF TITE ROLES OF THE DOPAMINE AND

NORADRENALINE PATIIWAYS IN DEXTROA}IPTIETAMINE AROUSAL

IN TIUMAN SUBJECTS Introductlon

page 1 1. IntroducElon. 9

I 2. Amphetamlne Arousal fn IIumans. 10

1. 2.1. Illstorlcal review. 10 1. 2.2. Cl1n1ca1 uses. t4

1. 2.3. Amphetamlne abuse. 16

l. 2.4. Experimental use. T7

1. 2.5. The pharmacology of amphetamlne. 18

I 3. Central Catecholamine Pathways. 20

1. 3 I. Introductlon. 20

l. 3 2. tlistory. 2T

1. 3 3. Neuroanatomy. 24

a The noradrenal lne pa thway s . 24

b The dopamlne pa thway s . 26

I 3 4. Neurophyslology of the caEecholamlnes. 30

a Neurotrânsmitters. 30

b Receptors. 30 í. Alpha and beEa receptors. 31 ii. pre- and postsynaptlc receptors. 31 iti. Adaptlve changes 1n recept,ors. 35 iv. Current vlews on catecholamine n e u r o p h y s I o 1 o g y . 37

c The role of the catecholamine pathh/ays in psychobiologlcal functlonlng. 4T 1. Noradrenerglc pat,hways. 4L 11. Dopamlnergic pathhrays. 50 1it. Evfdence for a dopamlne - noradrenallne lnteract. lon. 55 t 4 Prevlous AttemPÈs to Elucidate the Role of the Dopamlne and Noradrenallne PaEhways 1n Amphetamlne Arousal. 57 I 4.I . Experlmental animal s. 57 I 4.2. lluman subJecEs. 60

I 5 RecepEor Blocklng Drugs. 62 t 5.1. Introductlon. 62

I 5 .2 . Plmo zTde . 63 I .5.3. Thymoxamfne. 65 INTRODU CT ION

1.1. Introductfon

Dextroamphe Eamfne produce s a cons i s tent elevatlon of mood and arousal 1n humans. Its pharmacologfcal action provldes a rnethod of comparfng the roles of the different catecholamlne pathhtays in mood and arousal since dextroamphetamlne has been shown 1n experimental animals to release newly formed dopamlne and noradrenal ine presynapt,ically, thereby acting as an fndtrect dopamlnerglc and noradrenergic agonist. l^le know that the dopamlne and noradrenaline pathhrays are lnvolved fn mood and arousal both ln health and disease, but Eheir preclse roles remain uncertaln. Indeed sorne earlier âssumptlons about t,he functlons of these pathways have required re-evaluatlon in the light of recent advances.

Following a review of amphe tamfne arousal 1n humans, a detailed revlew of the structure and func!1on of the cenÈra1 cat.echolamine pathways will be glven. Previous efforEs to elucldate the relaEÍve roles of the dopamine and noradrenal ine paEhways in psychological functioning in both expe r lnental aninals and human subjecEs are examined. The íntroduction to Parl I will conclude by reviewing the clinlcal pharrnacology of the two blocking drugs used. 10

1.2. Amphetamlne Arousal 1n Humans

I .2.I. Ill storlcal revlew

Amphetanine kras flrst manufactured and studfed by Gordon

A11es in the late 1920's and early t 930' s as part of a search for an ephedrine-1tke drug for the treatment of as thma; the natural source of ephedrlne ( the plant ePhedra vulgaris), havíng been exhausÈed. A1les found that phenyl-1so-propylamine (amphetamine) r¡Ias an effective substltute (lttes and Prlnzme|al, 1933; Leake, 1970). Experimenting on hímse1f, A11es found that the isomer dextroamphetamine had signíficant mood elevaÈing effects (Leake, 1970). Very early rePorts had suggested thaE the drug !ras without signlf lcant sub j ecEive ef f ects (t"tt11er and piness, Ig28, sêe also the comprehensive review by

Silverstone and l,le11s, 1980) .

Psychologieal and behavioural effects of amphetanine I¡¡ere íncreaslngly reported shortly after iEs cllnlcal introductlon. PrtnzmeEal and Bloomberg ( 1935) reported thaE íL r{as effective 1n the treatment of narcolepsy and that overdosage caused insomnia. The drug- s anorectic action v/as observed in passing by Prinzmetal and Bloomberg ( 1935) and by Peoples and Guttman (1936). The latter reported that amphetarnine had signiflcant effects on the pulse rate and blood pressure of subjects ,as well as their mood and talkaEiveness. In open trial s, Nathanson ( 1937) and Davidof f and Reifenstein (t.aSl ) found that amphetamíne 11 cau sed an elevatlon 1n mood and reduced fatigue. Both normal subJects and a varieÈy of paElents sufferlng dlfferent psychlatric disorders partlclpated in these early studies.

The general consensus view which emerged was that anphet,amine had a signlflcant central nervous system stimulatory effect with relatively litt1e perlpheral stimulatlon. An oral dose of 10 to 20 mg 1ed to euphoria, exhllaration and, ln some subjects, lrrftability, lessenlng of fatiBUêr lncreased energy and capaciEy for work and fncreased talkatlveness. The drug reduced t.he symptoms of narcolepsy and caused insomnia and anorexla. Davldoff and Reifensteín ( I937) reported irrítablltty and res!lessness as a comrnon accompaníment. HohJever, dul1ness, forgetfulness, drowsiness, depression, de1írlum or halluclnations hrere reported by some subjects.

The abiliEy of amphetamíne drugs to reduce fatigue and sleep lead to Eheir wldespread use 1n I,/or1d War Two by

Brl ti sh, German and Japane se servícemen ( Leake 19 70 ) . Thi s ability too, Eogether with their efflcacy in irnproving endurance capabilíty and hence at.hletic performance, led to Eheir use by some athletes and theír subsequent banning (SitversEone and t/e11s, 1980).

Interest in the ampheEamine drugs continued ínto the post f¡/ar period. Levine et aI , ( rg+g) , in an open study on patients with a variety of psychiatric illnesses, reporEed slmilar findings Eo the earlíer studies. They found that t2

intravenou s me thyl amphe tamíne produced wakefulne s s, ellmination of fatlgue r increased talkatlveness and restlessness. Itypomanic patlents and tense patients, however, became more relaxed and one became drowsy, whereas psychotfc symptoms Eended to hrorsen. Slmilar ftndings were reported by Lassagna and his colleagues (Lassagna et a1, 1955) tn studies using a subcuÈaneous injectlon of anphetamfne sulphate.

Later controlled st,udies, whlch used a varlety of measuring Ínstruments, confirmed Ehese earlier open studies whlch relted largely on anecdotal reports. An oral dose of

elther 10 or 20 mg of dextroamphetamine sulphate caused a rise ín mood and arousal as measured by the profile of nood

( a ,+ sEates and linear mood scale Smith and Davis, L977), lJ modlfled adjective checkllst (Brown et aI, L978) and vlsua1 analogue scales (Sitverstone et aI , 1983). In additíon to t.he elevatlon of subj ective mood and arousal, amphetamlne drugs give ri se to anorexia and reduced food intake

( Sitverstone and Kyriakedes, L982; Silverstone et aI, 1983) . As far as psychophysiologlcal measures are concerned, amphetarnine causes a rise in pulse rate, blood pressure and skln conductance (Martin et a1, I97I; Zahn et aI, 1975; 1981; Morselli et a1, 1978; GoldsÈeín et 41, 1983; Nurnberger et a1, I984) and administration leads to a rise in che secreEion of cortisol and changes 1n the secretion of the different anterior piEuitary hormones (See Part II).

llowever the response to amphetamine is variable. As early 13

as L937 Davldoff and Retfenstefn (1937) commented on the variablllty of the psychophysfological. responses. In some subJects drowsiness and a reductlon ln alertness 1s noted ( Tecce and Cole , I97 4) . Checkley ( 19 78 ) commented on the variablllty of the subJective response to amphetamfne. Thfs varlablllty can be demonstrated ln a number of measures and appears to be fnfluenced by Èhe tlne that has elapsed slnce the drug was admlnfstered - which presumably reflects dlfferences 1n blood 1eve1s (Tecce and Cole , 197 4) . 0ther factors whlch fnfluence resporrse Eo amphetamfne are age (napoport et a1, 1980), and psychot,lclsm and neuroticlsm scores on the Eysenck Personallty Inventory ( Clarfdge and Blrehall , 1973).

1lil i

I

r 74

L.2.2. Clfnlcal uses

AmpheLamine derivatfves have been used in a diversfty of cllnlca1 sf tuaÈlons sfnce thelr introducElon over fifty years ago ( Sllverstone and VJe11s, 1980) . Their effect on sleep 1ed to Èheir belng used ln t.he treatment of narcolepsy for which purpose they are sti11 prescribed. Their anorectlc actlon lead to their hrldespread use in the treatment of obesity. Levine et aI, ( I948) reported that subjects, and 1n partlcular psychiatrfc patienÈs, became more talkative. This observatlon 1ed to its use 1n

psychíat.ry as an abreactant, of ten f n conj unctlon h¡lth a barbiturate (Slater and Roth, 1969). Amphetamine derfvaElves, as well as another sEimulant methylphenídaEe, erere found to be effective in t.he treatment of hyperkinetic

syndrome (Arnold et a1, 197 2) for which they have been extensively prescribed ln the USA. The treatment seems to be wlt,hout long term benefft however and subjecÈ to a varlety

of different risks ( Barcley , I977) .

In splte of their mood elevating effeeE, amphetamine drugs have not proved partlcularly useful as antidepressant

agents. Checkley ( 1978) demonstrated thaE the mood elevaEing and antidepressant effects of meÈhy1 amphetamine hrere dtfferent in that the latEer effect q¡as a nore delayed

one. Favrcett and Siornopoulos (197 L ) proposed that a

t positlve response to dextroamphetanine generally predícted

I that a depressed patient would respond Eo imipramine, a

findíng whlch has been confirmed more recently (t/an Kammeçt 15 and Murphy, 1978). There is also some evldence that dextroamphetamfne may have a role as an antldepressant in pattents who fa11 to respond to conventional antldepressant regf mes (tlard and Lampe, 1982). The value of amphetamlne compounds as therapeutlc agents though has been overshadowed by thelr use as recreational drugs. 1,6

1.2.3. Anphetamfne abuse

In Èhe post war period, abuse of ampheEamlne drugs hlas wldespread. In 1958 Connell reported Ehat heavy amphetamine usage was assoclated with a paranoid psychosis which was very slmllar to paranold schlzophrenla ( Conne11, 1958) . The psycho'sls could be reproduced experfmentally (ne11, I973) and slmllaritles hrere noticed wlth behavlour observed in anlmals receiving hlgh doses of anphetamfne ( E11lnwood, 1967; El1lnwood et a1, 1973; E111son and Elson, 1983). The psychosls 1s accompanled by marked stereotyPy, insomnla, alertness, hypersexuality, feat, susplciousness, increased vigilance, and hallucinations (particularl-y visual and Eactile) . There is, hoI¡¡ever, a relatlve absence of f ormal EhoughE df sorder ( 8e11, I973) . In ot.her r¡rt¡rds, there are signlfícant dífferences between the phenomena of ampheEamine psychosis and paranoid schizophrenla. Thls has not deterred researchers using amphetamine lnduced psychosls as a model for schlzophrenía ( Snyder, I973) . The "model psychosls" has played an lmport,ant role ln the formulation of the dopamine hypothesis of schlzophrenia ( Snyder, I972; Snyder et 41,

197 4) . 77

L.2.4. Experinental use

Because of the serlous psychologfcal and social sequelae of their abuser âf,phetamlnes have been hriÈhdra$rn frorn clinical use. Under strlet.ly controlled conditíons however, they stí11 have a valuable and established role ln psychopharmacological re search. As they give a reasonably reproduceable response, psychologically and biologica11y, they have been used 1n a diversity of approaches to study psychfatric illnesses. Thus the drugs have been used as a model for psychiatric i1lne ss ( Snyder, L97 3; Robblns and Sahaklan, 1980; Jacobs, 1983) ( see Part. III) , ín an atÈempt to esEablish a pharmacological marker for the treatment of depression (Fawcett and Siomopoulos, I97I ) and to investigate the neuroendocrlne system in Affective Illness (see Part II). As amphetamine drugs ln moderate doses act by the release of boEh noradrenaline and dopamine from the presynaptic neurone ( see 1 .2.5. ) , they have been used to study the relative roles of the dopamine and noradrenaline pathways in dlfferent behaviours 1n experinental aníma1s and ín psychological and neuroendocrine functioning in humans. This w111 be dlscussed ln detaí1 in the relevant sectfons that fo11ow. 18

1.2.5. The pharmacology of amphetamfne

Amphetamine derivatlves are readlly absorbed from the gastrolntestinal tract and are 1itt1e affected by firsÈ pass hepatfc metabolfsm ( Innes and Nfckerson, 1975) . They rapldly enter the braln and are found 1n high concenÈrations there. Peak plasma level s occur tsro to three hours after oral administratlon.

A subst.antlal part of elimínatlon 1s vla excretf on unchanged fn the urlne. As amphetamlne has a pKa value of 9.93, eliminatlon 1s greatly facilltated by acid urine. Some is metabollzed ln the llver by p-hydroxylaElon or n-demethylatlon, deamination and conjugation. The plasma half life (urine ptt 6 - 7.5) is approxlmately ten hours (Snepherd et aI , 1968; Innes and Nickerson, L975; Checkley, 1982[a]).

Dextroamphetamine exerts its effecc by the release of newly formed dopamlne and noradrenallne frorn the presynaptlc neurone ( Carl s son , L97 0; Scheel-Kruger, L97 2; Chiueh and Moore, I975; Groves and Rebec, I976; Moore, L977) , a conclusíon reached by the following observatlons. The release 1s associated with an íncrease in the coûcentratlon of the metabolites of dopamlne and noradrenaline formed extracellularly ( 3-me thoxytyramíne and norme tanephrine ) ; at the same time, there i s a drop of íntrace11u1ar dopamine and noradrenaline leve1s (Carlsson, I970).

Amphetamíne causes a release of dopamlne and noradrenaline I9

1n reserpine sensitlzed anlmals, suggestlng that Ehe site of release 1s pr1marl1y exÈragranular (Itansson, I967; Carlssoll' IgTO; Moore, L977) . Furthermore, release is blocked by prlor admlnlstraEion of alpha meLhylparatyrosine r Providing further evldence that dopamlne and noradrenalíne are released from a newly formed, readily releasable, catecholamlne pool ( Carl s son, L97 O; Scheel-Kruger , 797 2) . AE hlgher doses, amphetamine can exert an inhibltory action orl the re-uptake pump but thl s mechani sm I s generally consldered to be of secondary lmporÈance ( Carlsson, I9701' Scheel-Kruger, 1972; Felgenbaum et a1, 1982) . At higher doses sti11, re-uptake of serotonin may also be inhtbfÈed (Groves and Rebec, I976). The amphetamines appear to have no direct stímulatory action on recept,ors, nor do they have any inhibitory ef f ect on monoamine oxidase, aS I{as earlier propo sed ( Carl s son , L97 0) .

The neuronal response to dextroamphetamine is rePorted Eo be biphasic (Rebec and Sega1, 1978), wlth very low doses reduclng the eetivlty of noradrenaline and dopamine neurones presumably by preferential action Presynaptically ( Engberg and Svensson , L979; Iluang and Maas, 198I) . AE higher doses it acts postsynaptically. AC doses used in the experiment to be descrlbed, it is unlikely that presynaptic receptor influences are important. 20

I .3 . CenEral Catecholamlne Pathways

1.3.1. Introductlon

In recent years extensive lnvestlgations using experinental anlmal s, have lmplicated a wlde range of functions for the doparnlnergic and noradrenerglc neurotransmitter systems. Thls review will focus on research studles that lnvestigate Èhe role of the catecholamine neurotransmltter systems in changes in mood and arousal from Ehe psychologícal and Psychophysiologlcal perspective. Thelr role 1n neuroendocrine functlonlng will be considered 1n Part II and in psychiatrlc disease with particular reference Èo mania in Part III. This review wí11 give greater weíght to studles 1n humans since 1t cannot be assumed that Ehe neurophysiology of Èhese pathways and Èheir role in psychobiologlcal functíoníng I s directly comParable beÈween experimental animals and humans. 2t

I.3.2. IIlsEory

sir Henry Dale ( 1938) reporÈed rhat the flrst steps towards an understandlng of Èhe funcÈ1on of noradrenalfne occurred ln L894. Dr George 011ver had lnvented an lnsÈrument to measure the dlameter of arEerles Ehrough the unbroken skin. trIhlle experimenting on his son, he observed that subcutaneous inJections of extracÈs of calf-s suprarenal gland caused narrowing of the radial artery. Dr 01lver rras inf t.ia11y unsuccessful 1n lmpressing t,he physiologist Professor Edward Schafer r¿iÈh his flndlng until he v¡as able to persuade the professor to lnject some of Ehe extract into aR anaesthetísed dog from which he had been recording the arterial blood pressure. To Professor Schafer's surprise the exEract caused a profound rise 1n blood pressure. E111ott ( 1904) verlfied an observation that the re sponse Eo the extract from t.he calf- s suPrarenal gland resembled the effect of stlmulating the sympathetic nervous systen. He identlfíed adrenaline as the active lngredient and proposed that sympathetlc nerves act by release of adrenaline (or its immedíate precursor).

Followlng the classical work of the Nobel prtze winner Loewi (t922) which demons trated the chemical transmiEter actlon of ace ty1cho11-ne , several workers turned their attention t.o the sympaEhet.ic nervous system. Cannon and Rosenblueth (1933) found evidence that a sympathetíc transmltter existed, that 1t h/as probably noE. adrenaline, and that it existed in two forms which they cal1ed Sympathin 22

E and I, respectlvely. They felt that the transni Eter may be ambifunctlonal but combined wi th dlfferent " receptive substances" ln the effector ce11. (Eventually it became establlshed that there ürere not two forms of transmitter subsLance but two different Èypes of receptors, the alpha and beta adrenoceptor IAh1quíst, 1948] ).

Doubts began to grow that the transmitter substance released with sympaEhetic nerve stlmulatlon vras adrenallne. Dale hlmself expressed thls doubÈ as early as 1910 ( Barger and Da1e, 19I0) ln view of the dlfferential effects of various amines. Nevertheless he proposed Èhat Èhose nerve flbres or impulses transmitÈ1ng their effect by adrenallne (or something very 11ke 1t) be ca11ed "adrenergfc". Àccordlng to Da1e, hi s use of the term dld noE lnclude the transmltting substance or the effector ce11. Von Euler (I947) also questíoned the evídence that adrenaline vlas the substance released on sympathetic nerve stimulation. In research for which he t.¡as awarded t.he Nobel prtze Von Euler found that the actlon of adrenergic nerve fibre extract more closely resembled Ehe astion of norâdrenaline ( Sympathin E). He believed that Sympathin I may be adrenaline. Noradrenaline and adrenaline r¡¡ere identífíed in the braín and assumed by Von Euler to occur in the cerebral vascular motor nerves.

t/ogE (tgSq) mapped the concentration of both noradrenal Íne and adrenaline in t.he various sectlons of the brain. She showed thaE noradrenalíne had a specific pattern of 23 dlstrlbutlon ln the braln strongly suggesting that it played a speciallsed role ln brain functlon. The areas of htghest concentratlon lncluded the hypothalamus and other sites where the synpathetlc nervous system eras belfeved to be rePresented centrally.

As 1t was known that dopamlne is the Precursor of noradrenalLne, f t had been anticlpated thaÈ dopamíne would also be found ln the central nervous system. It was surprlsing Èhen when dopamine hras diseovered aE relatlvely hlgh concentrations at slLes other than those of hlgh noradrenallne concentratlon, ê8, the caudate nucleus ' putamen and substantla nlgra ( Carlsson et a1, 1958) . 24 f.3.3. Neuroaîatoßy

In the 1960- s experimental technlques such as the histochemlcal fluorescence techníque (Falck et ãL, L962) , vrere developed to glve detailed mapping of t.he catecholamlne neurones within the central nervous system and thelr associated pathways in animals, parEicul axt.y the rat (Oantstrom and Fuxe, 1965) . The precision of rnapplng has been lmproved subsequently by supplementary technlques such as producing lesfons steriotaxically or by injeetfon of 6 hydroxydopamine (Fuxe et a1, I970; Ungerstedt, 197I) and more recently by the development of mlcrofluorescent technlques and autoradiographíc Èracings ( for reviews see Moore and Bloom , 1979; C1ark, 1979; Robbtns and Everitt, 19S2) . Dy t,hese means, two maj or ascendíng noradrenerglc pathways have been ldentlfled, the locus coeruleus noradrenergic system, the maj or component of which is the dorsal noradrenergic pathh¡ay ( DNP) , and the ventral Èegmental pathway ( Vfp ) . Four maj or dopamíne pathÍtays have also been described.

a. The noradrenaline pathr¡¡ays

Three ascendlng pathl¡lays origlnate from the locus coeruleus. The largest, the DNP, ascends through the mesencephalon, ventral and lateral to the periaquaductal grey. A second smaller pathway ascends wíthln Èhe central grey as part of the dorsal longitudinal fasciculus, and à third ascends through the ventral tegmental tract to join the median forebrain bundle. The DÌ{P !urns ventrally at the 25

1eve1 of the fasclculus reÈroflexus to j oln the dorsal portlon of the medían forebrain bundle at the 1eve1 of the hypothalamus. Flbres leave the tract to lnnervate the thalamus and epithalamus. The DNP ascends as Part of the medían forebrain bundle with fibres leavlng to J olnr o0 the one hand, the ansa pedunculari s ventral amygdalold system to innervate the amygdala and ventral hippocamPus r and, on the other hand, t,he mammilothalamic tract to innervate the anterlor thalamus. At the leve1 of t,he caudal sePtum the DNP ftbres in the medían forebraín bundle break up lnto five main groups. These fibres enter the fornix, the stría medullaris, stria terminalls and cíngulum or contínue as t.he median forebrain bundle. These pathways lnnervaLe the hlppocampal formation, habenula, amygdaloid complex, neocortex and olefactory tubercle. Innervatlon is largely lpsilateral (UngerstedÈ, I97I; Jacobowltz, 1978; Moore and Bloom , 1979 i Clark , 1979 i Robbins and EveritE, 1982) . See f igure 1.1 .

Pa thway s a1 s o project lateraily from the locus coeruleus to lnnervate the molecular layer of the cerebellar cortex and descendlng fibres innervate the sensory nucleí of the lower braín stem (tfoore and 81oom, I979; Robbins and Everítt, 1982).

The second ascendíng noradrenerglc pathway 1s the ventral tegmental paEhway (VTP). It arises from ce11s scattered throughout the medulla and pons, ín particular, the lateral retieular nucleus, the ventrolateral medullary area and 26

subcoerular group, the axons forrning a plexus rather Ehan a discrete bund.le or tract. they enter the VTP throuBh, and ventral to, the decussatlon of the superlor cerebellar peduncle, then dlsperse amongst the catecholamfne radlation to j oln the nedian forebrain bundle ln the me sencePhalon before ascending to the diencephalon. Ascending fibres of the VTP mlx with its descending fibres and with the ascending fibres of the locus coeruleus noradrenergic system. Flbres have a wide dlstribution withln the mesencephalon and diencephalon, but 1n contrast to the locus coeruleus system I proj ections of the VTP are resEricted to largely subcortíca1 areas. the pat.hr¡IayS ínnervate ' ipsl1ateral1y, the whole of the hypothalamus, the lateral septal nucleus and ventral amygdaloid nucleus as well as some braln stem nuclei, lncluding the substantfa nlgra and ventral t,egmental area and Èhe mídbraln raphe nuclel (UngerstedE, 197I; Moore and Bloorn , 1979 Robblns and Everitt, 1982). See figure 1.1.

b. The dopamine pathways

Dopamlne neurons in the CNS are involved 1n a number of different systems; the nígrostriatal, mesolimbíe and mesocortíca1, tuberoínfundíbuLat, retína1 and medullary. The dopamíne neurones in the mesencephalon give rise Eo t.he nigrostriatal, mesolimbíc and mesocorLical tracts and probably form a continuous crescentic cluster of cel1s rather than being separated as previously thought ( Iversen and Fray, I982; Iversen and Alpert, 1983). Axons arising C.tral¡l Xo!¡dr.ñ.r¡lc P¡rhY.v¡

r¡t ttt 27 0 lf¡caort fuò.r!]r

llaccorf¡¡

â¡t¡d. ¡o ld

t¡b.nula L¿!.¡aI 5rpc rl lluc l.l Elppocalpc¡

C.nr¡¡l ,l¡ytd¡lold Iuc ¡. I

brgcßh.lu¡

byld.l. åFb

Suba!¡n3 l. l{ltr. loa Tù.1.È.^nrca llld E..fo l.ph. 1b.¡d¡

Ep ¡¿h. lars¡ v¡tr! ra I T.5ùnßt¡ Àraa

L¡arr.¡ lc! lcul.. lluc l a ^¡ Locua !. co¡¡u lu¡ C¡Ìab. ¡ ¡@ Âó lnl.¡lor O¡tù. A¡

^5 Súil.ory Iuc¡¡a trrln Sr.r A1

llotc¡ llucl.a ¡¡¡ln St.!

Figure 1.1 Sclnretic representarion of r_tæ cencral rnradrerergic parhmys.

DIIP Dorsal noradrenergic parhway. VT? Ventral fegnnntal pathway. MFB Median forebrain bundle. St- Term Stria terminal,is. Sr Med Stria nedullaris. APUA Ansa pedun<:-ulari s venrral anrygdaloid rract, 28

f rom the substant, la nigra and ventral tegrnental area ' run via the median forebrain bundle in the lateral hypothalamus putamen, accumbens septal and lnnervate the caudaÈe nucleus ' and amygdalold nuclei, and t.he medial frontal cortex ( Fuxe

197 and EvereÈt 1982i et â1, 1970; Ungerstedt, I; Robbins ' Iversen and Fray , I982; Iversen and Alpert, 19S3).

The t,hree pathways are nohr known to be highly functlonally integraÈed. The most lateral dopamine neurones 1n the zorla compacta of the substantia nlgra ProJ ect to Ehe striatum and the most medlal, in the ventral tegmenÈum, to the frontal corEex and lfmbfc sEructures. Ilowever lateral 410 neurones proJect to the rnedial sEriat.um whí1e medial L9 neurones proJect Eo 1lmbic areas. Furthermore Ehere are feedback circuits. The nucleus accumbens nelrrones recelvlng dopamlne inputs, have efferents to the zor'a reticularl s in the substanEia nlgra. Efferent fibres from the medial cortex proj ect to the same reglon of the nucleus accumbens that receive inputs from fibres from the Al0 region. The caudate nucleus also receives efferents from the motor cortex and the limblc component of the dopamine system as well as

efferents from the hippocampus ( Iversen and Alpert, 1983) . (see figure 1.2).

The tuberoínfundíbu1ar pathway consísts of a short band of fibres that connect the arcuate and periventricular nuclei of Ehe hypothalarnus to the median eminence ( puxe et a1, 197O; Robbins and Everitt, i982). Cencrrl Dooanlnc Pathu¡v¡ 29

Fronte I Cort 6x

Mesocortfc¡l P¡thuay

N. Accr¡nbens Hlppocampus Sept uo Amygorle

llesollnblc Pathway

CaudaÈê l{o¡or CorÈex Nuc leus

Nlgro Strlatsl

A9 A10 SubsÈant la Nlgrå ZR zc

A8

Itypocha laoue Arcuate Per I N Vent Eicular N

Mad f¿n Eflnlnencs

FigÌ¡re 1.2 Sctrnâtíc r€pres€ntåEiqr of tlre cer¡tral dopmi¡E patÏÈys.

ZR Zona reticularis. ZC Zona ccçacta. 30

I.3.4. Neurophyslology of the catecholanfnes

a, Neurotransmf tters

Both dopamine and noradrenaline fulfill the crlterla for a neurotransmitter 1n Èhe central nervous system ( tversent I979; Slgglns, I979; Van Dongen, 1981 ) . In addltion to acting as synaptic neurotransmitters, both dopamlne and noradrenallne may act as non-synaptlc neuroÈransnft.ters and neurohormones. In the tuberoinfundlbular-median emlnence systen for example, dopamlne is released lnto the portal pltuitary blood and acts as pltuitary lnhibitory factor (l,tu11er et a1, 1977 [a]). Van Dongen (1981) concluded that noradrenalfne acts as a synaptic and non-synaptlc neurotransmltter and that noradrenallne released from the locus coeruleus into the ventríc1e might act as a CSF hormone.

b. Receptors

The final component of the synaptlc neurotransmí Eter mechanism is the recepEor. Recent work has expanded our knowledge in Èhis aspect of the synâpse to the extent that hre are now obliged to reconsider earlier hypotheses regarding Ehe mode of acEion of psychotrophic drugs. This in turn has meanE a re-evaluation of hypotheses relating to the f unctloning of the neurotransmi tter pat.hI4Iays based on the effects of these drugs and, as a consequence, theories of the nature of psychiatric illnesses based on pharmacological evidence. 31

t . Alpha and be ta adrenoceptor s

Ahlqufst ( 1948) compared the effect of dlfferent, syrnpathomimet,ic amlnes on a varlety of physlologlcal functlons and concluded Ehat there were thlo dtfferent adrenerglc receptors, one essentially excítatory and the other inhibltory (wlth t.he lmportanÈ exceptÍon of myocardial excitation). As Èhere seemed to be only one adrenerglc mediatlng substance he concluded Èhat Ewo different receptors h¡ere f nvolved ( ttre alpha and beta adrenoceptor) rather than the tv¡o forms of sympathin ( n or I) proposed earlfer. The subsequent search for and dlscovery of effectlve beÈa adrenergic blocking drugs has been a milestone Ín t.he Lreatment of hypertension.

ti. Pre- and postsynaptic receptors.

UnEll the beginnlng of the 1as t decade i t hlas generally assumed that adrenoceptors were locaEed only on the membrane of the postsynaptlc sErucEures, Since then, evidence has accumulaEed that adrenoceptors are also located ofì the outer surface of adrenoceptor vacuosltles. These have become known as presynaptíc receptors. They modulate stímu1us evoked transmieter release. Presynaptic receptors are present f or both the alpha and beta noradrenergic systems (Strombom, 1975; Langer, 1978; 1981; Dubocovích, 1984) and

Ehe dopamine pathüIays (Roth, I9B4; Rebec, l9B4) . 32

Noradrenallne recepÈors

: the dlfferent noradrenerglc recepÈors are noqr classlfled pharmacologically, based on dlfferential effecEs by selecElve agonisEs and antagonists, and by receptor binding

studfes as alpha 1 and alpha 2 or beta I and beta 2 receptors.

Alpha 1 noradrenergic receptors (or adrenocePtors) are postsynaptic 1n nature and, perlpherally at 1east, rnediate

an excltatory response in t,he synaPSe. The alpha 2 adrenoceptors are generally presynaPtlc (but may also be

post synapEically located). The PresynapElc alpha 2 adrenocepEors are lnhibitory, produclng their effect by reducing t.he amounE of noradrenergic stinulation in the .'ì '!J be I synapse. The postsynaptlc alpha 2 recePEors may exclt.atory, for example, 1n Ehelr involvement in the control of cardiovascular function (Ou¡ocovich, 1984).

BeEa receptors are similarly subdivided into postsynaptic (or beta I ) adrenoceptors and presynaptic (beta 2) adrenoceptors. Beta 2 receptors can be posEsynaptically situated and provlde posiEive feedback.

Three of the four subtypes of adrenergic recePEors are linked (períphera11y at least) to the same biochemical effector, the adenylate cyclase sysEem, which in turn

influences the ce1lu1ar 1eve1s of adenosine 3 5 monophosphate (cyclic AMP). Beta 1 and beEa 2 receptors stimulate adenylate cyclase whereas the alpha 2 recep Eor

I 33

lnhibits tt. Alpha 1 receptors lncrease lntracellular calclum 1eve1s. The drugs which are actlve at noradrenergic

receptors and whfch can be clas slfied as affectlng alpha 1 or alpha 2, beta 1 or beta 2 xecepÈors either as adrenergle agonlsts or antagonlsts are llsted 1n table 1. I . (Langer, L978; 1981; MoÈu1sky and Insel, I982; Lefkowítz eE aL, 1984; Sulser, 1984).

Table I .l

Receptor a1 pha 1 al pha 2 be ta 1 be ta 2

Loca È I on post- Pre- post- pre- synaptíc post- synaptic post- n on- non - synapÈic synapEic

Mechani sm increase inhíbition stimulatlon stimulation rI lnEra- adenylate adenylaÈe adenylate rl,t ce11u1ar cyclase cycl a se cyclase Ca lons (not CNS) Agonist phenyl - clonídine lso- salbutamol ephrine prenal ine adrenal lne AnLagonist thymoxamlne yohlmbine propranolol propranol o1 pÊazosin

Nora renerg c agon s t an antagonist rugs.

It is not certain how this classificatlon is related to the human central nervous system. The drugs described are not as speclflc in their action at pre- or PostsynapElc sites as is often assumed. Clonldine, for example, is generally considered to be a presynaptíc alpha noradrenerglc agonist, but it also has a postsynapElc action on some functions (flexor reflex activity, motor activity and perhaps blood pressure)(Strombom, 1975; Anden et aI , J.976;

þ 34

Kobtnger, L978; Langer, 1978; 1981; Vel1ey et aL, 1982). Clonidine sedatlon would appear to be vla presynaptic alpha 2 receptor sÈfmulatlon (Monti, 1982). Clonidlne tends to exert more of a posEsynaptlc than presynaptlc action r.¡lth lncreaslng doses as does yohlmblne, whlch I s usually regarded as a presynaptlc noradrenerglc antagonisÈ (Anden et

â1 , L97 6; L982) .

Dopamine receptors

Dopamlne receptors have also been subclassífíed. FirsEly

dopamine receptors in the central nervous syst.em may be elther pre- or posÈsynaptíca11y sltuated. Presynaptlc inhibirory autorecepEore for exanple may be etimulatcd by 1ow doses of apomorphlne whích ín turn cause a decrease in motor actívíty 1n experimental animals. Higher doses preferentially sEimulate posÈsynaptic receptors (Strombom, I975; Nagy et a1, I978; Rebec, 1984; Roth, 1984). In addítlon, doparnine recePtors have been divided into t-tto subtypes, the D1 and D2 receptors, dependlng on the preserice or absence of adenylate cyclase linkage. The D2 site (or butyrophenone siÈe) may be more closely linked with dopamlne induced behavíour, Pârkinson-s disease and psychologlcal dysfunction than the D1 síte ( Creese and Snyder, 1978; Schachter et a1, 1980; 0ffermeier and Van Rooyen, I982; Stoof and Kebabian, I984; Rebec, 1984). The presynaptic It I receptors have been designated D3 and D4 receptors, the latter being those located presynaptically on cortico

I 35 strlatal glutamate nerve ftbres (UngerstedE et ãI , 1982).

A second system of classlfícatlon has been proposed by Cools and Van Rossum (1980)(Coo1s 1981). They caÈegorise dopamine receptors lnto the excltaÈory neostrlatal DAE and the inhibltory mesollmbic DAI receptors ( the latter belng regulated by mesollmbic alpha-1lke noradrenergic receptors).

i1l. Adaptive changes in recePtors.

Adap t ive change s may occur in Ehe recep tor s when change s in neurotransml tter activíty occur over a period of time, for example following sustained drug usage or followlng a lesion of the relevant pathways. Generally speaking, hetghtcncd activity of t.he synapse and increased rec.ePÈor stimulatlon ( f or example using an agonist, drug) is f o11or,¡ed by reduction 1n Èransmitter synthesis and turnover, via aet,ivation of presynapt, lc receptors ( see previous sectton) or down regulation of the recePtor. Reduced synaptic acÈlvlty (as caused for example by an antagonist drug or followlng a Iesion in the pathway) is associated with heightened sensítlvity of the receptor. Adaptive receptor changes occur at presynaptic as well as pos tsynaptic receptors and are associated hlith changes in the receptor-s af.f.ínity for the neuroEransmitter, or the number of receptors (receptor density) ( Byland, L979; Resine, 1981; Sulser, f984; Rebec, 1984).

Appreciation of these changes has lead to a re-evaluation 36 of the actlon of drugs 1n the treatment of psyehiatric ll1nesses, for example the antldepressanÈs in depressive 11lness (Leonard, 1982; Sulser, 1984). Chronic administratlon of antfdepressants and ECT fnduce a subsensitivlty of the noradrenallne sensitlve adenylate cyclase, linked to down regulatlon of beta adrenoceptors; whl1st some also cause down regulatlon of the alpha 2 receptors (Garela-Sevi11a et aLr 1981; Sulser, 1984). Down regulatlon of the dopamine autoreceptor rnay a1 so be import,ant 1n the therapeutle effect of anLldepressants and ECT (¿,nte1man et â1, L982).

As the downgrading of receptors wlEh prolonged antidepressanÈ therapy correlates wlth the delayed therapeutfc response, the original hypothesis for the role of the catecholamine in affectlve 111ness ( Sctrildkraut, 1965; L973) must be reappraised (t"laas and Huang, 1980; Sulser, 1984).

The experíment reported in thi s the sl s deal s wf th change s following acute drug admlnistratlon. Although subJects presented at leasE weekly for four . sessions, three uslng active drugs r tt ls unlikely that receptor changes would have developed wl Eh such a regime. 37 iv. Current vlews on catecholamine neurophysío1ogy

Noradrenal lne

Developments over the last flve yeats suggesÈ that the functlon of boCh the noradrenergic and dopamlnergic pathways are more complex Èhan prevlously considered. The work of Bloom (L978; 1980) and his colleagues (Moore and 81oom, I979; Aston-Jones and B1oom, 198 I ) is espectally relevant in Ehis context. These workers have used lontophoretically applied noradrenaline to show that noradrenaline usually slou¡s the firlng rate of ce11 s in Èhe cerebellar cortex, htppocarnpus, lateral genlculate body and cerebral cortex. ilowever even though noradrenaline usually lnhlbits spontaneous discharge, the response to certain sensory lnputs may be increased by noradrenallne. For examPle, t.he relatlve signal to noise ratlo of resPonses by ce11s ln the audítory cortex to vocalisaElons is lncreased because noradrenaline produces a SteaÈer suPPresslon of sponEaneous actívlty than Ehe response to vocalisation. Locus coeruleus stimulation carr increase the discharge of hippocampal cel1s

to a condl tloned s tirnulus . Bloom has proposed that noradrenaline pathu¿ays and the arborisatlon of axons, act to set the background tonal activity of an area in a "bias adjusting r modulatory way. t{e suggests this may be relevant in aEtrlbuting reínforcing value to sensaÈions on the one hand, and in influencing the animals- ability to distinguish between relevant aad irrelevant stimuli on the other. The DNP may suppress vegetative functions while 38 enhanclng activity concerned erlth processing salient external stlmulf (Aston -Jones and 81oom, I981). Bloom proposes: " Such a functlonal system would add a valuable adj uncÈ to the vocabulary of ce1lu1ar communlcatlon slgnals by whfch neurones communlcate" (81oom, L977; 1978). Sfmllar proposals have been put forward by other workers (Woodward et aL, 1979; Rogawski and AghaJanian, 1980;1982).

Dopamfne and noradrenalfne lnteract.lon

Recent evidence of an lnteracEion between the dopamine and noradrenallne paths¡ays has add.ed further complexlty to the situation. Antelman and Caggul11a (1977) have proposed that iL lnay be profitable to consider an lnteractive relatlonship between the tvro paEhways. They clte a variety of examples that point. to such an int,eraction and propose that the effect of noradrenaline is dependent on an lntact dopamíne system and that the Potentiatlon or depr-ession of behavíour by noraclrenergic pathLJays depends on actlvational feat,ures in the environment. They suggesÈ that ln normal funct.ionlng, noradrenalfne exerts an indírect modulatory ínfluence on the dopamine systern and regulates lts function. When the activity of the rroradrenergic path\{ays 1s diminished and t.he organísm is stressed, facilitation of dopamine mediated behaviour is 1ike1y. In conditions of minlmal stress or acEivation, diminished funcÈion of the noradrenaline neurones w111 either have no effect or will depress function. 39

A modulatory role by the noradrenergic pathways htas also proposed by Bloom (1977; 1978) ( see above) . 0ther srrlters have since described neuroanatomlcal, neurochemlcal and pharmacologlcal evldence givlng support to Èhe Posslbillty of an lnteractlon between dopamlne and noradrenalile. Cools and Van Rossurn ( 1980) and Cools ( 19Sl ) , Elve anatomical and neurochemical evldence for such an lnteraction. They report that dopamine receptors are funct.ionally different in the nucleus accumbens from the caudat.e nucleus. The lnhibftory DAI neurones in the nucleus accumbens dfffer from the DAE neurones in belng directly controlled by alpha noradrenerglc receptors.

There i s biochemical and neurophysío1ogfca1 evídence of an lnteraction of dopamíne and noradrenaline neurones though their precise nature and behavloural consequences remaln unclear (L1oyd, 1978; Iversen, t9s0) . Robbíns and Everltt ( 1982) reviewed the evidence for an lnteraction between the pathürays as proposed by Antelman and Cagguilla. They described a varlety of biochemical and pharmacological difficulties encountered ln confirming the Antelman and Caggul11a hypoEhesis experímentally. They conclude Ehat

" Ehere would appear to be sufficíent behavloural neuroanatomieal and pharmaeological evidence to j ustífy considerable effort 1n dí scerning t.he relationship between them (the noradrenergic and dopaminergic sysEems) as this may considerably inform our understandlng of the control mechani sms underlying many forms of behaviour. " Robbins 40

( 1984) more recently proposed a tü¡o tiered lnteractlon between the t¡ro sy s tem s coordinating Ehe response to st.ress

( see above ) .

Kostowskl and his colleagues (t

c The role of the catecholamine pathways fn psychoblological functlonlng

1. Noradrenerglc pathways

Early ldeas

As the 1nÈracerebral connections of the noradrenergic pathways elere worked out., other evldence abouE them started t,o accumulate from leslon studles 1n exPerimental anína1s and from pharmacologlcal studíes 1n experimental animals and 1n humans. By the end of the 1960- s, the psychobiologlcal functíon of the noradrenergíc pathhlays aPpeared Eo be reasonably well establi shed ( scníldkraut and Kety , 1967; Fuxe et aI , I97O). Schíldkraut and Kety suggested thaE noradrenaline played a role 1n anxiety and arousal. They drew attentlon to the simllariÈy between the effects of lnEravenous noradrenaline and the physíological responses to arousal and anger, as well as to observatlons that anxious, hyperacÈive or a,:oused tndivídua1s excreted high 1eve1s of noradrenaline and íts metabolltes. Pharmacologíca1 studies indicated that catecholamíne depletion (by reserpine or alpha methylparat-yrosine) 1ed Eo sedation or depression whilst stimulation of catecholamine Pathl¡/ays (by amphetamine or antidepressants ) 1ed to elation or to relief of depression. Schildkraut and Kety conjectured that there h/as a dlrect relationship between noradrenallne and elevation of 42

arousal, anger and rnood.

The catecholamlne hypothesis of affective 111ness was proposed by schildkraut ( 1965) . He hyPotheslsed that "some Lf, not all depressions, are assoclated wlth an absoluÈe or relatlve deftciency of catecholamines, partlcularly noradrenaline, at functlonally important adrenergic receptor sf tes of the braln. Elation conversely may be associated w1Èh an excess of such amines. "

Fuxe et al ( 1970) proposed a sinilar role for noradrenallne in alertness and hyperactlvity. They reviewed evidence from neurophyslological and pharmacologlcal studles in experimental aníma1 s and concluded that alertness reflected activi ty in the DNP, whereas autonomlc functioning

and aggE ession reflected actívi ty of t,he VTP. Locomotor activlty and exploratory behaviour, they suggest.ed, involved t,he activi ty of both noradrenerglc and dopamínergic

pa Ehway s .

Confirmatory evidence for a sinilar role for the catecholamínes in humans seemed Èo come from a detailed comparlson of the relative ef ficacy of dextro versus laevo amphetamine in inducing arousal and alertness ( Snyder, I972; L973). Dextroamphetannine appeared much more actlve than laevoamphetamine in preventlng reuptake, and promoting the

release of noradrenal ine from the pre synaptic neurone , whereas the th/o isorners appeared equally active in promotlng the release of dopamíne. Snyder therefore argued that, where lhe tr,Jo isomers exerted a similar clinlcal or 43 behavloural effecÈ, this was due to an action on dopamine pathways (paranold psychos'ls). Those resPonses where dextroamphetamine h¡as considerably more potent (eg alerting and mood elevating) reflected noradrenergic actfvity.

0ther investigators have subsequently challenged both the behavloural and biochemlcal bases for these concluslons. For exanple SmiEh and Davis ( 1977) r¡rere unable to replicate Ehe psychological dlfferences 1n response to dextro or laevo amphetamíne ln a carefully standardised experíment.

Feigenbaum et al ( 1982) reported thaÈ no preferentfal reuptake inhibition of either dopamlne or noradrenallne

could be demonstrated and that reuptake lnhíbiEion was a mínor action of amphetamine drugs compared with catecholamine release (netgenbaum and Yanaí, 1983). 0Èher biochemical studles have demonstrated that dextro and laevo amphetamine are equlpotent in influenclng the act.ivity of noradrenergíc pathvrays but that laevoamphetamine ís relatívely less effectlve than dextroamphetamlne ín dopamine paÈhways (Bunney et aI , 1975). Thls would give an interpretation opposite to that originally proposed by Snyder.

As mentioned in section I .3.4. b. recent evidence on the changes in catecholamlne receptors have cast Some doubt on interpretations from pharmacological sources on the role of Ehe catecholanines in affective il1ness.

Conclusíons based on the dtf.f.erent 1eve1s of catecholamine 44 and their metaboli tes ln the plasma urine and CSF are confounded by conElnuing uncertalnty about the central and perlpheral effects of noradrenaline. SÈudles comParing the 1eve1 of noradrenaline and lts metabolltes cannot differentlaEe between central and perfpheral actlvity and be tween primary and secondary phenomena ( Pos t and Goodwln, 1973).

These issues have 1ed to a reappraisal of the role of the noradrenerglc pathhrays in psychobiologlcal functloning.

Recent trend s animal studles

over the past. Len years or so I¡Ie have seen that many of the behaviours previously linked wlth noradrenergÍc functions are noI¡¡ established as dopaminergic behavlours' Mesoltmble dopanine pathr¡râys are thought to be lnvolved wlth locomotor actlvity, behavioural motívation and arousal. SEriaEal dopamine pathways are lnvolved 1n the inltiating and sequencing of voluntary movenent and sensory-motor integratlon, wh11e the mesofrontal dopamine pathways are involved u¡lth organ ized and focused behaviour, for example, respondíng to interloceptive stimull (Iversen, 1980; UngersEedt et a1, 19B2; Iversen and Fray, I9B2). See section 1.3.4.b.

Thus activatlon of behaviour seems to depend on central

( dopamine me chani sm s . The dorsal noradrenergic pathway DNP)

may be involved ln the organi-zaLion of a coordlnated 45 response to stress over a range of dlfferent behavlours and f unctlons (Robbins, 19S4) . Robbins proposes a tr¡ro Èiered system of lnteraction between dopamine and noradrenallne, an upper and lower arousal mechanf sm. The lower (dopamine mechanism) resPonds to intensive arousfng stimull, while Ehe upper noradrenergle mechanf sm compensate s for sub- or suPra- opt.imal actívity of the lower mechanism.

The role of noradrenergic pathways in other psychobiological and behavioural activaÈíes has come under scrutlny as we11. For example, evldence I s emerging from studies in experirnental animals, that t,he noradrenerglc pat.hways have a role in '1 earning, more specif 1ca11y in extinct,ion rat.her Èhan 1n the acquisition of behavf our. DNP lesloned aninals also show lncreased df strâctab111b.y (lnlason, 1980; 1981; 1983). Considerable research into thís area has 1ed Mason Eo propose Ehat the DNP has a role in the anlmal being able to filter and ignore írrelevant lnformat.íon (Mason, 1980; 1981; 1983; McNaughton and Mason' 1980;

Iversen, 1980; Robbins ' 1984).

Noradrenergic pathways have been shown to be lnvolved in the development of visual plasEiclty (Ro¡blns, 1984) and they also probably have an inhibíuory role in aggression (Ucl{aughton and Mason, l9S0). They are involved in the regulation of eating behaviour, sexual behavíour ( ltcNaughton and Mason, 1980), sleep (Gí11in et aL, 1978[al¡ llonti, I980), seizure control (t'tcNaughton and Mason, I980) and homeostasis via the hypothalamo anterior pituitary sJ¡stern 46

(ttul1er et ãL, t977Íal; Robblns and Everitt, 1982) .

Recent studles h unan

As mentfoned earller the notlon that the noradrenerglc mood arousal pathways hlere prlmarlly involved 1n changes ln ' and ln affective illness needs reconsideratlon.

Considerable uncertalnty sti1l remalns whether a direct relationship between arousal, anxíety and noradrenergic functioning exlsÈs or whether the proposal that the noradrenergic pathh¡ays exert, a modulatory role on the actívi ty of dopamine pathways I s more aPproprfate.

Rece-nt pharmacological studÍes using human subj ects have fatled to resolve the issue. Clonidíne, âr alpha 2 noradrenerglc agoaist, and yohimbine, âr alpha 2 noradrenergic antagoni s È are sedatíng and alerting respectlvely when glven to normal subjects (Mont1, 1980; Slevers et a1, l98I: t{oehn - Sarlc, 1982; Charney et aL, 'I 983; 1984) . Charney et a1 ( 1983; 1984) f or examPle, report panl-c, t.hat yohimbine increased symptoms of nervousness ' restlessness and blood pressure but interestingly, caused a para11e1 increase in ratings of drowsiness. They suggest that anxiety and panic may reflect increased sensítívÍty to augmented noradrenerglc function and that impaired presynaptic neuronal regulation may exist with panic disorder. Some doubt remaÍns, however a1¡out hotr much Ehe action of clonidine and yohimbine rests on involvement of 47

presynaPtic comPared wlth postsynaptic receptors in the central or peripheral nervous sysEem (Strombom, 1975; Anden, 1976; 1982).

The postsynâptic alpha and beta noradrenerglc antagonlsts, thymoxamfne and propranolol, seem to be without clear or conslstent central effects 1n normal subjects (Jacobs and Sllverstone, unpublished; Lader and Tyrer ' L97 2) . Propranolol-s effects on the somatic symptoms of anxlety are ltke1y ro be peripherally mediated (Lader and Tyrer, L972;

Gottschalk et a1, I97 4') .

0ther pharmacologlcal studles are confounded by the lack of specific actlon of the drugs used and by varlabillty ín response. Most anEidepressant druBS r for examPle, have as a prlmary actlon the preventlon of the re-uPtake into the presynaptíc neurone of noradrenaline and other neurotransmitter substances namely serotonín, dopamlne and acetylcholine ( Sílverstone and Turner, 1982) . In additlon to sedation and reducing the symPtoms of panlc and anxiety ( Sheenan et â1 , I980) , anEídepressants elevate mood 1n depressed patíents and may preclpítate mania (tlehr and Goodwín, 1979). Doubt has been raised as to whether these changes reflect adaptive changes by pre- or post synaptic receptors over the period of time before t,he drugs exert

their therapeutic action (t'taas and Huãfl8¡ f 9B01' W^1 drneier, 1981; Leonard, L9B2; Sulser, 1984)(see sectíon 1.3.4.b) 48

PsychiaErlc disorders

The role of noradrenaline 1n psychologlcal disease also remains uncertain. As r¡i11 be descrlbed subsequenElY ( Part III) a central role for dopamine has emerged in mania.

As far as anxlety states are concerned, it is possible t,hat noradrenaline has a central nervous system as we'l 1 aS peripheral nervous system ro1e. As mentloned earlier, the role of perlpheral noradrenerglc receptors is demonstrated in the cllnlcal efflcacy of Propranolol (Cottschalk et 41, I97 4) . The effects of clonidine and yohimbine are 1ike1y to involve cent.ral receptors too but in a manner that remains Eo be resolved (no11ery et a1, 1975; Jouvent et a1, 1980; Iioehn-Saric, Ig82; Charney et a1, 1983; 1984) ( see above).

Even the central role of noradrenaline 1n the depressive phase of affective illness has come under crlticísm. The catecholamine hypothesis ( Schí1dkraut, L965 ) stated that

depressÍon $¡as assoeiated wí th a E elatlve lack or hypofunction of the noradrenergic synaPSe. The hypoEhesis

r^ras proposed before the recent work on adaptive receptor changes vtere known. Antidepressant drugs, after continuous therapyr cause a down regulatíon of postsynaptic beta adrenoceptors and alpha 2 presynaptic adrenoceptors and hence may exert their therapeutic action by lowering the activity of noradrenergíc pathvtays, implying relatlve hyperactiviEy of the patht¡/ays in depression (Wat¿meíer, 1981; Reisine, 1981; I'eonard, L9B2; Sulser, 198L: Sulser et

a1, I9E4 ) ( see 1 .3.4. b. ) 49

Although 1t has been assumed thaÈ dopamine plays a pre-eminenE role 1n the pathogenesls of schizophrenía (Matthysse, I97 t+) , Hornykleu¡1cz ( 1982) proposed that the role of noradrenaline in schfzophrenia had been underestimated. The work by Mason and his colleagues (McNaughton and Mason, I979; Mason, 1980; 1981; 1983) suggests that Ehe DNP has a role in selectlve attention. In the rat forebraín, noradrenaline depletion leads to lncreased distractablllty, a perseveration of inapproprlate behavlour (or a resisÈance Èo extlnction) and an apparent failure Èo ftlter out lrrelevant stlmuli. Mason points out that there may be a slmilarity bet$¡een these observatlons and the perseveration of inappropríate response Patterns in schlzophrenlc pat,ients. Increâsed attenEic¡n Lt¡ lrrelevant stimuli ís also observed ln schizophrenic patlenEs. The abnormalities o f a Perceptual filter rnechanism seen with schizophrenic patlents may correspond to those seen in experlmental aníma1s wiEh noradrenaline pathway lesions. Alterations in attention and the ability to filter lrreleva timuli, may provide a blological explanation of the schizophrenic-s abnormal ldeas and halluclnatlons (l'fason, 1981). 50 it. Dopaminergfc pathways.

Anlmal studies

The role of the dopamlne patht¡¡ays ín motor ac tlvl ty has been demonstrated using leslon studies and pharmacologlcal methods. From the pharmacologlcal PersPectlve, dopamlne precursors or agonists, for example L Dopa, methylphenldate, apomorphine and amphetamine, have an act.ivating actlon ln experimental animals (Randrup and Munkvad, I966; Costall and Naylor, 1974; Iversen and Iversen, I975; Fray et aL, 1980; Nlckolson, 1981; Rebec, 1984) , provided that Èhe dosage ls high enough that the drug acts predomínanEly at PosÈ synaptic receptors (Rebec and Sega1, I978; Rebec, 1984) . Activatíon 1s attenuated by t,he neuroleptlcs whose common actíon ís dopamine blockade (Murphy and Redmond, I975; Groves and Rebec, Ig76; Ljungberg and ungerstedt, 197S).

Looklng at amphetamine ln partícu1ar, the lncrease in loconotor acEívity that follows a relatively 1ow dose of ampheEamlne, involves doparnine neurones in the nucleus accumbens rvhllst the stereoEypy which follows high doses involves dopamine neurones ín the caudate nucleus (Ke11y et a1, Lg75; Groves and Rebec, 1976; Robbins and Everitt, le82).

Confirmatory evidence for the role of the dopamine pathr¡rays ín the initiation and coordínation of motor behaviour came from Èhe dí scovery that degeneration of the nigrostriaEal dopamine neurones was associated with 51

Parkinson-s disease and thaE syrnptoms eould be reversed by L dopa (HornykIewLez, L978; UngerstedÈ et aL, 1982). Dopamlne paEhways appeared to be lnvolved in mental functlons in vlew of the efficacy of t,he neuroleptic drugs in the treatnent of schlzophrenia and mania (Fuxe et 41, 1970; Snyder et a1, Lg74; Silverstone and Turner, 1982). Dopamlne pathways seemed also to be involved in Èhe control of anterior pftuiEary hormone secreÈion, Eêmperature regulation and emesis (puxe et â1 , I97O; Mu11er eE aI , tg77l,al; Sllverstone and Turner, 1982) . FurEher studíes, particularly those involving chemlcal ablative technlques, lmp1y that dopamlne pathways are ímportant. 1n t.he organlsatlon of the dífferent types of responses that contribute to motlvation (Robbins and Everitt, 1982).

As described earller (t.:.3.b.), the nigrostriatal rnesollmbic and mesocortical pathh¡ays have now been shown Èo form closely integrated circuits with nucleus accumbens substantia nl.gra1, cortlcostrlatal and corticolinbic connections. AblaÈive lesions of the nigrostrfatal system are associaE.ed wlth sensory motor neglect ( Iversen and Alpert, 1983; Ungerstedt et a1, 1982) . The neglect appears to reflect. a lack of attention to exterloceptive cues (Iversen, 1980). A bl1at,era1 1esíon causes total sensory motor neglect, even to food and qlater ( lversen and Fray, 1982; Ungerstedt et 41, 1982i Iversen and Alpert, 1983). Iversen and Fray ( tggZ) suggest that the dopamínergic input 1n the strlâtun facllltates the íntegration of sensory flow with motor responses, vla t.he cortex. 52

Leslons in the mesolimb1c pathütays on the other hand ri attenuate the amphetamine tnduced lncreaSe 1n locomotor actlvlÈy and, in unstlmulaEed animals, cause a fa11 in sponLaneous acElvlty. Anfmals are unable to respond to change. This area therefore 1s probably associated w1Èh moElvational ( lnterioceptive ) stimuli, i. e. affective, reinforcing or aversive stimuli processed by the hypothalamo-1tmbíc system ( Iversen and Fray, 19821, Ungerstedt et 41, 1982; Iversen and Alpert, 1983) ' wíth adaptlve behaviour depending on integration of both pathways.

The corcical dopamine pathways form ParE of the íntegrated dopamine circuits via the cortfcostriatal and cortlcollmbic I+ pathh¡ays. Dopamlne neurones in the anterior cortex recelve sensory information from other cortical areas whlch is int,egrated and Eransnítted to the striaÈum and limblc system ( Iversen and Fray , I9B2; Ungerstedt et a1, I982; Iversen and Alpert, 1983).

Human behav i our

Earlier predictlons r¡Iere Ehat noradrenaline would emerge as the maj or alerting caEecholamine 1n humans ( Schildkraut, 1965; Fuxe et a1, I97O)(see earlier). over the last decade however, the role of dopamine in human psychological and behavioural functionirrg has become lncreasingly c1ear. 53

Drugs which enhance dopamfnergic aeÈlvi ty by lncreasing precursor load ( l, Dopa) , by releasing dopamlne fnto the synapse ( t"tethylphenidate, amphetamine ) r or by actlng as dlrect dopamine agonfsts (bromocríptine), may lncrease mood and activlty. They may also reverse depresslon and preclpltare manía (t'turphy et a1, 1973; Murphy and Redmond, L975; Randrup et aL, L975; Gerner et a1, I976; Silverstone' 1978). On the other hand, drugs which suppress the activity of dopaminergic pathhrays, either by lnhlbltíon of synÈhesls (a1pha methylparatyrosine) or by dopamine recePtor blockfng action (neuroleptlcs ) cause sedation and reduce the hyperactlvity of mania (Randrup et a1, I975; Sllverstone, 1978).

:l The role of dopamlne pathhtays l¡r r¡lótür behaviour is !t clearly demonsErated in Parklnson-s Dlsease where there is a degeneration of substantla nigra neurones and the nigrostriatal tract accompanied by gross depletion of striatal dopamfne. The defect may be reversed, in part at leasÈ, by Lhe doparnlne precursor L Dopa (ttornykiewLcz, I978; Ungerstedt et àL, 1982). In additlon to the bradykinesia and other motor symptoms, depression is a common ,rtOto* of Parkinson-s dísease (Randrup et aI, 1975).

! 54

Psychiatric disorder

Dopamlne pathways are belleved to have a role ln the pathogenesis of schlzophrenia ( Snyder, I972; I973; Snyder et aL, I974; Matthysse, L974), though their lnvolvement may not be as close as first proPosed. The original dopamlne hypothesis was based on the observatlon that all antlpsychotic neuroleptics have dopamine blocking activlEy and the drugs- capacity to block dopamine activity hlas dírectly related to the drugs- antipsyehotíc potentlal

( Snyder, 197 3) . Further supPort was produced by studle s of the schlzophrenía-ltke Psychosis fnduced by hlgh or

prolonged doses of amphetamlne ( Sett , L965; E11ínwood, I967 ; Snyder, lg72; 1973). Snyder (I972) reasoned that dopamine

,.'l _rtl was ínvolved because dextro- and laevo- amphetamine \¡Iere equipotent in causíng re-uptake lnhibition and release of dopamine and in lndueíng the paranold psychosí s. Furthermore, neuroleptics h¡ere able t,o ínhíbit the presentation of amphetamíne psychosis (Conne11, 195E).

The role of dopamine and noradrenallne ln Eh,e biology of mania will be covered ln detail ln Part III.

I 55

ff1. Evldence for doPamine noradrenallne lnteractlon.

Some writers have proposed that the noradrenaline dopamlne stress response system may be central Eo certain psychlatrlc and neurological dlsorders. This may apply in Particular to affectlve illness (both mania and dePresslon), schlzophrenia and Parkinson-s disease and therefore that the Pathhlays should not be considered in fsolation (Iversen, 1980;

Ilornykiewicz, I982; Plaznik and Kostowski , 1983 ) .

As described earller ( t . ¡.4. b) r rêuroanatomical and neurophysiologíca1 evidence ex1 sts for an interaction between the thlo catecholamine pathhlays, wlth Èhe dírection of noradrenergic modulatíon of the dopamine pathhrays being present. Thus dependent on the degree of arousal ' noradrenergic stimulatlon would facllttaEe the activlty of the dopamine pathways ln the unaroused st,ate, but inhlbit them in the aroused condítion (lntelman and Cagguilla, I977; Iversen, 1980; Robbins and Everltt' I9B2; Robbins, 1984).

l' To date, the question of an lnEeracticn between doparnlne and noradrenallne patht,tays has not been directly tested in

human sub jeccs. Sorne pharmacological data may be interpreted as supportíng thi s hypothesi s. Blocking noradrenaline synthesis, by giving a dopamine bet.a hydroxylase inhibitor, accentuates the psychotic symptoms of aroused maníc patients ( Sack and Goodwin, I97 4) . Amphetamine I I drugs have differential effects depending on the state of l¡ I arousal. Amphetamine drugs in moderate doses may âccenÈuate

arousal and mood in normal individuals (Sílverstone et aI ,

I 56

1983) , ln depressed pat.lents (Fawcett and Slomopoulos, L97I; I,lard and Lampe, Lg82), and may preclpitate manLa (Gerner et a1, L976 ) or cause a schizophrenlform paranold psychosis ( 8e11, 1965; Elllnwood, L967) . on the other hand, they may produee sedatlon 1n normal subJects ( Tecce and Cole , L97 4) , reduce the symptoms of anxfety 1n obsessfve-compulslve patlenEs ( Insel et a1, 1983) , attenuate the symPtoms of manla ( Beckman and Heinemann, 197 6 ) and reduce the symPtoms

1n some schfzophreoic patlents (Van Kammen et 41, I982) . Thus the sedatfng effect of amphetamlne ln condi tlons of relatlve hyperarousal mlghE reflect the amphetamine lnduced stlmulatlon of noradrenergfc Pathways exertlng a modulating influence on an overactive dopamine system. 57

L.4. Prevlous Attempts to Elucldate the Relatlve Roles of the Dopamfne and Noradrenallne Pathways fn Amphetamine Arousal

I .4. I . Experlmental anfmal s

The effects on experimental anlmals of amphetamlne derlvatives have been wldely studled and hav e served âs a maj or pharmacological tool 1n re searchlng the catecholamine pathways.

In experimental anlmals lower doses of amphetamine derlvatives, when given acutelY, cause an lncrease 1n arousal and locomotor activtty. In hlgher doses they produce stereotyped behaviours ( Iversen and Iversen' I975; Groves and Rebec, L976).

There is strong evldence to suggest that the increâse 1n locomotor actlvtty is due to the stirnulation of dopamine pathh¡ays and that the site of action is Ehe nucleus accumbens (fetty eÈ aL, 1975; Iversen and Fray , I982). The lccomotor effect may be blocked by alpha meÈhylparaEyrosine but not by a dopamine beta hydroxylase inhlbitor (Ho11íster et â1, I974) . It is also blocked by dopamíne blocking drugs but it is either not blocked, or only partially blocked, by noradrenaline blocking drugs ( Rollnski and Scheel-Kruger,

197 3; Moore , L977) . Noradrenergic involvement in the increase in locomotor activiEy induced by dextroampheEamine

remains controversial hohrever. Roberts et al- (L97 5 ) report that a lesion 1n the 'doparninergic nigrostriatal palhway 58 attenuated dextroamPhet,amine lnduced locomotor activlty whereas a leslon ln both noradrenerglc pathways faí1ed to influence the ac tlvl ty . Ilowever 1n a more recent s tudy Kostowski et al (1982) report some attenuatíon of dextroamphetamlne locomotor activlty by similar lesions in Èhe noradrenallne pathways. If noradrenalíne 1s involved, lts role seems t,o be of secondary ímportance ( Groves and Rebec, I97 6) . Indeed reducing noradrenergfc acEivi Ey was reported by Ungerstedt ( 1971 ) Eo increase amphetamlne lnduced behaviour, suBgestlng that Èhe Pathhtays may play a modulaEory ro1e.

Dopanine pathways are prlrnarily lnvolved in amphetamlne induced stereotypy wlth no evídence of afl, involvement of noradrenal ine pat.hways ( t a1 and Sourke s , I97 2; Grove s and Rebec, I97 6) . The site of actlon aPpears Èo be in the caudate nucleus (reLfy et a1, 1975).

Experimental animal s have been used to study oÈher amphetamlne lnduced behaviours. The se include anorexia and aberrant behavi our fo11 owing prolonged hlgh doses of the drug.

Amphet.amíne drugs produce anorexia in experimental aníma1s as they do in humans. Earlier evídence implicating the dopamlne pathr¡rays (ttottister et a1, 1975) must be revlewed in the llght of evidence t,hat only the anorectlc effect of high doses of ampheEamine I4Ias blocked by neuroleptics

( Samanln e t al , 197 B; Burridge and Blundell , 797 9) . Thi s suggested chat dopamine blockade night be exerting an ef fect 59 on the general behavlour of the animal, rather than a dlrect action on anorexla. Leslons 1n t.he VTP however Prevented dextroamphetamine anorexia (Samanin et 41, 1978). LelbowIEz ( fgA¿) has observed that Lhe anorexia lnduced by lntrahypothalamlc lnJectlons of amphetamine v¡as attenuated by beta noradrenerglc and dopamine blockers. In man, on the other hand, dopamine blockers do not aPPear to effect dextroamphetamlne índuced anorexia (Sitverstone et aL, 1980), but thymoxamine may attenuate it (Jacobs and Silverstone, 1n preparatlon).

Experimental aníma1 s have al so been exposed to contlnuous hígh doses of amphetamlne drugs 1n an effort to produce a model psychosis simllar to thaE induced ln humans. In anlmals exposed Eo dexLroarnphetamlne by implanCèd slow release pellets, Èhe stereotypy phase 1s followed by a period of relative inactivity and then by a phase 1n whlch t.he animal displays aberran!. social behaviour ( Ellison and Eison, 1983). The authors describe "parasitotic" and often "hallucinatory 11ke behavlour" as well as lncreased vigilance. The 1at Eer phase appears to be associated wi th irreversible alteratlons of dopaminergic lnnervatlon of the caudate nucleus. 60

1.4.2. Iluman subJects

There I s strong evldence that the elevation of mood and alertness are dependent on dextroamphetamlne-s abfltty to stfmulate dopamine receptors rather than noradrenergie recepEors. The elevation of mood followlng intravenous racemic amphetamine r¡ras blocked by alpha met.hylparatyrosine (Jonsson et â1, 197L) , pimozLde r âDd to a lesser exEentt chlorprom azLne, whereas thlorlda zLne r oE propranolol were lneffectlve (Jonsson, 1 972; Gunne et 41, I972). Phenoxybenzamfne s1lght1y lncreased the response to amphetamine ( Gunne et a1, 197 2) . IÈ should be noted that pimo zLde has a more specific dopaminergic blocking actíon than the oE,her neuroleptics used in these experiments (Anden et aI , 1970; Plnder et a1, 1976).

Pimo zlde r¡¡as also f ound to attenuate the stimulant actlon of an oral dose of dextroampheEamine as measured by the visual analogue ratlng scale (Silverstone et 41, 1980).

Pimozíde simllar1y blocked the sleep changes lnduced by an lntravenous dose of dextroamphetamlne ln normal subjects

(citttn et aL, 1978tb]). Intramuscular haloperidol h¡as reporLed to attenuate behavioural exciEatlon induced by intravenous dextroamphe tamine, but both intravenous propranolol and thymoxamine htere roithout ef f ect ( Nurnberger et a1, 1984). NeiÈher haloperidol or pimozíde however, altered the rise in pulse rate or blood pressure induced by intravenous dextroamphetarnine ( Rosenblatt et â1, I979; lTurnberger et â1, 198,1). 61

The paranoid psychosi s, induced by high or continuous usage of amphetamlne derlvatlves has been regarded as belng due to the drugs- stimulant effect on dopamine pathways (Snyder, 1972i 1973). See secÈ1on 1.3.4.c. 62

1.5. Catecholanlne Receptor Blocking Drugs

I .5.1. Introductlon

As has already been stated amphetamlne drugs act as lndlrect dopamlnerglc and noradrenergic agonlsts. ConsequenEly, speciflc catecholamine blocklng drugs can be used to study the relatlve roles of the tü¡o pathh¡ays 1n the amphetamlne response. Attenuatlon of the resPonse by blocklng a speciflc neurotransmltter pathway implies that response $ras dependent on that pat.hway, whereas accentuatlon of the response implies that the pathways concerned hlere exerÈlng an inhibitory or rnodulatory ac'tlon. In the experiment to be descríbed two caEecholamlne blocklng drugs were used, Pimozide and thymoxamine. Pimozíde i s a relaEively specific dopamine blockíng drug ( see below) whereas thymoxamlne has relaEívely specífic blocking actíon at the alpha I noradrenerglc sítes ( see below) . 63

I.5.2. PfmozLde

a Pharmac o1 ogy

Pimozlde ls one of the diphenylbuÈylplperidine group of drugs and i s used as a neurolepLfc drug. In both animals and humans, tÈ ls readily absorbed after oral adminfstratlon and readlly reaches the central nervous system. Biologlcal half life for llver, blood and braln 1s about five to sfx hours. In the brain, hlghest concentrations are found 1n the caudaÈe nucleus and the pltultary 91and. The pharmacological effects are probably due to the unchanged drug. It is met,âbol1sed mainly by oxidatlve dealkylation and excreted ln Ehe urine and faeces. In human subjecEs' the plasma .ha1f 1ífe is eighteen hours (see Plnder et aI ,

197 6) .

b . Mechani sm of ac t í on

PimozLde appears Eo selectively block central dopamine

receptors rather than noradrenaline receptors (Anden et ãI , I970) and is effecÈive ín blocklng dopamine agonist behaviour in experimental aníma1s (pinder et a1, L976). AlEhough, ín an in víÈro study, plmozlde caused an inhlbitíon of noradrenaline sensltive cycllc AMP 1n limbíc forebraln tlssue (glumberg et a1, L975), it causes only slighC ehanges in the 1eve1 of endogenous noradrenaline

( Pinder et a1, 197 6) , Pimo zLde has been widely used in pharmacological research as a selective dopamine recePtor blocking drug. It is generally wlthout signíficant 64 perlpheral actlon on t.he autonomlc nervous system or the cardiovascular system.

For these reasons pimozLde would appear to be the most. specific and suitable dopamine agonlst to use for pharrnacological investlgation. 0ther neuroleptfcs have signiflcant noradrenergic or cholinergtc blocking actlon (uct

c. Uses in psychíatrY

Earller reports suggested Ehat pimoztde may be particul ar!y efftcacious in patlenLs sufferlng from chronic schizophrenla who are relatively inert as tt lacked the marked sedaElve actlon of oÈher neurolepEics (Plnder et aI , 1976) . It has, however, also been found to be effectíve in psychotic illness with agítation, especía11y ln man1a. Indeed pímo zíde appeared to have a nore speclflc antimanic action than chlorpromazlne (Cookson et a1, 19Bl). It ls effective, too, 1n acute schLzophrenia ( Sttverstone et a1, 1984) and has been recornmended in monosymptomatic deluslonal psychosis (Munro, 1980) . 6s

1 .5.3. Thymoxamlne

The search for a sultable postsynapElc alpha noradrenergfc blocking drug has been more difflcul t. Some alpha noradrenergie blocking drugs have a preferenttal actlon at presynapÈic sít,es (yohlmbine, PhenÈolamine), are comparatíve1y toxic (phenoxybenzamine), or are less speciflc in their actlon (chlorpromazíne)(tlickerson and collfer, 1975; Drew et aI, 1979; Anden et al, L976; L982).

d Pharmac o1 o gy

Thymoxarnine, the thymyl ester of a1 kylamine, has alpha-adrenoceptor blockíng actlon. Its cllnical uses are ln the treatment of ast.hna, labyrint.hine ischaemia and peripheral vascular dfsease, and a8 an agent to induce mlosls in ophthalmology. Little information is avaÍ1ab1e about its pharmacokinetfc properties.

b. Mechanlsm of actlon

Thyrnoxamine, together wíth lts metabolltes t deacetylthyrnoxamine and N-demeEhyldeacetylEhymoxamlne, has a relatively specific competitive alpha-adrenocePtor blockíng activity with no beEa-adrenocePEor blocking or seroÈonin blocking actlon ( ¡irrningharn and Szolcsanyi, 1965; Creuzet et a1, 1980; Roquebert et â1, 1981[a]). Blrrningham and Szolcsanyi ( 1965) report that thymoxamine has m11d

antihistarnine properties as we11. Thymoxamine- s alpha-adrenoceptor blocking acEivity 1s at Post synapEic rather than presynaptic receptor sites as it r,ras not 66 effectlve ln reverslng a variety of clontdlne lnduced changes as distfnct from yohfmbfne and phentolamine (Drew, L976; Drew et a1, L979; Roquebert et al, 198ltbl ).

ThymoxamLne-s actlvlty within the central neivous system can be lmplfed as lntravenous thymoxamlne reduced the lncreased tendon Jerk lnduced by methylamphetamine (pUf111ps et aL, L973) , attenuated the rlse of ACTH followlng methylampheEamlne Rees et ãL, 1970) and Lncreased REM sleep (0swa1d et aL, 1975). There ls no record of the c1fnlcal use of thymoxamlne ln psychiatric f11ness. Me thod s

Page I .6 . Introductlon. 68 L.7. SubJects. 70

L.7 .L. SubJect proflles. 7T

I .7 .2. Instructfons to subj ects . 72 1.8. Measurements. 73 I .8.1 . Psychological measure s. 73 I.8.2. Psychophyslologlcal measures. 75 1.8.3. Blood samples. 79 I .8 .4. Recordlng schedule s. 80 I .9. Drugs Used. 80 1.9.1. Pi1ot. studY. 80 I.9.2. Experimental deslgn. 82 1.10. SEatistical AnalYsls. 83

1 .1 I . Ethlcal Approval and Informed Consenu. 84 68

METIIODS

f .6. IntroductfoD

Four experinents hrere perf ormed 1n all. Two studies ütere deslgned to fnvesÈigate the effect of prlor doPamlnergic blockade by plmo zLde r or prlor alphanoradrenerglc blockade by thymoxamlne, on Ehe responses 1n normal volunEeers to 20 mg of oral dextroamphetamlne. In both of these experimenEs twelve subjects presented on four occasions. In addftion, tb¡o further studles I¡Iere perf ormed to lnvestlgate the effects of the tno blocking drugs alone wlth four subJecLs betng used in each. SubJecÈs in these studies presented on t.hree occaslons.

In describing the procedures, Èhe different experinents are designated as f o11ows.

ExperÍmenÈ A: P ímo zlde a1 one .

Experiment B: Plmo zLde and dextroarnphetamine. ExperimenE Thymoxamine a1one.

Experiment D: Thymoxamine and dextroampheÈamfne.

All measures, psychologicalr PsychoPhysiological and neuroendocrine $Jere performed in each group. The results from the occasion in experiments B and D in whlch dextroamphetamine was given alone ( placebo blocker 69

dextroamphetamlne 20 mg) have been pooled and compared to the placebo only occasion ( placebo blocker - placebo dextroamphetainíne) from Èhese tv¡o exper iment s .

Part I will describe Ehe results of the psychologlcal and psychophyslologlcal tests.

Part II wt11 consider neuroendocrlne aspects, both of the dextroamphetamine response alone and Ehe effect of dopamíne and noradrenallne blockade; further details of relevant methodology will be glven in thaE section.

ParÈ III wt11 examine t,he pooled results t o c om pare the effects of dextroamphetamine alone wíth the phenomena and psychophyslological concomftanEs of mí1d manía. Furt,her relevant meEhodologlcal detalls wt11 be glven in ParE III.

All experlments $rere conducEed in the Academlc Unlt of [luman Psychopharmacology, St Bartholomews and the London Hospitals sltuated at the German Ilospltal 1n London (Unlted

Kingdom ) . 70

L.7 . SubJects

young men aged T7 All the subjects who parttclpated srere ' - 31 years and were either students or professional and all but one were whfte. The study üras canvassed by word of mouth. They $rere pald Èen pounds sterling for each attendance.

Prior to participatlon volunteers Presented for a screenlng lnterview conducted by the investigator. At this intervfew a history of prlor and current physical health and prior and current psychologfcal health vias e1lcited. A detaí1ed review of prlor or current drug usage ( prescribed, unprescrlbed or 111ícit) I¡¡as conducted. A thorough Physical examínation was carried out reviewlng all systens wi th particular reference to the cardfovascular sysEem. Iteíght and welght were recorded. Subj ects completed an Eysenck Personal I ty Inventory.

The nature of the study Ir¡as dfscussed in detail with the sub j ect s who v¡ere acquainÈed wi th Ehe drugs used and pot.entlal risks. Subjects \¡¡ere familiarised with t.he schedule of the experiment and the routíne that would be followed. They r¡rere acqualnted wi th the laboratory and experímental equlpment that would be used. Seven subjects interviewed h/ere denied admission to the study as they gave a history of pasl or current drug and alcohol misuse (two), past psychological difficulties ( two ) , or ev i dence on physical examínation of poor health (three). 7t

One subJect was discharged from the study after he experienced nausea on Èhe first exPerimental run. In retrospecE Èhls seemed an ldlosyncratlc reactlon to thymoxamlne and was the only di scomfort encountered by any of the subJ ec t s .

L.7.L. SubJect proffles

Details of subjects (means +- SEM) are sumnarlsed ln Eable t.2

TABLE T.2

Exper ment A B C D

Drug Pl{Z al one Pt"lz TMX a1 one TMX comb ina t, i on +dAMP +d AMP number 4 I2 4 I2 mean age 23 .3 23 .3 24 .8 24 .6 (years) (+-2.6) (+- 4 .2) (+-a.0) (+-3.a) mean height 179.9 r81.2 179.9 181.5 (cm) (+-s.e) (+-s.7) (+-s.e) (+-5.5) mean weight 68.6 7r.5 69 .5 69 .5 (ke) (+-e.e) (+-s.5) (+-t0.4) (+-7.3)

EPI mean E score 13.5 r4.6 t1 .0 13 a (+-s.7) (+-a.6) ( +-3.7) ( +-4.6) mean N score 6.5 6.3 9.3 8.5 (+-r.7) (+-3.3) (+-4.1) (++.4)

Detalls o subjects use 72

L.7 .2. Instructlons to subJects

After the evaluatfon interview, subJects presented on four evenlngs, at least seven days apart. They were lnstructed to avold teâ¡.cof fee, tobacco or alcohol 1n the türenty-f our hours prlor to the experlment. lf, for any reason' prescribed drugs had been recommended durfng the experimental perlod, attendance htas postponed (e.g. on one occaslon a subJect used a nasal decongestant for a cold).

SubJeets fasÈed after breakfast apatt from drlnklng fruit

J uiee and water durlng the day. They pre sented to the laboratory 1n the late afternoon when the recordlng apparatus was connected, the drugs admlnistered and Ehe experimenÈ commenced.

Durlng the experlmenE subJ eets sat alone and could read or watch televlsfon. The design of the department enabled the experimenter to run the equlpment 1n a separate room. At the concluslon of the experiment a ¡nea1 v¡as provlded and the subJect hras taken home. 13

1.8. Measuremeûts

All psychologlcal and psychophyslologlcal measures vrere taken and the data analysed by the experlmenEer. Analysis of plasma samples for dextroamphetamine 1evels Itas conducted by Servler Laboratorie s London, whil s E the analyse s of plasma corÈiso1 and serum anterlor pltuítary hormone levels hrere underEaken 1n the department of C1lnlca1 Endocrinology, SÈ Bartholomew-s Itospital, London.

1 .8. I . Psychologfcal measures

A number of criEeria had to be consldered when selecting the most approprlate measurement of changes of mental state. Any measure of nental state is essentially subjectlve in nature. As one aim of the study involved comparing the response to dextroampheÈamine wit.h the phenomena of mania, flextbiltty ín selectlng aPpropriate dlmensions hras necessary.

It $¡as intended that measures of menEal state be recorded at half hourly intervals which required that the test be easily repeated and rapidly adminístered.

The test had to be of proven sensitlviÈY' reliability and va1ídltir. In this experímental deslgn the visual analogue rating scale htâs found to fu1fi1 the above criteria rather than one of the mood adjective checklists (MacKay, 1980). V1sua1 analogue rating scales ( nl tken , I9 69; Ai tken and

ZeaILy , I97 0; lf axwe11 , 1978) are sensitlve and accurate 74

ratlng scales partlcularly for wi thln subj ect comparL sons of change and rrere consldered nost apProprfate for the needs of thi s experfment.

Vi s ual anal ogue ra t lng scale s were used to lnvestigate

changes wlthin an lndivldual over time. As raÌ{r scores s¡ere

not used there was no valld reason ln thfs circumstance to expose the data to any partlcular transformatlon ¡ ë8, 1og e ( Bond and Lader, I97 4) or arcsine (¡,ttken and ZeaIIy, 1970) beyond the conversion of scores to a change from a reference zero tlne (Maxwe11 1978). Change scores htere subJect to wlthln subJeet statlstical comparfson.

The dimenslons st.udied were as f olloqrs:

,l rj Mood. I feel very miserable I feel very happy. I feel very placid I feel very írri table and angrY. Arousal. I feel very drowsy - I feel very a1ert. I feel mentally s1 cwed - I feel that my mind is racing very fast. I feel very resEful and physically fnacEive I feel very restless and fidgetY. I feel lethargíc / I feel fu11 of energy.

Subjects hrere asked to rate the qualitY of of their

previous night-s sleep on the morning after attendance on a 5 point scale (very well very badly). t 75

Comments made by the subJecÈs either during the ex,perlment or afterwards, were recorded as were any oÈher observations considered relevant by the experlmenter.

L.8.2. Psychophysfologfcal measures

Although subJectlve measures of menÈal state uslng vlsual analogue scales are flextble, sensitlve and a1low repeated measures of change over a perlod of time, the fact that they are a subJective measure requlres t,hat tdea11y, they should not be used 1n isolaEion fn psychopharmacological studles.

A variety of objective psychophyslologlcal measures reflectíng arousal - sedation have been found sufficienÈ1y sensiÈ1ve to detect, changes following drug admlnlstratlon :l _rrl (Lader, 1975).

Arousal q¡as de termined in thi s experiment by the followlng measures:

a Pulse rate.

b Blood pressure.

c Skin galvanome try.

I Skin conductance 1eve1 s. ií. Number of spontaneous flucÈuations ln skln conductance.

Changes 1n plasma cortisol which I¡Iere alSo measured in Ehis experíment have been used in other studies to reflect changes in arousal. In Ehis study however, change s ín plasna cortisol r¡¡ere not used to study arousal; raEher the l 76

effect of pimozíde or thymoxamlne pre treatment. on plasna

cortisol secretlon r¡ras considered a1 ong wl th o Eher studles exam lning the catecholamlne eontrol of corti so1 secretlon. See Part II.

Pulse rate and sysÈo1ic blood pressure can glve a sensitive objectíve measure of arousal (Lader, 1975). However, as drugs used in this experlment have peripheral catecholaminerglc actlvíty, changes recorded may reflect peripheral rather than central action.

a . Pu1 se rate

In the pilot, study pulse rate r¡ras recorded graphically using a dtgltal pulse recorder. However as this lnstrument

,,1 rq gave an audlble c1íck whlch could glve the subJecÈ feedback about the effect of the medication he may have taken, it was

fel t preferable to measure the pu1 se rate manua11y. The radial pulse hras counted for one minuEe every thirty ninutes throughout the experlment.

b. Blood pressure

Systolic and diastolic blood pressure hras recorded every

thirty ninutes E.hroughout the experirnent using a mercury

sphygmomanomomeÈer. Díastolic blood pressure r¡/as taken a t the poinl Ehe sounds became muffled.

c . Skin Galvanome t.ry TI I Skin galvanometry a11ows an accurate objectlve measure of

background arousal. The sq¡ea t glands, although acting under I 77

the conErol of the sympathetlc nervous system, are unlque 1n that the control is cholínergic (Venables and Christle, 1980). Thus changes fn caÈecholamlne functioning measured by skin galvanometry are more like1y Eo reflect central rather than perlpheral changes durlng the experlnent (Lader, 1975).

The measures of arousal uslng skln galvanometry 1n thi s experiment r¡rere the skin conduc tance level and the number of spontaneous fluctuat,ions in skin conducEance. The methodology f ollowed that. descrlbed by Lader and I.ling ( I966) and Lader (t975).

Newly made sl1ver-s11ver chloríde electrodes urere used.

Each vras 11 mm ín dlameter ( gS square mm) and set ln a recessed plastic holder wíth a depth of 1 mm to al1ow packlng of conductlve medlum. Electrodes qrere replaced if

the sl1ver chlorlde coaE. lng hras damaged. The conductíve nedium q¡as.05 molar KCL prepared 1n an agar PasEe (Venables and Chrístíe I973).

SubJects washed their hands wfEhouE soap on arrlval.

A uni polar elec Èrode placement r/ra s u sed . Af ter the area irras inspected for cuts or scars a circular foam cornplaster r/âs applled to the palmar surface of the thumb cenEering on the thumb print whorl . Thi s ensured a cons tanE surface area

of skín 9.5 mm in diameter and an area of 7 I square mm. The

I recess of the active electrode and the well of the corn

plaster was packed wi th c onduc t ive me d i um and the electrode

secured fírm1y 1n place wlth micro-pore dressing. An 78 lnactlve electrode was applled to the anterlor surface of the forearm whlch had been carefully abraded with an emery board using Èhe same conduct, lng medium.

Skln resistance I¡tas measured using a Servíoscrlbe recorder for five minutes every thirty mlnut,es, fifteen mlnutes after measures of vlsual analogue scale rat,ings, pulse and blood pre s sure ere re made and b1 ood sample s taken . Skln re s i s tance

(nffohms) was recorded graphlcally for flve minutes. The mean of five measures at one mfnute lntervals vras calculated, converÈed to a measure of the skin conductance 1eve1 (lticromhos) and logged (Lader and tJíng, I966; Lader, 197 5) . Log converslon of the skln conductarice 1eve1 is customary practÍce and has been va1ldaÈed by Venables and Chrisrie (1980).

A second re1lab1e measure of arousal deríved from the skln galvanometric reading hras the number of spontaneous flucÈuat,ions ín skln conductance (Lader and lltng, I966; Lader, 1975). Those spontaneous fluctuations greater than .003 LoE Micromhos that occurred ín a forty second períod ín every minute of the five minute recording hras counted and the mean for a forty secorid period calculated. 79

1.8.3. Blood Sanples

At 1700 hours, after basal readings were taken, a venous cannula r¡ras lnserted lnto a f orearm veln ( scalp veln cannula 21 gauge). This $¡as kept patent., fnltlally and af ter each blood sample $ras drawn, by a 0 .05 m1 lnJ ectlon of heparin diluted in normal sallne ( tOO units in 1 m1 ) . Immedíately prior to the dextroamphetamine dose and hourly thereafter blood was collected 1n lithium heparin tubes, centrifuged lmmediately and the supernatant plasma stored at minus 20 degrees cent.igrade for plasma dextroamphetamine estimatíon. Plasma dextroampheEaml-ne 1evels r¡Iere assayed by Servier Laborat,oríe s ( Or. Bruce Campbell ) using a gas chromaEographíc method ( Campbell 1969) .

Further blood samples ûrere collected thírty mlnutes prior to the dextroamphetamine dose, inmediately prior to the dextroamphetamlne dose r ârd hourly thereafter. It was collected in lithium heparin tubes and centrlfuged immedíate1y, or placed ln glass tubes and centrifuged after clotting, and the supernatant plasma or serum I¡¡as stored at minus 20 degrees centigrade for estímation of plasma cortisol and serum prolactin, growÈh hormone, thyroid stirnulatíng hormone, fo11ic1e stimulating hormone and luEe irrLzing hormone. Samples hlere assayed at the Department of C1ínica1 Endocrinology, St Bartholomews Hospital (professor Lesley Rees) by the fluorínetric method for free 11 hydroxy corticosteroids or by the double radlo-immuno assay rnethod for the other hormones' See Part II. 80

1 .8 .4. Recordlng schedule

Psychologfcal and psychophysiological measurements were conmenced aÈ 1700 hours and repeated at half hourly intervals untl1 2200 hours. The skin galvanometric measures were performed fifteen mlnuÈes after the other meaSures. Blood samples hrere taken at 1730 hrs, and at 1800, and repeated hourly thereafter.

t .9 . Drug s Used

1.9.1. Pl1ot studfes

Pitot studles Tdere conducted 1n an open manner to lnvesEígat.e the optímum doses, routes of admlnlstraLlon and timing of the dosage schedules. These experlments revealed that using oral dextroamphetamlne 20 mg rather than I0 mg gave a nore reproducible rise ln arousal and mood as measured by visual analogue scales, Èhe maximal rise being recorded tr¡ro to three hour S af ter the Cextroamphe Eamine dosage. It r¡ras not felt ethically j ustlfied to expose Èhe subjects to parenteral dextroamphetamine.

DoPanine blockade

Two alternaÈive methods of dopamine blockade \tere considered:

(a) Intravenous droperidol given immedíate1y prior to dextroanphetamine. 81

(b) Pimo zLde given orally 2 hours prlor to the dextroamphe tamine do sage.

Intravenous droperfdol at a dose of 0.5 mg when given alone or just prior to a dosage of 20 mg of dextroamphetamine, caused marked di scomfort 1n the subjects. Subjects reported such anxfetY, dysphorla and lrrltablliÈy that they r¡rere reluctant to continue.

Plmo zlde on the other hand caused no subj ecÈive dlscomfort. Both doses (2 mg and 4 ng) caused a rise ln prolactin tvto to four hours after the dosage, with that fol1owíng 4 mg belng slgnificantly greater than that followlng 2 ng. In order that the maximal dopamine blockade by pimozlde would coincide with the peak response to dextroamphetamine, it 1l¡as decided thât pimozide should be given two hours prior to amphetamine.

Alphanoradrenergic Blockade

Thymoxamine r4ras chosen as the preferred noradrenergic blocking drug, as it is a relatively selective alpha I Postsynaptic noradrenergíc antagonist. It is available ín both parent.eral and oral f orn. Intravenous thymoxamine rùas given eíther immediately prlor to dextroamphetamine or ninety minutes after the dextroamphetamine, aE a dose of 0.1 mg per kilogram. 0ra1 thymoxamlne r¡¡as given at a do se of 80 or 160 mg one hour prÍor to dextroamphet.amine ' The oral route proved the more suitable. 82

1.9 ,2. Experfmental design

In experiments A and C, when t.he ef f ects of the b1 ocking drugs alone were investígated, both doses of the ac t fve drugs or t.heir placebo were administered at 1700 hours and measurements hrere taken for the three combinatlons for the fo11 owing f lve hour s .

In both Experiments B and D, dextroamphetamlne 20 mgs or lts placebo sras given at 1800 hours. In Experlment B' either 2 or 4 mg of pimozLde or plmoztde placebo r¡ras glven at 1600 hours. In ExperfnenÈ D, elther 80 or 160 mg of Ehymoxanine or thymoxamine placebo was gíven at 1700 hours. Thus t,here hlere f our drug combinations f or each exPeriment. See t.ab1e 1.3.

TABLE 1 .3

Experiment B Exper lment D 1600hr 1800hr 1700hr 1800hr

PMZ Placebo dAMP Placebo TMX Placebo dAMP Placebo

PMZ Placebo dAMP 20mg TMX Placebo dAMP 20ng

PttZ 2ng d Al'1P 2 0m g TMX B 0mg dAMP 2 0mg

Pll,Z 4n g d AMP 20mg TMX 1 6 0ng dAMP 20mg

Dosage ùg ule or extroamp etamine, pimozi ean t vmoxam ne used in experiments B and D.

All drugs r¡¡ere given in a double blind manner. The schedules h¡ere randomised using a Latin square design. 83

1.10. Statfstical Analysis

The data for all dimensions hras converLed to change scores by subtractlng each value from the value scored by the subj ect at the commencement of the experiment, thereby allowing withtn subJect statlstical comParison. Two reference Èlmes hrere consldered. Values j ust prlor to the dose of dextroamphetamine or its placebo ( 1800 hours) was used to gauge the effect of the blocklng drugs on the response Èo dextroampheEamlne. Data was also assessed using

an earlier reference time for change scores ( 1700 hours ) , this being one hour prior to the dextroamphetamine dosage. Thi s latter reference tíme vras used 1n order to expose any changes. 1n basal staLe recordtngs caused by t.he blocking :)t T drugs occurrlng prior to the dextroamphetamine dose and thereby influencíng reference values.

In experíments B and D the change scores with the three active dextroarnphetamine combinations r¡rere comPared with the placebo blocker - placebo dextroamphetamine combinatlon. In a 11ke manner, the placebo blocker - dextroamphetamine 20rng combinatlon r.ras compared with the active blocker dextroamphetanine 20mg combination to deterrnine the effeet of the blocker on dextroamphetamine response. Subjective data (ie, that arising out of neasures of changes in mental state using the visual analogue ratlngs scales) ln experiments B and D \¡rere exposed to statlstical analysis using the nonparametrlc [^/ilcoxon palred rank difference test for each t ime measurement. As the nurnber s were so sma11 in I 84 exPeriments A and C, Student-s t tesl for matched pairs qras used.

Differences between means of change s of all other data vrere tesÈed using Student-s t tesE for matehed palr s. Statlstical signlflcance was taken at P < .05. Probablltty was calculated using the two tal1ed te s t .

I .1 t. Ethfcal Matters and Informed Consent

The protocol of the experlment. was Presented to, and approved by, the Ethlcs Commlttee, St. Bartholomews- Hospltal teachtng group. Informed consent was given by all

h ex erlment. Sub ects were excluded from participation 1f it Ìiras felt there may be some ri sk lnvo1ved. Results

page L.I2. Dextroamphetamlne Induced Arousal: Psychologlcal and Psychophysfologieal Aspects. 86

1.12.1. Introductfon. 86

I.I2.2. Results. 87 1.12.3. Dlscusslon. 94 1.13. The Role of the Dopamlne PaEhways ln Dextroamphe tamlne Induced Arousal . 96

I .13. f. Introductlon. 96

1.I3.2. Results. 97

a. PfmozLde a1one. 97

b Pharmacoklnetlc study. 100

c The lnfluence o f pimoztde pretreatment on the response Eo dextroamphe Èamfne. 102 1.13.3. Dfscussion. 116 I.L4. The Role of the Noradrenerglc Pathways 1n Dextroamphe tamlne Induced Arou sa1 . L20 1.14.1. Introduction. 120 L.L4,2. Results. r22

d Thymoxamlne a1one. 122 b Pharmacoklnetic study. r25

c The lnfluence of thymoxamine pretreatment on Ehe response to dextroamphetamlne. L28 1.14.3. Discusslon. r47 86

RE SULT S

L.L2. Dextroamphetanlne Induced Arousal: Psychologlcal and Psychophyslologfcal Aspects

1.12.1. Introductlon

ResulEs from exPerlments B and D fn whlch dextroamphetamíne Lras given alone ( placebo blocker - dextroamphetamlne 20 mg) have been pooled and cornpared wíth placebo only (placebo blocker - placebo dext,roamphetamine), thus glvíng 24 subjects ln all.

All daEa has been converted to change scores. Graphical preSenEat.ion will show dlfferences of mean ehange scores

f rom t.he placebo combinatÍon unle s s placebo condi tions Ì¡tere exertlng a stgnificanE lnfluence. As the direcEion of response can be antlcipated from earlier studies, the one tailed test for estimating statistlcal signlficance llras used. 87

1.I2.2. Results

The mean plasma leve1s of dextroamphetamine are seen in flgure I . 3 . The maxlnum 1eve1 s occurred be Èween 2 arrd 4 hours after adminlstratfon.

Psychologlcal data

The elevaÈion of visual analogue scale raÈlngs of haPplness and frritablllty was qulÈe modest. See figure I.4. The elevatlon of dlfferent ratings of arousal however' with the exceptlon of restlessness r wâs much more marked; Ehe rise in ratlngs hras statlstlcally sígnfflcanÈ at vírtua11y all recording times. See fígure 1.5.

The dextroamphetamine dosage also influenced th.e subjects- sleep during Ehe night followlng the experiment. The difference in the five point scale measuríng lmpaired sleep was +2.I, (p <.01).

Py s ch o phy s í o 1o g i c a1 d a t a

Dextroamphetamine induced a slgnifícant rise when compared with placebo 1n all measures apart from díasto1íc blood pressure and 1og skín conductance 1eve1s. The dífferences in mean changes ln pulse rate and systolic blood pressure ü¡ere highly significant after one hour. See figure 1.6. Placebo conditíons affected 1og skin conductance leveIs on1y. Dextroamphetamine, in' comparison, Produced a modest rise in levels 2.5 hours af ter administration. 0n the other hand the number of spontaneous fluctuations in skin 88

50

40

=ts cDc 30 o. = E 20

cl tr go 10 ÉL

o 1 2 3 4 hours

Figure 1.3 t"fean (1 SUU) plasma dAMP levels (nglml) f ollowíng oral dAMP 20mg ar 0 (1800) hours (18 subjects).

'I

I 89

VAS ratings(mml

5 *

o to (t o c 'ã. ct o 5

*

= tt o .:oË

o 1 2 3 4 hours

Figure 1.4 Difference in mean changes in VAS ratings (O - lOOmrn) from placebo (x axÍs) in'the miserable - happy and placid - irritabLe dimensions following oraL dAI4P 2omg given at 0 (1800) hours:

Difference versus placebo. 'tP (.05 VAS rat ¡ngs(mm)

¡| I 15 + I + I t t * + t + 90 { + * + :l I { * 10 I

ø 5 tn o c

(¡) o o

10 * + ø + tt, (¡, c 5 at u, o ø o 0

* 15 * I * * { . 10 'l* * * * * + I *

5 ol o c t

15

* * { + 10 * + * * ! + * a t '| o¡ I cL tt au- c o E o

o 1 2 3 4 hours

Figure 1.5 Difference in mean changes in VAS ratings (o - tOomm) from placebo (x axis) in the drowsy-alerr, restful-restless, Lethargic-energeEic and mentally slowed-mind racing dimensions following oral dAMp 2Omg given at 0 (i800) hours.

D j-f :r:kp f erence versus p lacebo. ''rP ( .05 ( , el ìkìçp < .01 9t a * + * * t 15 t I

I 10 * o t\l o 4¡ o tË L oo I cl -5 25 + 'l 'l* 2 * t + * a I 1 'l t { o I tr 5 oo- u o 0 .tt o -5

o 1 2 3 4 hours

Figure 1.6 Difference in mean changes in pulse rate (beats/min) and systolic blood pressure (mm Hg) from placebo (x axís) fotlowing oral dAMP 2Omg given at 0 (1800) hours:

Difference versus pLacebo. *P < .0025 :k,Jrp (.QQl 92

conductance vras lncreased by dextroamphe tamlne adminisÈraElon, particularJ-Y 1n the 1a t t.e r pârt of the study period. See figure 1.7. 93

o.04

I o.02 o o

o U' o.o2 E'¡ o -0.04

2

o * I 1 * o * * fil

(J 0 -"1il

o ct .n 1

o 1 2 3 4 hours

Figure 1.7 Mean changes in log SC (¡rmhos) and the number of spontaneous fluctuations in skin conducLance following oral dAMP 20mg given at 0 (18O 0) hours.

p Iacebo dAMP 20mg

Dif f erence versus placebo. 'kP <.05 :t-;rp (.QlJ

I 94

I.L2.3. Discusslon

The lncrease 1n ratlngs of mood and arousal and 1n most of the psychophysiologlcal measures used, by dextroamphetamine

20 mg r is generally conslsEent wlEh other studles.

The considerable difference in degree of subj ective response comparlng mood with arousal ratings is surprlÉtng and not reported 1n other studles ( Smtth and Davls, 1977; Silverstone et a1, 1983) , though less mood than arousal

changes Í¡Iere observed by Sllverstone et a1 ( 1980) '

Increased lrrltabiltty and happlness are to a degree

oppos I Èlona1 . Checkley ( Ig7 8 ) when s tudying the mood elevating and antidepressant effect of methylamphetamine, :l rrJ commented thaÈ mental staEe changes following amphetamlne : may be rnixed over tlme or even a! the same time, which may affect measurement uslng analogue scales.

The íncreases ín nost psychophyslologlcal measures are likewlse consístent wlth other studies (Martin et aI , I97l; Morselli et ai, 1978; Goldstein et aL, 1983; Nurnberger et aI, 1984). Orher workers have simllarly reported either a modest or no clear increase in skin conductance leve1s fo11owíng dextroamphetamlne (Zaht et 41, 1975; 1981; Rapoport et a1, 1980). The variabiltty of response is demonstraEed when skin conductance 1evels following

I dextroamphetamine in experíments B and D are compared. Skin conductance 1eve1s $rere significantly accenÈuated when compared with placebo in experiment B but noE in experíment

Ì 95

D. See 1.13.4.b. and 1.14.4.b.

Although lncreases in pulse rate and systolic blood pressure may reflect perlpheral actlvtty of dextroamphetamlne, changes ln skln conduCtance meaSures are more 1fkely to reflect central changes 1n arousal. Skln conducEance changes are mediated by a chollnerglc 19S0). symparhetlc pathh¡ay (Venables and Chrlstle ' Dextroamphetamlne appears to have no dlrect actlon on

chollnerglc neurones (Moore, L977) '

The narked elevation of arousal lnduced by

dextr oamphe tamlne 20 rng glven ora11Y t measured both

psychologically and p sychophy s i o1 ogl ca1lY' implles that

;¡ u occurrlng aE post synapElc rather than at presYnaPtic

sites. The latter may occur when a very 1ow dose of amphetamfne is glven. See introduction Parr rIr (t.2.5.).

The results in this section will be reconsídered 1n Part III when the response to dextroamphetamine w111 be compared with the kn.own phenomenar psychobiologlcal changes and pharmacologlcal correlates of rnild manla.

T lr

t 96

1.13. The Role of the Dopanloe PathwaYs

1n Dextroamphe tanine Induced Arousal

1. f3.1. Introductlon

This sectlon reviews the results of experiments B and D in which the effecÈs of Pretreatment by pfmo zLde on the psychologlcal and psychophysiologlcal resPonse to oral dextroamphetamf ne \¡tere measured. The ef f ects of pinoztde when given alone and the posslble effects of plmoztde on the pharmacokinetfcs of dextroamphetanlne w111 be considered first.

wlth the All data has been converted to change scores ' reference tfme being 1800 hours. Graphical presentatlon of data w111 no11mally show dlfferences of mean changes ln scores from the placebo - placebo combinaEion, unless

I placebo condi tions r¡rere exerting an inf luence. Graphs wl11 ,1 only be presented 1n those dimensions where a substantial ef f ect r¡ras recorded. The ef f ect of plmozlde 2 ng w111 not be demonstrated graphically if iEs influence was similar Èo the hlgher dose. Tables provide data at the tines of maximum response to dextroamphetamÍne and the time of maximum lnfluence by pimo z!ðe. Tabulated measures include +- Standard Error Measuremen!. It can be assumed that the lnfluences of the drugs at other ti¡nes are simllar unless otherwlse staÈed ln the texE. Statistical Probability I¡Ias estimated usíng the 2 Eailed test. I 97

L,L3.2. Results

d Pimo zlde al one

1. Psyehological meâsures

Mood

Pimo zLde a1 one produced no consl stent response 1n the four subJects ln the vi sual analogue scale ratlngs of happfness or arousal.

Arousal

In the various dlmenslons reflecting arousal and hyperacEivlty, pimozLde 4 mg tended to elevate ratfngs 1n

1l th doses elevated scores ln the restlessness dimenslons. No changes reached sEatistical slgnificance.

i1. Psychophyslological measures

Cardiovascular neasures

Both doses of plmozide tended to reduce pulse raEe and diastolic blood pressure but íncrease systolic blood pressure. Though the pattern of responses I¡Ias reasonably conslstent over tlme, only one reading reached staÈlsÈica1 slgnificance - dlastolic blood pressure at 4.5 hours -6.2(+-f.2) mm HG, P <.02. 98

Skln galvanome try

Log skin conductance leveI s were modestly elevated followfng placebo alone. Both doses of pimo zLde lead to a notlceable drop ln 1og skfn conductance leve1 s which lncreased durlng the experlment. Thfs reached statistlcal slgnlficance fn the last hour followfng pimozLde 2 ng and ln

the las t hour and a hal f. f. o11owf ng plmo zlde 4 mg . See flgure 1.8. The dlfferences from placebo at four hours hrere: pimozlde ng and plmozlde 4 mg 2 -0.40(+-0.09) -0.41(+-0.09) ' P < .025, and at four and a half hours: pimoztde 2 ng -0.53(+-0.08) and pfmozLde 4 mg -0.41(+-0.05), P <.01.

No consistent changes hlere observed 1n the number of

pofltatreors f1 r¡ctuatlons frr skln sond uc Eance . 99

o-2

o o o

b - o-2

I o ll t Ø r¡{ ctr + - 0.4 t o +

- o.6

o 1 2 3 4 hou'r s

Figure 1.8 Mean changes in tog SC (¡rmhos) fotlowing pMZ 2mg, PIIIZ 4r;g given at O (1BOO) hours.

p 1 acebo l}rrrrrrrrr

PYIZ 2mg Y-r-rr

PNIZ 4mg ,¡lrrrr

f Dif erence versus placebo . )kp <.025 *rcp ( . el 100 b. Pharmacoklnetie studY

Neither dose of pimozlde significanÈ1y affected serum dextroamphetamlne 1evels lndlcatfng that any alteratlons of the dextroamphetamlne response due to plmozLde were not reflectlng changes 1n the pharmacoklnetlcs of dexEroamphetamine. See flgure 1.9.

Mean (+-SnU) area under the curve estlmates are as f o11oürs:

dAMP 20 mg: 89.5(+-t0.2)

Pl'lZ 2 ng + dAMP 20 mg: 81.3(+-11.7)

PþlZ 4 mg + dAMP 20 mg: 89.0(+-8.3) 01

50

40 I E 30 Ð T o- 20 = ï¡

t\l 10 o tÉ È

o 1 2 3 4 hours

Figure 1.9 Mean (! SnU) plasma (ng/ml) fotlowíng pretreatment by pimozíde given 2 hours prior to the dAllP dosage given at O hours:

Pl4Z placebo - dAMP 20mg PltZ Zmg - dAMP 20mg lþrrrr PlrtZ 4ng - dAMP 20mg brrrr

I

ì

I i 702 c. The tnfluence of pimozlde pretreatment on the resPonse Èo dextroamphe Èamlne.

1. Psychologleal measures

Mood scale s

The I2 subjects in experlment B recorded only a modesE rlse in the mlserable - haPpy and placid - irritable dirnensions, when dexÈroamphetamine 20 mg alone is cofnPared with the placebo - placebo combinatlon; the rise did not reach statistlcal slgnificance. Pretreatment wlth elther dose of pimozide fal1ed Eo cause any consistent change to the dextroamphetamine resPonse.

Arou sal

Dextroamphetamine 20mg alone when compared with Placebo caused a sígnlficant, rí se in the me an change s 1n visual analogue scale ratlngs 1n the drowsy alert and lethargy energetic, dirnensions on1y. The rise 1n the restful restless and mentally slow mínd raclng dímensions slere modest and f aí1ed to reach st,at.istical slgnif ícance.

PretreatnenE with the higher dose of plmoz!de glven two hours príor to dextroanpheÈamine, evoked a sma1l drop in

Some parameters, and a small apparenÈ rise ín the drowsy alerE dímensíon, none of which reached sEatistical signiftcance (see Table 1.4.). The changes in the energy and restlessness dimensions are graphlcally illustrated in figures 1.10 and I.11. 103

10 E

o E') .: 5 rú L tn o

E) S o o -5

o 1 2 3 4 hours

Figure 1.10 Differences in mean changes in VAS ratings (O - tOOmm) from the PMZ placebo - dAMP placebo combination (x axis) on the lethargíc - energetic dímension demonstrating the effecl of Pl4Z 4n.g 2 hours earlier on the response to oral dAMP 2Omg given at 0 (1800) hours.

PIIZ placebo - dAMP 20mg Pl4Z 4mg - dAMP 20mg Errrt 104

E o 1 o E'¡ tr +t ttl L Ø 5 o o o o o go o o L 5

4 o 1 2 3 hou rs

Figure 1.11 Differences in mean changes in VAS ratings placebo combination (O - lOOmm) from Ehe PMZ placebo - dAMP (xaxis)intherestful-restlessdimensiondemonstrating response the effect qf PÞ12 4mg given 2 hours earlíer on the to oral dAMP 2Omg given at O (1800) hours'

PMZ placebo - dAMP 20mg o- Pr4Z 4mg - dAMP 20mg F---l 105

Table 1.4. Arousal Ratlngs

D mens on Pþ12 Plac PMZ Plac Pl"lZ 2ng PMZ fng dAMP Plac dAMP 20mg dAMP 20ng d AMP 20ng rosrsy alert ¿¿ ¿ 2h +8 .7 +I6 .4 +16.6 -3.1 ú 4h +0.8 +7 .0 +9 .3 +6 .3 lethargy energy 2 .5h -0 .2 +9 .0 +4.7 +6 .4 * 3.5h -0 .9 +7 .0 +2 .9 +1 .1 ment . s1 ow mlnd racíng th +2 .I +5 .7 +5.'3 +1.8 ¿ 2 .5h +0 .5 +11 .0 +9 .3 +13.5 restful restless 2h +1 .8 +7 .4 +8 .7 +3.1

2 .5h +3 .4 +5 .4 +5.5 +0.3

Mean change s from 1 800 ours at t eÈ mes of maxírnum response to dextroamphetamíne and at the time of maxlmum influence by plmozide pretreatment. * P <.05, ** P <.02, comparing the active drug combínations r¿íth placebo - placebo.

There hras no consisEent change in the alteratíon of dextroamphetamíne induced sleep response by pimozíde.

The data were also analysed Eo invesEigaÈe wheEher pimozide q¡as exerEing any sedative action wlthin thro hours of íts administration ( ttrat is before the dextroamphetamíne dose) thereby influencing t.he reference value for comparing change, l.Ihen 1700 hours $¡as used as the reference time for comparing chanBês, a rní1d drop is seen in the drowsy - alert scores by 1800 hours (See Figure 1.12). Although this effect 106

15 ts dAMP E El 10 .s É Ø 5 g d 0 o ì o L ît -5

-10

o 1 2 3 4 5 rs

Figure 1.12 Differences in mean changes (0 = 17OO hours) in VAS ratings (0 - 100mrn) from the PMZ placebo - dAMP placebo combination (x axis) in rhe drowsy - alert dimension demonsÈrating the effect of PYIZ 4mg given 2 hours earlier (1600 hours) on the response to oral dAMP 20mg given at 1 (fAOO) hours:

PMZ placebo - dAMP 20mg PYIZ 4mg - dAMP 20mg þrrrt 107 does not reach sÈatistical signíficance, lt can be seen that uslng thl s time for comparl son 1n the drowsy - alerÈ dimensfon pimozlde pretreatment causes a late ' modest non-signíficant fa11 in arousal. Altering t.he reference tlme for comparlson of changes wiEh the other dimenslons did not influence the results.

1i. Psychophyslologlcal Measures

In the twelve subj ec t s in Exper lment B , dextroamphe tamlne adminisÈratlon led to a signiflcant rfse in pulse and systolic blood pressure when compared with the placebo placebo comblnation. The ri se h¡as maximal at two-and-a-half hours after admlnlstration. Diastollc blood pressure r,tas not affected by dextroamphetamine nor {¡Ias arLy pimozlde effect demonstrable in these subjects.

The larger dose of pimo zíde preÈreaÈment significantly reduced thè\ increase in pulse rate lnduced by dexEroamphetamine. For example at 2.5 hours Ehe difference between the ptmozide 4 ng - dexcroarnphetamlne 20 mg and pimo zlde placebo - dexLroamphetamlne 20 mg r¡/as -7 .6(+-2.3) beats /m1n (p <.01). See figure 1.13. Pimozlde pretreatment did not appear to ínfluence the systolic blood pressure response Eo dextroamphetamíne. (ft should be noted hoh/ever that if the earlier tíme for comparison of changes [1700] is used, pímozide preEreatment did modestly but signtficantly

reduce systolic blood pressure, the rnaximum effect being 2

hours afEer the dextroamphetamine dose {-q.A[+-2.:] mm HG, P <.0sÌ). 108

20

15

-l

10 *

I + OE t cl L !o eo

-5

0 1 2 3 4

hour s

Figure 1.13 Differences in mean changes in pulse rate (beats/minuEe) from the PMZ placebo - dAl4p placebo combination (x axis) demonstrating the effecr of PMZ 4mg given 2 hours earlier on Ehe response to oral dAMP 2Omg given ar O (1800) hours:

Pl'12 placebo - dAMP 2Omg PÞ12 4mg - dAMP 20mg l----

Difference induced by Pl4Z on the dAMP response.

,kP <.05 ;k;kp (.Ql :k:k*p ( . Ql 109

The means of change scores (+- SEM) aÈ the times of the maxinum dextroamphe tamlne re sponse and maximum lnfluence by pimozLde are 11sted in table 1.5.

Table 1.5. Cardlovascular Measures

Dlmen s 1 on PtlZ Plac PllZ Pla c PltZ 2ng Pl"lZ 4m g dAMP Plac dAMP 20ng dAMP 20mg dAMP 20ng pul se (beats/min) ¿&J *** ¿ 2 ,5h -r.4(+-r.6) +1 3 . 6(+-2.4) +10.6(+-1.7) +6.0(+-r.7)

!J¿ *** *** 4h -1.3(+-r.s) +16.1(+-3.4) +1r.9(+-2.7) +11.9(+-2.0) systollc BP ¿J¿ ¿ mm IlG ¿¿¿ 3h +2.0(+-r.6) +2r .9 (+- 2 .7 ) +18 . 2(+-2.4) +23 .4(+-2.4)

ean c ange s +- M from 1800 hours at the tlmes o max mum response to dextroamphetamine and the maximum influence by pimozlde (q¡hen dif f erent). * P <.05, ** P <.01' *** P <.001, comparing Èhe active drug combinatlons wfth placebo - placebo. 110

Skln galvanome try

There r4ras a rise in log skln conducÈance 1evels followlng placebo. Dextroamphet.anine 20 mg stgnlficantly accenÈuated Èhls rlse and thís accentuation I{as attenuated fn a dose related manner by pimo zide. See table 1.6. Thl s í s graphíca11y illustrated in ffgures 1.14 and 1. I5; Ehe latter uslng differenceS of means of change scores clearly reveals the effect of pimozlde on the dextroamphetamine response.

Table 1.6. Skin galvanometrY

Dr ug PYIZ Plac PM,Z Plac PllZ 2ng PllZ 4ng condltíon dAMP Plac dAMP 20ng dAMP 20mg dAMP 20ng

1og SC umhos means of change s 1945h +0.071 +0.143 +0.087 +0.058 (+-.044) (+-.047) (+-.03s) (+-.03s) díff from plac - plac +0.07 2 +0.016 -0.010 (+-.03s) (+-.033) (+-.043) means of change s 20r5h +0.059 +0.134 +0.081 +0.064 ( +- . 0 s 5 ) (+-.049) (+-.041) (+-.0a0) diff from plac - plac +0.07 +0.022 +0.055 (+-.041) (+-.047) (+-.0s8)

Mean c ange s an fferences from t ep ace o - placebo conbinatíon in 1og skín conductance 1eve1s ( umhos) at the times of maximum response to dextroamphetani ne and the maximum influence by pimozíde.

The maxínum lnfluence by pirno zide pretreatnent on the dextroamphetamine induced changes in 1og skin conductance 1eve1s h/as at I945 hours; -0.085(+-c.0-î7) umhcs, P < .05. 111

dAMP o.15

o.1 o o

o. t o Ø c'| o o 1715 1815 1915 2 015 2115 t ime

Figure 1.14 Mean changes in log SC (¡¡mhos) in the response to oral dAMP 20mg given at 1800 hours following PMZ given at 1600 hours:

PYIZ placebo - dAMP placebo Q rrrrrrrrr PMZ placebo - dAMP 20mg tr- PMZ 4mg - dAMP 20mg b¡r¡

Difference induced by PYIZ 4mg pretreatment on the dAMP response.

'kP ( .05 tr2 0.08

dAMP

o.04 o o

E o o o

CD o

-o.o4

1715 1815 1915 2015 2115 time

Figure 1 .15 Dif f erences in mean changes in log SC (,¡¡mhos ) from the PMZ placebo - dAMP placebo combinaEion (x axis)'in the response to oral dAMP 20mg given at 1800 hours following PVZ 2mg and PMZ 4mg given at 1600 hours:

Pl4Z placebo - dAMP 20mg c- PÞ12 2ng - dAMP 20mg l}rr-rr Pl{Z 4mg - dAMP .20mg

Difference induced by PY1Z pretreatment on the dAMP response. Y.P < .05 113

The number of spontaneous fluctuatlons ln skln conductance did not change after placebo. Mean changes 1n scores (+-SEM) are recorded in tabl e I .7 . and lllustrated graphlcally in flgure 1.16. DexEroamphetamlne 20 mg produced a signíficant rlse 1n Èhe number of spontaneous fluctuations when cornpared wiEh the placebo - placebo condiEions at most readíngs. Thís rlse was attenuaEed 1n Part by plmozlde, partlcularly by the hlgher dose. The naximum influence by pimozide r¡ras at three hours; -2.20(+0-.85), P <.025.

Table 1.7. Spontaneous flucÈuations

Dru g PY1Z P 1a c PMZ Plac Pl"lz 2ng PMZ 4nB conditions dAMP Plac dAMP 20ng dAMP 20ng dAMP 20mg

+ spont. fluct rj ¿-L fto . 2 .5h -0.3(+-0.67) +1.5(+-r.0) +0.3(+-0.9) -0.7(+-i.0)

¿J 3h -0.7 (+-o. s) +1.9(+-0.8) +1.3(+-r.0) +1.4(+-1.0)

Mean c ange s +- E nt e nunber o spontaneous fluctuations in skin conductance, from 1800 hours, at the tlmes of maximum response to dextroamphetamine 20ng and maximum influence by pimozLde pretreaEment,. * P<.05':k* P<.01' comparing the active drug combinations with placebo - placebo.

In summaty t the only demonsÈrab1e effect of pimo zide alone sras a reducEíon in 1og skín conductance 1eve1s. Pimozide pretreaEment did not affect plasma dexLroamphe ta¡nine 1eve1s.

The effect of pimozide pretreatment on the dextroamphetamine response measured by PSychological ratings riras modest r,rith some tendency to reduce ratings; no effect

I LT4

.ti

3 o o Itl ¿ +. o

r.- 1 .t o coo G' o ct Ø -l

o 1 2 3 4 hours r¡ &l

Figure 1.1ó Differences in mean changes in the number of spontaneous fluctuations in skin conductance from the PMZ placebo - dAMP placebo combination (x axís) demonstrating the effect of. PI"IZ 4mg given 2 hours.earlier on the response to oral dAMP given at 0 hours:

PltlZ pLacebo - dAMP 2Omg rb PYIZ 4ng - dAMP 2Omg !rrrr

)kP < .05

T 115

ûrâs statistically slgnlflcant. Pimozlde pret'reatment dld' however, reduce dextroamPhetamlne arousal measured psychophysfologlcally; reducing pulse rate systollc blood

pre s sure , 1og skin conductance 1eve1 s and the number of spontâneous fluctuatlons 1n skln conductance. Thls effect ls partlcularly apparent 1f an earlier time for estimatlon of change values ütas used.

I

l l

I

I

:l

I lr

! t76

1.13.3. Dfscusslon

Pimozide when glven alone had 1lÈtle consi stent effect on

the varf ou s psychological ratlngs or psychophyslological

measures aparf from skin conductance 1eve1s. This may be a reflection of some sedating actlon of the drug.

Thls study failed Èo demonstrate aîy effect by pímoztde on dextroamphetamlne lnduced mood changes and thus did not

replfcate the findings of Jonsson (197 2) . In that sÈudy pirno zLde blocked the mood elevating ef f ect of very hlgh doses of intravenous dextroamphet.amíne.

The ví sual analogue scale rat.ings of the differenÈ arousal - hyperactivlÈy dimenslons demonsÈrated the stlmulatory actlon by dextroampheCamine. Pimoàtde tended to reduce t.his but this Èrend failed to reach sEaEistical significance.

Plmo zlde failed to influence significantly the raEing of Èhe qual i ty of sleep durlng the night followlng the experiment. However pimo zlde pretreatmenE lead to a drop ín the psychophyslological measures of the dextroamphetamine response.

Neither Rosenblatt er a1 (1979) nor Nurnberger et aI (I984) were able to demonstrate an attenuation of the

ca rd í ova s c u1a r re s p on s e to íntravenous dextroamphetamine by pimozLde or the related dopamine blocker haloperldol. In the latter attenuated the rise in I st,udy though, haloperidol subjective arousal.

'The site of actíon of pínozLde on cardiovaseular measures

I tr7

skln conductance ls unclear r however the reductlon ln measures pregumably reflects a central actlon. As ment'loned earller, skln conductance changes are medlâted by chollnergic sympathetic ffbres (Venables and Chrtstle, 19SO). Pimoz:-ð.e 1s a speclfle centrally acting dopamlne blocking drug and llke dextroamphetamlne has no dlrecE actlon on cholinerglc neurooes (ptnder et aL, I976; MacKay, 1982).

Taking all these results together, tt seems reasonable to suggest that dopamine blockade by plmo zlde attenuated 1n part aE 1east, the arousal response to dextroamphetamlne, lmplying thaÈ such dextroamphetamine lnduced changes involve

These flndings are 1n keeping wlth Prevlous studles lnvestigatlng the effect of pimo zLde on the dextroamphetamlne response. Jonsson (I972) reported that plmo zLde aEtenuated the mood elevating effect of a large intravenous dose of dextroamphetanine, thi s attenuatlon being more specifíc than that lnduced by chlorpromazlne or

thi or i da zLne ( Gunne e t aL , 197 2) .

Silverstone et a1 ( 1980) reported t.hat pimozíde attenuated subjective arousal as measured by vlsual analogue scales in normal young \"¡omen. In E,hat study the mood elevating effect of dextroamphetamlne r¡ras too sma11 for an attenuating effect

Eo be neasured. In a sirní1ar manner Gi11in et a1 (tgl s tb I ) reported that pimo zlde reduced the sleep-reduclng effecE lnduced by dextroamphetamine ( not replicated in the present 118

sEudy).

Although the effect of other neuroleptlcs on the dextroamphetamlne response have not been wfdely s tudied 1n humans, they have been extenslvely studled 1n exPerimental animal s . For examPle , the abil f ty of a drug to block

i s dextroamphetamine lnduced motor actlvf ty and stereotyPy ' used as a biologlcal measure of Ehe drugs- PotenÈía1 as a neurolepEic agent (.lanssen et a!, 1965). Dopamine blockade or lnt.errupt,ion of the dopamine PathÌ.¡ays selectlvely attenuates dextroampheEamine lnduced hyPeracÈtvity. (See

Introduction 1 .4. )

The results of this experlment taken ln conJunction with ftndings of simllar experiments both using exPerimental anlmals and human st,udies glve furEher confirmatlon that dopamlne blockade attenuates the arousal and mood elevating effects of dextroamphetamine.

From this can be 1mp11ed that dopamlne pathl¡¡ays are directly involved 1n arousal in experinental animals and in arousal and mood ln humans. Thís 1s in keeplng wlth evídence from animal experlments lnvestigating the role of t,he dopamine pathways using leslons and pharmacologíca1 procedures. The findings are also 1n keeplng with other' predominantly pharmacological, studie s in humans, which point to the dopamine paEh$/ays being ínvolved ín states of elevated nood and hyperactivily 1n both healEh and disease. See introduction 1.3.4.c. LT9

The role of the dopamlne pathways ln mania will be discussed 1n detail in Part III. t20

1.14. the Role of Noradrenerglc Pathways 1n Dextroanphetanlne Induced Arousal

1.14.1. IatroducÈ1on

Thls section w111 review the resulEs of experiments C and D which lnvesÈigated the effect of pretreatment by thymoxamine on the psychological and psychophysiological responses to dextroamphetarnlne. The ef f ects of thymoxa'.nine when given alone and the questíon of whether thymoxamine lnfluences the pharmacokinetics of dextroamphetamine w111 be considered flrst.

All data has been converted to change score s. The reference time for change scores 1s f 800 hours (just prlor to the adminlstratlon of dextroamphetamine or íts placebo) unless otherwise specified.

Graphs will be presented only for those dimensíons that dernonstrated sígnificant changes. I"lhen the effects of the smaller dose of thymoxamÍne I¡/ere similar to, but quantitatíve1y smaller than Ehe higher dose, they have not been illustrated. I'lhen the ef f ect $¡as in a dif f erent dírection to that induced by the higher dose, the results are shown. In order to nake the graphical presentation clearer, data aristng from the placebo conditíons have only been presented in those cases when placebo exerted an t2t

influence on the results. RaÈher the data ha s been pre sente d graphically as dtfferences 1n the mean change s from the placebo placebo comblnatlon (thereby maklng Èhe plaeebo placebo response the X axis).

All stâtlstlcal probablliÈ1es hrere calculated elther uslng the S¡l11coxon paired rank difference test or Student-s t test, uslng the tû¡o tailed test. r22

I.L4.2. Results

a Thym oxam I ne al one

f. Psychological measures

Neither dose of Ehymoxamine produced any conslstent change in the mfserable - happy dimenslon. In the lrrftabl11ty ratlngs r Ehe higher dose tended to elevate r and the lower dose to reduce the scores but nelther of Lhese changes reached statlstlcal significance

Of the different vlsual analogue scale ratings of arousal and hyperactivtty only those scores ln the drowsy - alert dímenslon hlere elevated by the higher dose of thynoxamlne

( see figure 1.17. ) . No consistent change hlas manlfest by elther dose of Èhymoxamine ln the ot er rat ngs o arousa

1t. Psychophyslologieal mea sure s

80 mg of Ehymoxamine tended Èo reduce pulse rate and

systolie blood pressure whl1e the higher dose lead to a sma11 lncrease, though agaln neither change reached suatísEical slgnfficance. The hlgher dose of thymoxamlne reduced dÍasto1íc blood Pressure and thls reached hours (+-t .7) and statlstical significance aE 1 and 4.5 ' -6.3 -7 .3(+-t.7) mm HG, P <.05. See flgure 1.18.

Log skín conductance r¡¡as Ehe only measure ín which placebo condltions exerted an inf luence. The leve1s I¡Iere increased after placebo and this rlse was attenuated by both doses of thymoxarnine. The number of Spontaneous flucEuatlons on the VAS rat¡ngs (mm) 723 10

5

; o¡ o r\t -5

-10

10

5

o

¡ -5 É \L-'-*'\.-.-./ 't'y' -10

o 1 2 3 4 5 hours

Figure 1.17 Mean changes in VAS ratings (0 - 100mm) in drowsy - alert and placid - irritable dimensions following TMX 80mg and TMX 160mg given at 0 hours:

p Iacebo frrrrrrrrrrr

TMX 80mg !'.-.-r

TMX 160mg J---- L24

5

¡. (9 \ t o E \ t E \ o. .?Q o \- Ë o t iia t o .! !, 1

o 1 2 3 4 5 hours

Figure 1.18 Dífferences in mean changes ín diastolic BP (mm Hg) from placebo (x axis) fotlowing TMX 80mg and TMX 160mg given at 0 hours:

TMX 80mg !¡r-¡-

TMX 160mg iI----r

Difference versus placebo. rrP < .05 125 other hand tended to rlse followlng both doses of thymoxamine¡ The relatlve drop ín skln conductance 1eve1s and the rise ln spontanêous fluctuatlons measures both falled to reach statlstleal slgniflcance. See ftgure 1 .19.

b. Pharmacoklnetlc s tudy

Netther dose of thymoxamfne slgnlflcantly affected serum leve1s of dextroamphetamine lndtcating that changes lnduced by thymoxamfne in the dextroamphetamlne response stere not due to changes ln Èhe pharmacokinetfcs of dextroamphetanLne. ( See figure 1.20. ) .

Estlmates of the areas under Èhe curve (+-SEM) are as f o11ows.

dAmp 20mg: 120.5 (+- 10.3)

TMX 80m + dAMP 20mg: 105.6 (+-2.1 )

TMX 16Omg + dAMP 20mgz 129.0 (+-S.7)

Unfortunately some assay samples hlere lost. I.lhe n esEimaÈes using matching palrs are comPared, no effect by either dose of blocklng drug 1s aPParent. 726

o-2

o.1

Ia o o ts:t c) Ø -o.1 c'¡ o -o-2

2

1 u a o c\ o -1

0 1 2 3 4 hours

Figure 1.19 Mean changes in log SC (/¡mhos) and in the number of spontaneous fluctuations in skin conductance following TMX 80mg and TMX 160mg given at 0 hours:

p I acebo lrrrrrrrrrr TMX 80mg F.-.- TMX 16Omg r---- t27

50 J ----t- 40 -1 h

E't 30 È

= 20 r, I a Itl

Ø 10 ñ o.

o 1 2 3 4 hours

Figure 1.2O Mean (l SAU) plasma dAlfP (ng/ml) fotlowing

pretreatment by thymoxamine given t hour prior to the dAMP dosage þiven at 0 hours (6 subjects):

TMX placebo - dAMP 2Omg TMX 80mg - dAMP 20mg ¡}-r-r- TMX 160mg - dAMP 2Omg ]¡---. 128

c. The influence of Èhymoxanine pretreatment on the response to dextroamphetamlne

i. Psychologlcal measures

Mo od

In Experiment D dextroamphetamíne 20 mg 1ed to a nodest rise 1n happlness and lrritabillty ratings when compared wi th the placebo - placebo combínation, though the resPonse was varlable (See table 1.8.).

Table 1.8

Dimen s i on TMX Plac TMX PIac TMX 80mg TMX 1 6 0mg -dAMP Plac -dAMP 20mg -dAMP 20mg -dAMP 20mg miserabl-e- haPpy 2 .5h -r.7 +1 .4 +4.0 +2.6 3.5h -0.6 -0.9 -¿.)ôE +1.5 placid- irritable 2 .5h -5 .4 +2 ,6 +4.6 +6 .6*

3h -3.6 -3 .2 +6 .6 +5.7* VAS ratlngs of mood dimensions at t et mes of the maxlmum response to dAMP and the maximum Ínfluence of TMX pretreatment.. * P<.05 comparing the active drug combination wi th the placebo - placebo combinatlon.

The increased irritabiliÈy following dextroamphetanine 20

mg when compared wi th the placebo - placebo combínation h/as

maximal at 2.5 hours (+8.0, P <.1). Thymoxamíne 160 mg pretreatnent caused a significanE increase in irritabilíty

compared r¿ith the placebo - placebo combinatlon at 2.5 and 3 hours and compared with the placebo - dextroamphetamine 20 129 mg comblnatlon at 3 hours (+8.9, P <.02). See figure I.2L.

Arousal

Dextroamphetamlne 20 mg when given alone, caused a rise 1n Èhe vlsual analogue scale ratíngs in the four dimenslons reflectíng arousal; drowsy - alerE, physlcally inactive restless, mentally slowed- mind raclng, and let.hargy energy. See table 1.9.

TABLE 1 .9

Dlmen s I on TMX Plac TMX Plac TMX 8 0mg TMX I 6 0mg dAMP Plac dAMP 20ng dAMP 20ng dAMP 20mg drowsy alert 1.5h -2 5 +B .3** +g .3** +15.0***

2 .5h - 6;2 +12 .2** +l0;0*** f 9-6** rest.ful- restless th -r.7 +0 .2 +6.9 +13.7*** 1.5h -4.1 +6 .0 +8.7* +l 3.0***

1e thargy energy 3h -5.6 +5.6 +11.1 îo./,r¿r^t / tJ-L¿ 3.5h -7 .6 +10.4*x* +5 .1 +6 . 9 'r** ment. slowed -m ind racing th -2.4 +5.1 +6.7* +11.4***

2.511 +9.3* f o . / ^ +8.5*^"

VAS ratings o arousa imensions at t et mes of the max mum re sponse to dAMP and the rnaximum re sponse by TMX pretreatnent. *P<.05, **P<.02, ***P<.01, comparing actlve drug wi th the placebo - placebo combination. 130

15

Þ Þ g'o 10 I +. tú L' U' -

o .c¡ É +¡ L L -5

o 1 2 3 4 hours

Figure 1.21 Differences Ín rnean changes in VAS raEings (1 - 1o0mm) from the TMX placebo - dAMp pracebo combinarion (x axis) in the placid - irritable dimension demonstrating che effect of TMX L6Omg given t hour earlier on rhe response to oral dAMP 20mg given at O hours:

TMX placebo - dAMP 2Omg TMX 160mg - dAMP 2Omg l¡--¡

Difference induced by TMX pretreatment on Lhe dAMp response. )kP < .02 131

Prior treatment wlth thymoxanine, partlcularly the higher dose, caused an elevatlon 1n ratings when compared with the placebo - placebo combfnation. 160 mg thymoxamlne pretreatment lead to a slgnlficanÈ accentuatíon of the dextroamphetamine response in the restlessness dimenslon only, maximal at one hour (+I3.5, P <.05). See figure L.22.

Thymoxamine pretreatment dtd not alter the reduction in sleep induced by dextroamphe Eamlne.

11. Psychophyslological mea sure s

Cardlovascular measures

In the measures of pulse rate, sysEolic and diastolic blood pressure, dextroamphetamine admlnlstratíon 1ed Eo a ri se in score s when cornpared wl th placebo . The maximal difference from placebo occurs al different tlme s ' namely four hours (pu1se), two hours (systollc blood pressure) and at one and a half hours (diastolíc blood pressure). Thymoxamlne pretreatmenE 1ed to a modest, rlse in both blood pressure measures and a mild drop in pulse rate, none of which reached statístical signíficance. The values at the Èírne of the naximal change induced by dexEroamphetamine and of the maxlmal difference induced by thymoxamine

pretreaEnent are given 1n Table 1 .10.

A 1ike1y peripheral effect of Ehymoxamine make s i t díf.f.icu1t to ínterpret these changes 1n Eerms of alteration in central arousal. r32

20

15 E E o c'l 10 ;- rlt L Ø 5 I I o I o I o t!, o o o o o L -5

o 1 2 3 4 hours

Fígure 1.22 Differences in mean changes in VAS ratings (0 - 100mm) from the TMX placebo - dAMP placebo combination (x axis) in the restful - restless dimension demonsErating the effect of TMX 160mg given t hour earlier on the response to oraL dAMP 20mg given at 0 hours:

TMX placebo - dAMP 20mg TMX 16Omg dAMP 20mg I-----.

Difference induced by TMX pretreatment on the dAMP response.

'kP < .05 133

Table 1.10. Cardlovascular measures.

Dlmenslon TMX Plac TMX Plac TMX 80mg TMX t60mg dAMP Plac dAMP 20ng dAMP 20mg d AMP 20mg

pul se (beats/mln) * sù * 2 .5h -r.2(+-1.3) +8.7 (+-3 .1) +9.7(+-3.2) +4,6 (+-2.5)

ùJ ¿¿¿ 4h -r.4(+-1.3) +13.0(+-3.7) +12.4(+-3.0) +7,8(+-2.0) systollc J¿& ¿.L¿ BP mm HG *** 2h +5.0(+-2.5) +24.9(+-2.8) +28.3(+-2.5) +23 . I(+-2.9) * 3.5h +2.r(+-2.0) +15.3(+-2.3) +21.3(+-2.3) +20.0(+-3.1) dlastollc BP mm HG * J¿ I .5h +2.7(+-r.7) +8 .6 (+-2.4) +s.8 (+-2.4) +9.5(+-2.8)

3.5h +3.6(+-1.7 +1.41+.2.0) +3.4(+-1.s) +6 .4(+-Z .6)

Means o c ange scores +-SEM from 1B00hr at t e times o rnaximum response to dAMP and the maximum lnfluence by TMX pretreat,ment. *P<.05, **P<.01, ***P<.00I comparing the active drug combination wlth the placebo - placebo combÍnatlon.

Galvanometric measure s

In Exper iment, D, skin conduc tance 1eve1 s r{rere affected by the placebo conditions of Ehe experínent, an effect most

clear when the reference tíme for change scores is 1715 hours ( see figure 1.23). Dextroamphetamlne 20 mg did not

Ínfluence Ehe skin conductance 1evel when cornpared wlth the placebo placebo conditions. Both doses of thymoxamine

caused an augmentation of the skin conductance 1eve1 when t34

d AMP tl o.2

---Ù --Ltt^¡r! o.15 l--...

o.1 o o

0.05 o Ø ct) o 0 1715 1815 1915 2015 2115

t ime

'i

4

: Figure 1.23 Mean changes in log SC (¡mhos) ín the response to oral dAMP 20mg given at 1800 hours following TMX given at 170O hours:

TMX placebo - dAMP pLacebo $rrrrrrrrrrr TMX placebo - dAMP 20mg TMX 16Omg - dAMP 20mg !-----

Difference induced by TMX pretreatment. on the dAMP response.

r.P ( . 05 ìk*P <.02 5 135

compared vrlth that lnduced by dextroamphetamlne alone - The dlfferences vrere maxlmal fn the last hour of recordings. The differences between the thymoxamlne 160 mg dextroamphet.amlne 20 ng and the thymoxamine placebo dextroamphetamlne 20 mg combinations at 2045 and 2I45 hours r¡¡ere +0.083(+-0.031) and +0.1I2(+-0.048) umhos (P <.02 and <.05. respectively). See table 1.11. These chan8es aEe íllustraEed graphically ln figure I.24 in which the dífferences of the mean changes ln 1og skin conductance 1eve1s from the placebo - placebo condí tíons are Portrayed.

TABLE 1.11. Skin conductance 1eve1s.

1og SC TMX plac TMX plac TMX B 0mg TMX 1 6 0rng umho s dAMP p1 ac dAMP 20mg dAMP 20mg dAMP 20ng r'l r! 2015h +0.093 +0.131 +0 . 13 4 +0 . I7 3 (+-0.040) (+-.031) (+-.052) (+-.02) diff from plac - plac +0.380 +0.041 +0.080 (+-.0s4) (+-.0s1) (+-.0a7)

2r 45h +0 . 10 2 +0.068 +0.158 +0. i80 ( +- . 0 4 7 ) (+-.044) (+-.047) (+-.025) diff from plac - plac -0.340 +0.056 +0.078 (+-.051) (+-.049) (+-.0s5)

Means o c ange s +-SEM n og skin con uc tance eve um OS from 17 I5 h at the Eimes of maximum re sPonse to dAMP and the maxinum influence by TMX.

The number of spontaneous fluctuatíons in skin conductance data on the other hand, díd noE reveal any response to the The increase in the I placebo conditíons of the experiment. I number of spontaneous fluctuaEíons by dextroanphetamine 20 mg when compared wíth the placebo - placebo combination díd not reach statistical significance ' Thymoxanine

þ t36

dAMP o.o8 ___å + I I I I I a I I I I i o.o4 I I ':j I I .n I o a ¡-

o o U) ct) o

- o.o4 r''I

Y 1715 1 815 1915 2015 2115 time

Figure 1.24 Dif f erences in mean changes in log SC (¡.¡mhos ) f rom the TMX placebo - dAMP placebo combination (x axis) in the response to oral

TMX placebo - dAMP 20mg TMX dAMP 20mg l}. r. 80mg - -. TMX 160mg - dAMP 20mg D----r

Differences induced by TMX pretreatment on lhe dAMP response. ìkP < .05 :r:kP (.Ql! I r l

I 131

pretreatment lead to a dose related rlse ln the number of spontaneous fluctuatlons, maximal ín the lasE hours of recordlng. the changes of means and differences from the placebo - placebo combfnatlon are glven in table t .1 2. and demonstrated graphically 1n flgure I.25.

Table 1 .1 2. Spontaneous fluctuatlons in skfn conduntance.

spont. TMX Plac TMX Plac TMX 8Omg 160mg fluct. no. dAMP PIac dAMP 20mg dAMP 20ng d AMP 20mg

3h -0.4(+-1.0) -0.2(+-0.8) +1.1(+-1.a) +1.6(+-0.6) dlff from plac - plac +0.2 (+-1 .4) +1.5(+-1.8) +2.0(+-r.0) 4h -0.3(+-0.6) +0.7(+-0.9) +2.6(+-r.3) +2.8(+-r.l) dtff from ¿ 1ac - plac +1.0(+-r.2) +2.9(+-r.1) +3.1(+-1.2)

Mean s o c ange s +- E nt e number o spontaneous fluctuatlons in skin conduc tance at t.he times of maximun re sponse to dAMP and the maxlmum influence by TMX. *P<.05

The difference in the number of spontaneous fluctuations

1n skin conduct.ance between the thymoxamine f60 mg I dextroanphetamine 20 mg and the placeb<, thymoxamine placebo - dextroamphetarnine 20 .mg aE 3 and four hours u¡ere +1.8(+-0.5) and 2.1(+-r.2), (p <.01 and P <.1 respectively).

In all these experiments thymoxanine appeared to exert a dose related response, wiÈh the influence of the smaller dose of thymoxamíne being 1n the same direction but of less lt I inEensity t.han the hlgher dose. Change scores htere also estimated using the reference time of f700 hours (just prior I 138

4

3 .a o +. t lll 2 u rÊ 1 o o o o Irt +. ê Ø 1

o 1 2 3 4 hours

Figure 1.25 Differences in mean changes in the number of sponlaneous fluctuations in skín conductance compared with the TMX placebo - dAMP placebo combination (x axis) demonstrating the effect of TMX 80mg given t hour earlier on the response to oral dAMP 20mg given at 0 hours:

TMX placebo - dAMP 2 Orng TMX 1ó0mg - dAMP 2Omg Lr--.

Differences induced by TMX pretreatment on the dAMP response.

-;.P ( . 01 139

to the thymoxamine dose) 1n the dffferent measures' ln an attempÈ to detecÈ any early alteratlon 1n scores prior to dextroamphetamlne. In doing so i E was observed that thymoxamine 80 mg but not 160 mg caused a xapid drop in readings ln the flrst hour 1n the miserable - happy, drowsy - alert visual analogue scale ratings and in the number of spontaneous fluctuatlons in skin conductance. In these dimensions, uslng the earller reference time for est.imatlng change values r prêtreatment by thymoxamlne 80 mg attenuated the dext,roamphetamine response. Thts reached statistlcal signíficance in the two visual analogue ratlng scales. See f igure 1.26.

In summãty, no conslstent effect could be discerned from

da Ea when thymoxainine wa s given alone . ymoxafn ne not to influence plasma dextroamphetamíne 1eve1 s. Thymoxamine preEreatment., particul arl-y wlth the higher dose, signíflcantly accentuated the dextroamphetamlne response psychologically (as seen fn i-rrítability and restlessness

ratlngs ) and psychophyslologÍca11y. The latter ef f ect r¡¡as particularly clear 1n the skín conductance data. The smaller dose of thymoxamine may have exerÈed a rapld sedating act.ion, wlthín the first hour, whích may have influenced the reference values for estimaEing change values prior to dextroamphet.amine admlnístration. VAS ratings (mm) 10 r40 dAMP

5

q, ,ã.-*.- u, o (¡, ..1' 'aL \._.e ./ cL Ão -5

20

15

dAMP 10 7\. ,/' 5 I \ \

3-o q) c

(¡) o

-10

1700 1800 1900 2000 2100 2200 t ime

Figure 1.26 Differences in mean changes (O= 17OO hours) in VAS ratings (O - lOOmm) from the TMX placebo - dAMP placebo combination (x axis) in rhe miserable - happy and drowsy - alert dimensions, demonstrating the effect of TMX 80mg and TMX 160mg given at 17OO hours on the response to oral dAMP 2Omg given at 1800 hours.

TMX placebo - dAMP 20mg TMX 80mg - dAMP 20mg F.-r-. TMX 160mg - dAMP 20mg þrrrrr

Di fference induced by TMX on the dAMP response. -i.P (. .05

'r;kp ( . Ql 147

1.14.3. Dfscusslon

RegreÈtably litEle ls known of the pharmacokinetlcs of thyrnoxamlne when give ora11y. As 1E I s reported Èo be relatlvely poorly absorbed ora11y, t$to substantlal doses were used, twice and four tlmes the recommended dose for peripheral vasodllatlon ( ¿O mg ) . Thymoxamine alone at thi s dosage level caused no deleEerious effects aPart from ln one subJect who suffered nausea and vomiting. This response in retrospect was like1y to be an idiosyncratlc response Eo thymoxanine. He sras dl scharged from the exPerinent. No other subject !tas aware of discomfort from thymoxamine ei ther when given alone or ln combinat.ion wí th dextroamphetamlne.

Thymoxamine has been shown t.o be active in the cenEral nervous system after adminístratlon as 1t effects REM sleep ( 0swa1d et al, L975), t.he dextroarnphe tamlne inf luence of the knee jerk (Phi111ps et al, I97 3 ) and the secretion of cortisol and groh¡th hormone stimulated by meÈhylamphetamine (Rees et a1, 1970).

It is difficulÈ to draw flrm conclusions from the the results of the study of thymoxamine a1one. As the numbers are sma11, real trends may not have emerged or those chaE did emerge are 1ike1y Eo be apparent rather than rea1. In tÍro of subject,íve dimensions Ehe hígher dose of ,the thyrnoxamíne Eended to elevaÈe the scores. This trend was also suggested in its effect on pulse rate and systolic blood pressure. None of Èhese changes reached statical 742 sígniftcance. The effect of thymoxamlne 1n reducfng diastollc blood pressure presumably reflected its peripheral vasodilator activlty. There hrere no consistent, changes 1n the skin conductance measure s. One would have expected a sedatlve effect by thymoxamfne, reflectlng a stlmulatory role by the noradrenergic pathways 1n Èhe unaroused state. A sedatlve ef f ect by intravenous thymoxanine I4Ias ob served by Nurnberger et a1 ( 1984).

0vera11 the thymoxamine pret,reatment effect of oral ' partlcularly t,he higher dose, on the resPonse to oral dextroampheÈamlne ln normal human subj ects, r¡as to augment the response. This was observed in different visual analogue scale ratings, particularly irrltabllity and restlessness and in the skin galvanometric measures. T e smaller dose may have partlally attenuated the dextroamphetamine response in some measures. It would seem reasonable to conclude that Èhese changes reflect central

ac Eions of the drug.

These finding are contraEy to t.hose of Nurnberger et a1 ( 1984) r,¡ho reported that lntravenous thymoxamine did not ínfluence the psychological or the cardiovascular system response to íntravenous dextroanphetamlne.

Conclusions are difficult to draw from the effecEs of thymoxamine preEreatrnenL on Ehe cardlovascular response to dextroanphetamlne. The sma1l differences observed following thynoxamíne pretreatment are rnore 1ike1y to reflecE the sum of both it.s cenEral and peripheral actions. A peripheral r43

vasodilatory actlon bY thymoxamine vtas not evident 1n experlment D ln which no fa11 in diastollc blood pressure I¡tas meASured.

There can be several explanations for the effect of thymoxamíne on t.he dextroamphetamlne response observed 1n thfs study. Flrstly, the accentuatlon of irritability and arousal may have been a consequence of nausea or gastrointestlnal lrri t.ation lnduced by Ehymoxamlne. 0nly one sub ject, however, complained of discomf ort and r¡ras dl scharged from the experlmenÈ. No clear subj ective or objective measure of discomfort could be detected using thymoxamfne a1one. IÈ ls worth noting that the hlgher dose of Ehymoxamine attenuated the anorectíc effect of amph et,amine. If similar gastrolntestinal discomfort to the lone subJect who demonstrated nâusea r¡ras exPerienced bY other subjects, the anorectíc actlon of dextroamphet.amine would have been accenEuated.

A second posslbí11ty is that thymoxamine may exerE a dífferentía1 action at pre or Postsynaptic receptors depending on dose. Some drugs actlve at alpha noradrenergic receptor sltes are not sPecific tn their action, and may influence other receptors with increasing doses (Anden et al, L976; I9B2; LanSêr, 1981). If this hlere so with thymoxamlne, thi s mtght explain urhy the higher dose had an augmenting effect on dextroamphetamlne induced arousal whereas the smaller dose may have exerted a sedating effect. The lower dose of thymoxamine mlght act primarily r44 by blocklng posts.ynaptic alpha noradrenergic receptors whllst the hlgher dose may have acted preferenttally aE Presynaptlc receptors. In other words aÈ hlgher doses 1t may exert a yohlmblne like effect. In anlmals sÈudles however , thymoxamine and I t s me tabol f te s apPear to exer t thelr noradrenerglc blocking effects primarlly at the postsynaptlc alpha noradrenergle receptor sites wlth no evldence of slgnificant activlty at presynaPtic sltes (Drew, I976; Drew er al, L979; Roqueberr et aI , 1981[b]). To date there 1s no evidence that the preference between Pre- and postsynaptic sltes of actlon alcers wtth the dose of thymoxamlne.

Flna11y, the accentuaElon of the mood and arousal response to dextroamphetamine may be lnduced by Èhymoxamíne exerting a cent,ral post synaptlc alpha noradrenergie receptor blocking actlon. Thls would lmPly that these pathways nay be involved in an inhibitory manner, at least in the aroused (dopamlne hyperactive) state. In order to conflrm or refute this latter conjecture, further st,udies using other alpha blockers would be required.

IE has been clearly established that the arousal and activaEíng effect.s of dexÈroamphetamine in experimental anlmals and the mood elevaEiag and alerting effect.s of amphetamine drugs ín human subjects reflecUs activation of dopamine pathways ( Jons son , 197 2; Gunne et a1 , 197 2; Rolinski and Scheel-Kruger, L973; Ho11íster el 41, I974; RoberEs et aI , I975; Groves and Rebec, 1976; Moore, I977; t45

Gi11in et ãL, tgZSIb]; Silverstone et a1, 1980)' (See

Introduction 1 .4. ) . Thl s I s confirmed by the re su1 Ès 1n the study described earlíer in whlch Ehe speciftc dopamine blocker pimozLde attenuated, ln part at least, Èhe alertlng effects of dexÈroamphetamine , Pâr ticul atLy as manlfest in obJectlve measures of cent.ral arousal.

The role of the noradrenerglc pathways ln the response to dextroamphetamine has not been studied to such an extensive degree. Itollister et a1 (I97 4) comment that the earller animal studles lnvestlgating Èhe effect of a dopamine beta hydroxylase inhlbltor on the dexEroamphetamine response r.¡hich reported attenuatlon of response, f ailed to take inEo account the sedatlve actlon of the drug used. Attenuation of response eould not replicated ln thelr subsenuenE studies.

0ther anlmal studies using either lesions 1n the noradrenergic pathways or pharmacologlcal blockade r rePorted ei ther no effect or a relatlvely sma11 attenuating effect on amphetamíne arousal (lfantegazza et aL, 1968; Rollnski and Scheel-Kruger, I973; Roberts et aI, I975; Groves and Rebec, I976; Kostowski et aL, 1982). UngersEedt (lglt) observed that noradrenergie blockade may accentuaEe amphetamine induced behaviour.

As far as studies uslng human volunteers are concerned, Jonsson (Lg72) reported that noradrenergic blockade of Ehe re sponse to lnt,ravenous dexEroamphetamine 1ed to no ef fect or a s1lght accentuation of mood ( see also Gunne et a1, t46

1972) . Nurnberger et a1 ( 1984) reported that nefther intravenous thymoxamine nor proPranolol influenced the alertlng or cardlovascular response to lntravenous dextroamPhetamine.

It had been generally assumed that noradrenerglc Pathnays exert a stlmulatory role in boEh anlmals and human subjects ( Sctrlldkraut and Kety , 1967 ; Fuxe eÈ aI, 1970; Snyder, 1973). These concluslons e¡ere reached followlng observaEíons that peripherally adminlstered noradrenaline gave rise t,o rhe fltghr and ffghÈ response. states of hyPeractlvlty seemed to be assoclated wlth htgher levels of noradrenallne and its metabolites. Lesions of Ehe noradrenergic pathways appeared to give results consístent wlt.h t.his view, Furthermore, drugs which cause depletion of monoamínes gave rise to hypoacEiviÈy in animals and depression ín humans, whtch could be reversed by drugs r¿hich act Èo lncrease the synaptlc concent.ration of the monoamfnes, in partlcular, noradrenallne (for example, the trlcyclic antídePressanEs). Furthermore, the different degree of arousal and hyperactivíty fo1lowíng dextro- or laevo- amphetamíne seemed to reflect their assumed relative action metaboltcally.

More recent evidence on t.he nature and functioning of the noradrenerglc pathways from a varieÈy of sources has caused t.hese earlier hypotheses Eo be re-evaluated. (See detailed review in the Introduction, 1.3.4.c.). For example, norâdrenallne given peripherally does not cross the blood brain barrler and it is nohr known that the peripheral action 147 of noradrenalfne 1s an lmportant comPonent of anxiety.

Blocking beta noradrenerglc actlvlty peripherally has a signiflcant effect on anxiety and arousal (Lader an4 Tyrer' 1972; Gottschalk et a1, L974) . Drugs like reserpíne and the tricyclic antidepressants, influence a wide varieÈy of neurotransmitter systems. Furthermore, the antidepressant effect of tricyclic ant.idePressants seems to depend on adapt.lve changes ln the nelevant receptors rather than a simple lncrease ln the concentratlo.n of neurotransmitter in the synapse. Indeed, by interpretlng such receptor changes, some workers have concluded that depresslon may be a reflection of too great noradrenerglc actlvlty rat.her Èhan too 1ittle (l'taas and [uang, 1980; llaldmeier, 1981). The role of Ehe noradrenergic pathhrays from lnterpretation based on the relatfve alerting actions of dextro- and laevo- amphe tamine have l ikeu¡1se been challenged by rnore recent

researeh on Eheir neuropharmacological actlon (Bunney et aI , I975; Felgenbaum et aI, I9B2; Felgenbaum and Yanal, 1983).

Further pharmacological evldence for an alerting role by noradrenaline pathways has been suggesEed by the fact that clonidlne, a central alpha 2 noradrenerglc âgonlst, ls sedating (Anden et aL, 1976; Langer, I978; Slever et 41, lgBl ) whereas the alpha 2 arìtagonlst, yohimbine, ís alerting and causes anxiety in normal subjects (Charney et a1, 1983; 1984) . Doubt renaíns, however, abouE the proportion of pre- or postsynaptie alpha noradrenergic receptors ln the central nervous system. There is also evldence lhat both clonidlne and yohimblne are active at postsynaptic alpha 2 receptor 148 sLtes, parEicularly at higher doses (Anden et a1, L976; 1982).

Recent dat,a from a variety of anlmal studfes suggests that the noradrenergic paÈhways exert a blas adJ usting or modulatory role and that they lnteract wlth lntact dopamlne pathways 1n a manner dependant upon the state of arousal (¿,ntelman and Caggull1a, L977; Bloom I978; !Joodward et 41, L979; Kostowski, I979; Kostowskl et aL, L982; Iversen' 1980; Robbfns, 1984) ( See detalled review 1n the Introductfon 1.3.4.c.).

There appear s to be no prev I ou s experl.ment s de scr lbed testing these lssues in humans.

n ngs nt s stu Y¡ t aEa P a nora renerg c pathhrays appear to exert an inhíbf tory action ofl dextroamphetamlne fnduced arousal, though they may be stlrnulatory ln the non-aroused sEate, 1s ln keeping thelr

emergent role in the literature. They probably exert a central modulatory acEion; a speclfic lnteractlon occuring between the dopamíne and noradrenallne pathways 1s 1ike1y ' "arousal the lnEeractlon betng dependent on the state o f (lntelman and Caggul11a, I977; Robbins and Everltt, I982l' Robblns, 1984).

If thls hypothesls proves correct, 1t would help to explaln a variety of pharmacologieal ftndings that have prevlously appeared to be inconslstent. For example, although tricyclic anEidepressants exert an antidepressanE 1.49

effect usually after treatment for several weeks, in the short term (presumably aE the Lime when Ehey are acting as indlrect monoamlne, and, 1n partleular, noradrenergic agonlsts) they are sedatlng and exert an anxiolytlc effeet' ( Streenan, 1980) . Amphetamlne derfvatives can have diverse effects. In normal subJ ects they can cause a mixed mood response ( Cheekley, 1980) and sedatlon ( Tecce and Co1e, Ig74). One explanatfon for the sedation may be that ít ls a manifestaÈ1on of amphetamlne-s actlon predomlnanÈ1y on presynaptlc recePtors at lower doses as sedatlon tends to occur shortly after the drug is given, Presumably when the concentratlons are sti11 relatively low ( Tecce and Co1e, I974,lTaas and tluang, 1980). Amphetamine is also known to be sedatin varlous aroused and hyperactlve patients ¡ èg t in hyp.ractive chlldren (Arnold et a1, I972), manic patíents (rulcsar, Ig66; Beckman and lleinmann , I97 6) and some schlzophrenic paÈients (Van Kammen et aI, I982). It is qulte possible that, in these situations of hyperarousal, anphetamlnes exert a sedative aetlon via increased act.lvlty of the noradrenergic pathways. According to the dopamlne noradrenaline interactlon hypot.hesis, such increased noradrenerglc activíty in the presence of íncreased actívity ln the dopamine pat.hhrays, would modulate t,hat increased actlvity.

In concluslon, cornpared with the dopaminergíc component of the responsé to dextroamphetamine, which aPpears to be slimulatoEyr the alphanoradrenergic component of the dextroamphetanine response may be inhíbitory. This ia 150

keeplng wlth evldence 1n Èhe lfterature of a dopaminergic noradrenerglc lnteractlon, whlch 1s ltke1y Èo be dependent on the state of arousal of the lndlvldual. If ft can be conflrmed, t,hfs flndlng glves evldence of a modulatoryr oE blas adJ usÈ1ng role, of noradrenerglc pathways proposed from anlmal studles.

I PART II

TTIE RESPONSE OF lIIE NEI]ROENDOCRINE SYSTEI,f TO DEXTROAIIPIIETAIIINE: EFFECTS 0F DOPAIIINERGIC AND NORADRENERGIC BLOCKADE page 2.r General InÈroductlon. 153

2.2 MeÈhodology. 158 a. Subjects, drugs and experfmental desfgn 158 b. Blood samples r58 c. Ilormone assays 159 d. Data analysls 160

2 3 The Response of the Neuroendocrine System to Dext,roamphe tamine . 163 2.3.r Líterature revlew 163 2.3.2 Results. 169 2,3,3 Dlscusslon. t79 2.4. Effects of dopaminergic and noradrenerglc b1 ockade on Èhe re sponse of the neuroendocrLne system to dextroamphetamine. 183 2.4 I Introduction. 183

2.4 2 ACTIT - Cor t 1s o1 . 185 a Llterature review. 185 b Results. 189 c Discussion. 196

2.4 3 Prolactin. 199 a Literature review. 199 b Results. 203 c Discussíon. 209

2.4 4 Growth hormone. 2r0 a Literature review. 2r0 b Results. 216 c Discusslon. 222

2. t+ 5 Thyrotrophin. 228 a Llterat,ure revlew. 228 b Results. 232 c Discussion. 238

2.4 6 Gonadotrophíns. Luteinlzing hormone and foIlicle stirnulating hormone. 24r a Llterature review. 24r b Resu1t.s. 249 c Díscussíon. 260 2.4.7. Conclusions. 264 153

2.I. General Introductlon

[,]e have seen how the relatlve roles- of noradrenallne and doparnlne can be examined in Èhe helghtened state of arousal produced by dextroamphetamine. In Ehis, and other states of increased arousal, there I s frequently a concomi tant lncrease in secretlon of one or more pftuítary hormones. It was therefore of lnterest to examine the relaÈive roles of noradrenallne and dopamlne fn these changes fn hormonal actlvlty brought abouE by dextroanphetamine.

The living braln ls a uniquely ínaccessible organ to s tudy . The neuroendocrine v sÈem a11ows an indírect avenue of objective study of brain functlonlng, particulari-y hypothalanie functioning, as the hormones released are noh¡ relatively easily measured. Furthermore there 1s an intimaEe relationship between the neuroendoerine system, psychological status and psychíatric i11ness.

As part of its role in maintaining homeostasis the neuroendocrlne systen i s responsive to the psychological as well as physical status of the animal, showíng many adaptive respoDses to stress. FurEhermore, abnormaliEíes in neuroendocrine functÍoning can be associated I.Jíth changes in psychological status and behaviour. Examples lnclude the psychological sequelae of thyrotoxicosis and myxoedema, Cushing' s disease and Addison-s disease, hyperprolactínaemia and acromegaly as well as the sequelae of peripheral 754

endocrine disease, for example, phaeochromocytoma and parathyroid disease (ttshman, 1978).

Conslderable lnteresÈ has been dlrected towards correlatlng changes in neuroendocrine functloning wíth both normal psychobiologlcal sÈatus and psychiatric 111ness. Thls has led to the development of the dexamethasone suppresslon Èest and the TSH response to TRH tesÈ as biological state markers in majol. affect.ive disorder ( Carroll et a1, I981 i Carro11, Ig82; Kírke gaald et a1, 197 5; 197S). In additlon other researchers have investigaÈed the neuroendocrlne re sponse to pharmacological challenge ín affectíve disorder in an effort t.o enlarge our understanding of the blology of these conditions. Pharmacologíca1 chaJ.lenge of the neuroendocr 1- e system is necessary as manY anterior pi tui tary hormone leve1s in the physlologically basal state are so 1ow, Ehat it is dtffícu1E to measure and compare differences. Accordíng1y a variety of stimulatory procedures have been adopted.

Arnphetamine derívatives have been used for Èhis purpose sínce Besser et a1 (1969) demonstrated a' rise in plasma cortisol and growEh hormone following lntravenous nethylamphetamine. Subsequently, neuroendocrine stimulation by amphetarnine derivatives have been used in thro avenues of

p s ychoneuroend ocrinol ogi ca1 re s earch.

Firstly, researchers have used a challenge by amphetamine derivatives to study the functioning of the neuroendocrine syst.en and indirectly the hypothal-amus, in psychiatric 155

f 11ness. Arnphetanine drugs $rere used because of thelr

)l J' actfon fn stimulating central catecholamine pathways; these pathways rirere known to be lnvolved in regulating anterior pftuftary hormone release and in psychlatrlc dl sorders. These studles lead to the dlscovery of an abnormal response 1n serum cortlsol, and posstbly growth hormone, to amphetamlne derfvatlves 1n patlents suffering from affective dl sorder when compared wlth normal volunteers or upon recovery (Ctreckley and Crammer, L977; Langer et 41, 1976; Checkley, I979; Sachar et aL, 1980; AraEo eÈ a1, 1983).

These aut,hors observed that ampheEamine derlvatlves lnduce

cortlsol and groh¡t,h hornone release but that that release 1s reduced ln affectlve disorder. As noradrenergic path!¡ays il=l ume ome a e n e secre oûo o ese iii hormones, !he results of these studies have been Eaken to imply abnormalities of the noradrenerglc pathways in affective disorder (Langer et a1, I976; Check1ey, l9B0; 1982[b]; Slever et aI, 198i). Clearly it ís essential to

I deternfne the nature and dlrection of the neuroendocrlne response to amphetamíne in normal volunteers before lnferences can be made of the relative response 1n affectlve disorder.

Uncertainty persl sts however over the consistency of the growth hormone and prolactln response Eo amphetanlne derlvatlves by normal subjects. Dlfferent rqsponses are described under dlfferent experimental condítions. ( See 2.3.r.) r 156

The responses of TSII, LH and FSlt to dextroamphe tamine have

":i i not, been directly studied in human subJects.

The second area of concern r¿hlch 1s ralsed by studles uslng pharmacologlcal challenge to invesÈigate neuroendocrine functionlng and hence the biology of affectlve disorder, ls that, the roles of the dopamine and noradrenaline pathways in the control of release of some of the different anteríor pitultary hormones 1n humans are yet.

to be re s olved .

The dopaminerglc and noradrenerglc pathways p1 ay an important, role fn the control of secretlon of the dlfferenÈ elements of the neuroendocrine system. The catecholamlne control of anterior pítuítary hormone secretlon has been

-,tJ intensively studied 1n different animal species, using both ln vitro and in vivo techniques. The control of some of the anteríor pituiEary hormones 1n humans have been relaE.ively well studied, others less so. There are interspecies differences though; the control of secretion 1n humans often differs from other animals. It seems 1ike1y from recenE research findings that the catecholamine control of anterlor pituitary hormones is more eomplex than firsE imagined.

Thus, a second avenue of neuroendocrlne research can make use of the known action of arnphetamlne derivatives to provide a pharmacological procedure Eo compare the relatíve t roles of the dopamine anC noradrenaline path$/ays in the cont.rol of the release of t.he anterior pítultary hormones.

* t57

Pharmacological techniques are one of the methods

available for studylng the catecholamine control of human pituitary functiontng. The effects on basal secretfon of the hormones by pharmacological agonlsts and antagonlsts alone may be so smal1 Èhat dtfferences are dlfffcult to

detect. ExperLments gain valldfEy 1f the response to an agonlst can be lnfluenced by a speclflc pharmacolo,glcal

antagonist,. AtÈenuation of response would imply that Èhe pathway 1s lnvolved 1n a stfmulatory manner whllst accentuatlon of the response fmplLes, on the other handr âr lnhfbitory relatfonshlp. However, although a number of relatlvely speciftc dopaminerglc and noradrenergic antagonist.s and dopaminergie agonists ex1st, amphetamine derlvatlves are one of the few sul table noradrener lc + ï agonists that act centrally. As amphetamlnes act as indirect dopamine and noradrenaline agonlsts, ( see lntroductlon ParL I) blockade of either catecholamine al1ows

a dlrect comparlson of the relaÈlve roles of the thro pathhrays in the secretlon of the hormone belng studied. 1i't' Thls pharmacologícal procedure has been widely used to lnvestigate the comparaÈive roles of the dopamínergie and

noradrenerglc pathways ln psychologíca1 functioning. ( See

Part I. 1 .2.5. ) . This approach was pioneered ln neuroendocrine research by Rees eE a1 ( 1970) Eo lnvestlgate the role of alpha and beta noradrenergic pathways ln the control of cortisol and growth hormone r secretion. lr

t 158

2.2. Methodology

a. Subjects, drug s and experlmental design

The subjeets and drugs used and experlmental design have been descrlbed 1n detail in ParÈ I.

b. Blood samples

AT 1700 hours a venous cannula r¡ras inserted lnÈo a forearm vein ( scalp vein cannul a 2L gauge ) . Thi s kras kept patent

initially and after each blood sample was drahrn, by a 0.05m1. lnjection of heparín diluted ln normal saline (100 units ln 1 m1) . Iq¡e!1ate1y p!ior to the admfnistratlon of dexEroamphetamlne and hourly thereafter, a 10 m1 blood 'l sanple r¡ras taken and transf erred to a lithíum heparin tube, lmmediately centrifuged and the supernatant plasma stored at

ninus 20 degrees cenÈlgrade for plasma dextroamphetamine and cortíso1 estimat,ions.

A further 15 m1 of blood was transferred Eo glass tubes thirty minutes before dextroampheEamine ( I730 hours), and again immedlately before ( tgO0 hours ) , and hourly thereafter. Immediately after clot,ting, it ü¡as centrífuged and the supernatanË serum stored at minus 20 degrees centigrade for estimation,of serum prolactin (pnl), growth I hormone ( ctt¡ , thyroid sEimurating hormone ( TSH) luteinizing ¡l , I hormone (ltt) and fo11ic1e stimularing horrnone (FSu). pLasma cortÍso1 and r"rur samples hrere assayed by the Department of * 159

Clinlcal Endocrinology, St Bartholomew-s Hospital London (Professor Lesley Rees).

c. Hormone assays

1. Plasma corti sol üras assayed by the fluorlmetric method for the es timatlon of free 11 hydroxy cortlcosteroids ln plamsa (l,tattlng1y, 1962). All the sample s of each hormone nere assayed fn the same batch.

Sensftivity: Lower end sensitivity: B0 - 90 n.moles / litre Normal range, 0900hr: 200 - 600 n.noles / 1ltre 2300hr: <200 n.moles / LLLre

Interas say coef f icient s:

Cortísol I00"Á fluorescence

Corticos terone 25"/" (negligible in hurnans )

Cortisone 0"1

Tetrahydrocortíso1 5"Á

11 - deoxycortisol 2"/"

Oestradlol 23"Á ( only lmportant in urine specímens )

The other hormone s h/ere as sayed by the double radioimmunoassay meEhod .

ii. Prolactin: The assay of Thorner et al ( Lg77 ) was employed modlfíed by using the First International Reference

Preparation (MnC75/ 504) as standard. The assay range was 60 - 4000 nU/L and the mean interassay coef f icient of variation

I¡Ja s I0 .32 . 160

i11. Growth Ilormone hras assayed by the radioimmunoassay me thod o f Castracane et a1 (1984). The assay range vras 1 - 50 nV/L and the mean coefficient of variation was 9.L7".

1v. Thyroid Stimulating Hormone: The North Thames Region Immunoassay Unit meÈhod hras used wlth MRC68/38 as standard.

As say range was I - 50 mU/ L and Ehe mean interas say coefflcient of variation was 9.77".

v. Luteinizing Hormone and Fo111c1e Stímulating Hormone:

These assays used antlsera kindly glven by Professor W. R. Butt (nutt et aI , 1975). LH sEandard hras MRC68/40, Èhe assay range was 1 - 50 lJ/L and the mean interassay coefficient of variatlon h¡as 8.72. The FSIÌ standard hras MRC69/I04, the assay range !¡as: 0.2 -25 U/L and the mean lnterassay coef f íclent of variation hras 9.47". Both used a second ant.ibody separation procedure.

d. Data analysls

Hormone 1eve1s thaE fe11 outside the assay range rÂrere given as the limit.s for assays.

Plasma and serum 1eve1s srere converced to an incremental value by subtracting each reading from the 1eve1 at 1800 hours. The net incremental hormone responses represent the differences between hormone change leve1s afEer the active drugs is cornpared with the placebo combination. This required some modification in the case of growth hormone. Basal ( pre - dextroamphetamíne ) 1eve1s of each hormone for 167 each drug comblnation ln each experimenÈa1 grouP hlere comparable apart f rom groû¡th hormàrr". [lere some subjects appeared to have exhiblted a surge of secreEfon in the basal state. Accordlngly, those subJects who showed a secreEion of grohlt,h hormone, f n the sample prlor to dextroamphetamine, greater than 5 nIJ/L, ûrere excluded f rom the data analysis.

the total hormone release over the four hour perfod hlas estlmated by calculatlng Èhe area beneath Ehe curve, using the trapezotd method, for each subject-s lncremental response for each hormone wlth each drug combínation.

In order t.o estimate the effect of dextroamphetamine challenge t.o the neuroendocríne system, changes in hormone sêcr et,lon following dextroamphetamine alone (placebo blocker

dextroamphetamlne 20 mg ) h¡ere compared wl th those followlng placebo alone ( placebo blocker placebo dextroâmphetamlne) in che 24 subjects who participaEed in experiments B and D.

Statistical analyses were calculated uslng Student-s t test for matched paírs. Statistíca1 significance was taken as P <.05 using the tr¡¡o tail test.

Results are expressed graphically as the mean hormone increment (+- standard error measure) above or below the 1800 hour reference value for each sanpling time. In order to s impl i fy the graphs , mean ( +- S¡lq) ne t íncremental leve1 s will be illustraEed when placebo values r¡/ere not lnfluencíng secretion (making placebo levels the x axis). The effect of t62

the snaller dose of t,he blocking drug w111 not usually be l11ustraÈed as the response stas generally ín a slmllar dlrectlon but to a lesser degree than the htgher dose. The effect of Thymoxamine 80 mg will be 111usÈrated 1f a dose response relaEionshlp I¡ras not observed.

r'| Ìrj

:

i t

I r63

2.3. The Respoûse of Ehe Neuroendocrfne SysÈem to Dextroamphe Èamfne

2.3.L. Llterature review

Arnphetamlne drugs have been widely used to study the functioning of the neuroendocrfne syst,em in human subjects slnce Besser et a1 ( 1969) observed a sÈimulatory resPonse 1n cortisol and growth hormone 1eve1s. Their use 1n animal experiment.s have not been so numerous. Animal exPerlments have shown, f or examPle, t,hat amphetamine drugs cause a drop and a reversal of the re serpine induced increase 1n prolactin secreElon (Meltzer eE aI , 1979; G1emens eE a1, 1980; Gudelsky, 1981 ) , but have litt1e effect on resting prolactln 1eve1s (t'tettzeç et a1, 19B2). Amphetamine reduces the stress induced ríse ln ACTI{ (Van Loon, I97L1 Mu11er eÈ

a1, Ig77 [ a] ) . Monkeys show an increase 1n TSH secretion f ollowing dextroamphetamine (l'lorley et a1, 1980) . Mice on the oEher hand had elevated T3 and T4 1eve1s but not TSH 1eve1s fo1lowíng amphetamíne suggesting a peripheral síte of

action (Uetander et 41, I97 6) .

In human subj ects the response of cortisol, prolactin and

growth hormone to amphe tamine derivative s have been examined both in normal subjects and in pattents sufferlng different psychiatric diseases. This will be discussed by consídering each ant.erior pltuitary horrnone in turn. t64

a. ACTIt Cortisol

Actlvatlon of the pitultary adrenal axis occurs $¡1Eh stress followlng a varlety of physlcal or psychological stinull. The cortisol response may be particularly responsive Èo psyehologlcal sÈimu1i (Marttn et ãL, 1977; Rees, I977).

Besser et a1 ( 1969) observed thaE the plasma cortisol 1eve1s in normal young men rose signlficantly followfng both lntravenous methylamphetamine and oral dexÈroamphetamfne, the response being most pronounced in the eveníng.

In depresslve illness the cortisol response to 1nÈravenous met.hylamphetamine r¡Ias found to be lower when patienLs vtere depressed than after recovery ( Cneckley and Crammer, I977 ;

Checkley, 197 9) . The authors propose that thi s finding supports the hypothesls Èhat, there is a functional defíeiency of noradrenallne at some central adrenergfc receptors. Sachar et a1 ( 1980) furthermore reported that dextroamphetamine glven !o depressed patienLs int,ravenous ' slgnlficantly suppressed elevated morning cortlsol 1eve1s.

b. Prolactin

Prolactin secreEion is stirnulated by stressful stírnu1i, particularly physical stimuli, for example anaesEhesia and

surgery (Martln eE a1, 1977; Thorrrer , 1977) .

The reported response by serun prolact.ín to amphe tamine s ín normal humau subjects has been varied, with s,ome authors t65

reporting a rise and others a fa11. Halbrelch et a1 ( 1981 ) and Nurnberger et a1 ( 1981 ) both demonstraEed an lncrease 1n prolactín secreÈion followlng amphetamine, with ttalbrelch et a1 ( 1981) noting that the ri se r¡ras apparent 1n young men 1n the evenlng but not Ín posE menopausal women. A fa11 in serum prolactin secretlon followíng amphetamine was rePorted by hÌe11s et a1 ( tSZa¡, DeLeo et al ( 1983) and Dommisse et al (1e84).

The prolactin response to dextroamphetamine has also been studied 1n psychiatric i11ness. In both depressed patients

(Slater eE aL, I976) and schizophreníc patlents (Van Kammen et 41, 1978 ) an elevation of secretion vtas reported.

c. Growth hormone

Grov¡th hormone secreEion responds to stress. Secretlon is lncreased by surgery, exerci se, hypoglycaemia and pyrogen administratíon (Cryer and Daughaday, I977; Johnson, I982). The responslveness to psychological stress in humans ís not so clear. For example prolonged envíronmental stress is assoclaEed with growth fallure (Martín et aI , I977). The stress response in experimental animals appears Eo be species specific (Martin et aL, 1977).

Generally gror¡rth hormone leve1s are increased by arnphetamine derivatives though the response is variable and depends on a variety of experimental conditions. Besser et a1 (tg0g ) reported that intravenous meEhylamphetamine, but not oral dextroamphetamine, gave a rise in serum growth r66

hormone 1eve1s. Rees et a1 ( f970) likewise demonstrated an lncrease in gro$rth hormone secretlon followfng intravenous methylamphetamlne, but oral dextroamphetamine produced a fa11 ( personal communÍcaÈ1on) . Intravenous dextro- and laevo- amphetamine were reported Èo be equlPotent ln stlmulating the release of groLrt,h hormone ( Langer and Matussek, 1977). Italbreích et a1 (1980) reported that growth hormone response to intravenous dextroamphetamlne riras sf gnlf icantly 1es s in pos tmenopausal r¡romen than young men. Young men had a hígher response ln the morning than the evening w1Èh the reverse being observed in the older lrromen.

In hyperklnetlc children Aarskog et a1 (I977) reported a rlse ln growth hormone following oral dextroamphetamine maximal at sixty mínxtes which was only neasurable then and at nlnety minuEes. This rise sras attenuated after the children had been Èreated for five months wlth methylphenidate. Long term treatment of hyperacElvíty in children by dextroamphetamine may cause growth retardaElon ( Safer and A11en, I97 2) , possibly by reducing growth hormone secretion. Intravenous dextroamphetamine had no effect on gror¡¡th hormone ln acromegalic patients (t"tu11er et aL, LeTTlal ).

Amphetarnlne derivatives have been used to sEudy growth

hormone secretion in psychiatric patients. Langer et aL (1976) reported a reduced response to lntravenous amphetamine in endogenously depressed patients, and an enhanced response in neurot.ic depressives, with the response in schizophrenic and alcoholic patienEs not differing from t6l

that. seen 1n normal subj ecÈs. The authors lnterpreÈ their observatlon as further evidence for the noradrenergic deficiency hypothesis fn some patients with affective

dlsorder. Checkley and Crammer ( 1 977) on the other hand reported that the lncrease 1n growth hormone secretion

fo11 owing 1nÈravenou s me thylamphe tamlne s¡as the same when the patlents r¡rere depressed or recovered. In a subsequent study, Checkley ( I979) rePorted that the lncrease in groútth hormone secreElon followlng lntravenous met.hylampheEamlne ü¡as similar ln both endogenously and reactively depressed patÍents and tn patients with other psychiatríc diagnoses.

d. TSH

#heanter1orpitruitaryadrena1ax1S'pro1aet1nandgeowth hormone have been generally regarded as belng responsive to stress. Less 1s known of the response by other anteríor pitultary hormones to stress. TSH secretion is spectfically st.lmulated by cold exposure. The relationshíp of psychological stress and the anterior pituítary thyroíd axis

is not c1ear. I{yperthyroidism has long been considered a dísease which ,n"V be induced by psychological stress though there 1s no sclentific evldence for this (Morley, 1981). Physical stress on the other hand tends to suppress thyroid f unctlon ln experlmental anlrnals and humans (Martin et â1, L977; Morley, 1981).

Morley et a1 ( 1980) observed thaE four paEients who had abused amphetamine, had elevated T4 levels and symptoms of hyperthyroldism. Thyroid function returned to normal on 168

withdrawal from amphetamfne. There appears to have been no dlrecÈ study measurlng changes fn TSIt secretfon fn human subJects following acute amphetamlne admlnfsÈratlon.

e. tlt and FSH

The response by LH and FSfl to sEress rema. lns uncerEaln. LH secretlon ls stimulated by audlEory sEfmull 1n both

experfmental anlmal s and humans ( Beardwood , I982) . Inhlbltlon of Ltt and FSH secretfoo by the stress of starvatlon (for example ln anorexfa nervosa) 1s well known

( Beumont and Russe11, 1982) .

There appears to be no study measuring changes 1n gonadotrophln secretfon 1n humans followlng amphetanines.

I 769

2.3.2. Results

a. Cortisol

Dextroamphetamlne 20 mg caused a slgnificant, ri se ln plasma corti sol secreÈion whereas there utas a steady fa11 after placebo (as expected due to the known diurnal rhythm of cortisol). See' Figure 2.L. The neE incremental rise in

plasma cortlsol following dextroamphetamine r¡ras statisEically signiflcant at all tlnes throughout the experiment,, being greatest at tü¡o hours when the difference was + 351.4(+-41.6) nmols/1, (P<.001).

The mean (+-SnU) est,imates of the area under the curve measures are as follows: ir !! i Placebo: -358.9(+-93.4) dAI.lP 20 mg: +470.0(+-67.6) dif f erence: +828.0(+-r06.4) (p <.ool)

i b . Prolac tin

Serum prolactin rose significantly following dexEroamphetamine administration. See figure 2.2. No change

in serum prolactin secretíon f ollowed placebo. The ri se r¡/as maximal at three hours when the difference between active

and placebo dextroamphetamine r¡¡as +62,1(+-28.2), mU/L

( P< . 0 s ) .

! llo

J * ã 300 t È

o 200 t tn I +J \r o * o 100 + fit

an fit o ê

o -100 c,¡

Irl o - 200

- 300

1+ !J 0 1 2 3 4 hours

Figure 2.1 Mean (t SEM) incremental plasma cortisol (nmol/L) from 0 (1800) hours:

placeho' Qrrrrrrrrrrrr dAMP 20mg D-

Dif f erence versus placebo. 'kP <.005 'r'rP <.001

I 171.

100

I J 80 Ð E 60 +. o G o L 40 0-

L 20 o o

o o gl

G u -20

':+ Y -40

o 1 2 3 4 hou rs

Figu¡e 2.2 Mean ( I SeM) incremenlal serum prolactin (mU/L) from 0 (1800) hours¡

p Lacebo $..r r r. r.. r dAMP 20mg

Difference versus placebo. 'kP < .05

t I ll I

I 772

The mean (+-SfU) estimates for the areas under the curves measures are as fo11ows.

Placebo: -2.3 (+-¿9. s) dAMP 20 mg: +137.3(+-44.6) difference: +139.s(+-69.2) (p <.1)

c. Growth Hormone

There r¡ras a late r sust.ained increase in growth hormone secretion fo11ow1ng plaeebo compared with an early nonsust,ained rise in serum growth hormone following dextroafnphetamlne. The lncrease in serum growth hormone levels following plaeebo adminlst.ration, reached statistical slgniffcance aE thro, three, and four hours when compared

rt wí th the pre - dextroamphe tamlne level . Incremental serum growth hormone leve1s following placebo (n=20) at these tlmes urere, +10.5(+-2.6) +8.7(+-a.0) and +10(+-2.8) nU/L; P<.001, <.05 and <.01 respecEively (see flgure 2.3).

The lncrease in groerth hormone secretion following

dextroamphetamlne was partlcularly evident in the flrst Eü¡o hours when the mean (+-SSl'1 ) incremental leve1s hiere; +9.9(+-¡.7) and +6,4(+-2.6) mu/L; P(.02 and <.05

respectively. The smal1 increase in secretion induced by the act,ive drug when compared wlth placebo at one hour failed to reach statistical signlficance. Dextroamphetamine

t 20mg however appeared to reduce the growth hormone response l¡ I when compared wlth placebo in the latter part of the study.

The ne t incremental growth hormone 1eve1 s at three and four

* t73

14

J Ð 12

o o 10

L o I I I o L (9 6

L o 4 ¡¡t

o Et

rË

-2

o 1 2 3 4 hour s

Figure 2.3 Mean (l S¡u) incremental serum growth hormone (mU/L) from 0 (1800) hours:

placebo Qrrrrrrrrrrrr dAMp 20mg 774

hours (uslng matched palred data onlyr r=13), were 3.9(+-2.0i) and -9.0(+-9.8) mU/L, (P <.1). (rne dffference at four hours reached statlstical signlflcance uslng the lJilcoxon palred rank df f f erence tes t Ip <.05 ] ) .

Estlmates of the mean (+-SnU) areas beneath Ehe curves are as f ollosrs: ( data f rom matchf ng palrs only N=13)

Placebo: +16.1(+-3.9)

dAMP 20mg: +10.t(+-2.L) dlfference: -s.s(+-3.1) (p<.r)

d. Tsn

Dextroamphetamine 20 mg led to a rise 1n TSIt secretion when compared wlth placebo. See Figure 2.4. There hras no change after plaeebo a1one. The effect of dextroâmphetamine was maxlmal aE tbro hours, +0.41(+-0.19) mu/L, (P <.05).

Estlmates of the areas under the curve are as follows:

Placebo: +0.14(+-0,22) dAMP 20 mg: +0.78(+-0.30) dlfference: +0.63(+-0.36) (p <.1) t75

0.6 t

J o.4

=E I v, F tr o.2 L o o .;

E'' l! u o

- o'2

o 1 2 3 4 hours

Figure 2.4 Mean (1 S¡U) incremenral TSH (mU/L) from 0 (1800) hours:

p lacebo Srrr...-r.r dAMP 20mg r'

Dif f erence versus placebo. :kP <. 05 t76

e Gonadotrophins

The effect of dextroamphetamlne 20 mg compared with placebo on LH and FSH release fs shown fn Flgures 2.5. and 2.6. No change rras manlf esÈ af ter placebo ln elther experiment. I.Itth both hormones the lncreâse 1n secretlon lnduced by dextroamphetamf ne r¡ras maximal at two hours, the net lncremenÈa1 LH (rnean +-SEM): +2,54(+-0.6S) U/f (p <.005) and net lncremental FSH: +0.71 (+-0.2) U/L (p <.005).

Estimates of the areas under the curves are as follokIs:

LH: Placebo: -0.9(+-r.4) dAMP 20 mg: +4.9 (+-1.2)

erence: + +-1.8 P< 05

FSH: Placebo: -0.3(+-0.3) dAMP 20 mg: +1 .3(+-0.4) dlfference: +1.6(+-0.s) (p <.00s) t77

3

ù * t

J 2 3 ¿ J

1 L o o

o o Ð Itl u

1

0 1 2 3 4 liou r s

Figure 2.5 Mean (1 SEM) incremenral LH(U/L) from O (1gOO) hours:

p 1ac ebo Qrrrrrrrrrr dAMP 20mg trÈ--

f Dif erence versus p lacebo . r.p < .O25 *+rp ç . gg5 1.78

o I t ¡| J 'l 0.6 a Ð

I a Ø I l! o-4

L o o-2 o

o o Þ)

CI u - o.2

- o.4

o I 2 3 4 hou rs

Figure 2.6 Mean (1 SEM) incremenral FSH (UlL) from O (1gOO) hours:

p lacebo Qrrrrrrrrrrr dAMP 2omg H--

Dif f erence versus placebo. 'kP 1 .OZ ìk)kp <. 01 )k,J-kp <. OO5 r79

2.3.3. Dtscussf on

0ra1 dextroamphetamfne 20 mg stfmulated t.he secret,lon of plasma corElsol and serum prolactln, TSH, LIt and FSH. This study appears to be the ffrst to dfrectly measure the effect of dextroamphetamfne on TSH, LH or FSH 1n normal human subjects, though Morley et aI (19S0) proposed a central st,lmulatory action by amphetamlne on thyrold activfty.

No change 1n hormone secretlon hras observed in the above after placebo wlth the exceptlon of cortisol wfth whlch the expected fa11 ln leve1s assoclated with the evening cornponent of l ts df urnal variation r4ras observed. The placebo condiÈions did signlffcantly lnfluence growth hormone secretlon however.

Many pharmacological studies of neuroendocrine functlon are conducted ín the morning. Thi s s tudy hras conducted 1n the laEe afternoon - earry evening. Due to the durat,lon of the experirnent (over slx hours) sufficlent, subjects who could take this amount of time away from work r¡rere simply noE avallable. As the anEerlor pitultary horrnones are secreted wlth a specific dlurnal pattern, these results may not be directly comparable wlth other studles conducted in the morning.

rt has been assumed that measuring plasma cortlsol leve1s gíves a saÈisfactory estimate of ACTH secreÈíon (gesser et â1, L969; Ganong, 1980). Besser er a1 (1969), for example, demoûsÈrated in th/o subj ec t,s that the ri se in cortl sol 180

secretlon fo1lowíng intravenous methylamphetamine hras

mlrrored by a sinilar rlse in ACTH. The work of Fehm et a1 ( 19s4) casts some doubt on this assumptlon however. They

were unable to demonstrate a corresponding rise 1n ACTH secretion wlth the methylamphetamlne induced rise in plasma cortisol levels although AcrH 1eve1s increased ln association with increased cortÍso1 leve1s followlng lnsulin induced hypoglycaemfa. Further studíe s will be requlred to resolve thfs question. This observation casts doubt on the lnferences drawn from studfes lnvestigatfng Ehe cortisol response to anphet,amfne in patients with affective dtsorder on the activlty of Ehe central noradrenergic pathhrays in depressíon.

The respoRsê of piolactln to dextroampheEamine 20 mg ín thís study conflrms Èhe observaEíons of some earller lnvestigations using normal subjects, or psychlatric patients (slater et a1, 1976; van Kammen et aI , I978;

Ilalbreich et a1, 1980). Thís is in contrast to l,Ie11s et a1 (1978) and DeLeo er a1 (1983) who reporÈed a fa11 in serurn prolact.in secretion, a response which might be expected ln vlew of dextroamphetamine-s potent índlrect dopamine agoníst action. The rise observed in the present study, and that of others, remains to be explained.

The growth hornone re sponse lo oral dextroamphe camine where dextroamphetamine, 1f anything, appeared to reduce the increase of secretion following placebo is also difficult to explain. Growth hormone secretion can be stimulated by a 181 variety of physiological and pharnacologfcal stlmull. Experimentally these have lncluded hyPoglycaemia, exerci se, stress, s1eep, argininer glucagonr vâsopressin and a range of other pharmacologlcal stimulants ( Ctreckley, 1980; Martln, 1980). It is possible that as the subjects had fasÈed for elght hours prlor to presentatlon 1n thls study, the rlse seen following placebo may have been secondary to lowered blood glucose 1eve1s or to the stress from venipuncture.

The growth hormone re sponse Eo amphetarnine derlvative s seens to be variable. Although rnany studies reporÈ a rise ín secretlon, thls depends on which amphetamine derivative was used, dose, route of administration, aEe of subjects' time of day, and presence of other stimulatory factors. fsee lIterâtureirellew 2,3.I.); Other studies suggest that oral dextroamphetamine has 1lttle stímulatory action on growth hormone secreEion. Besser et aI (1969) for exanple, reported that alEhough lntravenous methylamphetarnine caused a ríse 1n growth hormone, oral dextroamphetarnine in the evenlng dld not. Rees eE a1 (1970) described only a modest rise 1n growEh hormone followlng intravenous methylarnphetamine while oral dextroamphetamine caused a fa11

( personal communication) .

The variable response of serum gro-wth hormone to ampheEamine derivatives and Eo dífferent experlmental condltions, may account for E.he the differing reporEs of the gro\,rth hormone resPonse Eo amphetamíne derivatives ín psychiatrlc patients (Langer et ãI , I976; Checkley and r82

Crammer, Ig77; Checkley, L979) . In none of these studles hlas a placebo comparison made. The results of Ehe present study indlcate how necessary tt is to include a Placebo control. Furthermore thls study lndlcates that inferences about the role of the catecholamlne pathh¡ays 1n affective dl sorder, from observaÈfons of the response by depressed patlent,s to amphetamine drugs (Langer eÈ aL, I976; Langer and Matussek'

L97 7 ) may be unfounded .

In conclusíon, oral dextroamphetamlne would appear to be a satlsfactory stimulus for challengtng anterlor pltuitary hormone secreEion (with Èhe exception of growth hormone) boEh for the purpose of investigatíng cortisol and anterior pltuitary function in psychiat,ric lllness and the investiga tion of neuroe ocrine funcElon Íng iT heal th or disease. IE is apparent that the Procedure must be carefully standardlsed as the response can vary wiEh the dose and route of adminlstration, as well as other experimen ta1 conditlons. This 1s ParEícu1ar1y obvious when measuring the grovrth hormone re sponse Eo challenge by an

arnphe tamine derivative. 183

2.4. Effects of Prlor Dopamlnerglc aud Noradrenerglc Blockade on the Neuroendocrlne Response to Dextroamphe tamfne

2.4.1. Introductlon

This study htas conducted to investlgate the roles of t.he dopamlne and noradrenaline pathways on the secretlon of the different anterlor pituitary hormones.

As menttoned earller a variety of technlques have been employed to study t,he role of t.he catecholamine pathways in neuroendocrine functionlng, 1n Partlcular in exPerlmental anlmals, and to a varying degree 1n human subjects. As

inÈe ilpè-íe- dLf erence s oceurs wfth some hormones' the 1íterature revlew will concentrate on studies uslng human subjects.

l^Ilth a number of the hormones, Pharmacologf ca1 challenge of their secretion has been performed in patlents suffering from affective disorcier as a method of exploring the blology of this conditlon. affectlve disorders. These studles wí11 be reviewed. The conclusions drawn from these sEudíes on the functioning of t,he catecholamine Pathways ln affecEive disorder w111 be considered in the light of the results of the current experiment and other slrnilar studies that have investigated Ehe act.ion of Ehese pathways 1n human anterlor pltuitary hormone secretion.

A liEerature review, the results of the experiment 784

conducted and discussion wt11 be presented for each hormone in turn, with the exceptíon of LH and FSH whlch r.¡111 be considered together. 185

2.4.2. ACTH Cortfsol

a. Ll t.erâture revlew

ACTH, a 39 resldue peptlde, 1s under exeltatory control by the hypothalamus via cortlcotrophin releasing factor. It I s lnhibited by the negatlve feedback effects of cortisol (Martln et aL, I977; Ganong, 1980). Neurotransmltter regulatlon of ACTt{ appears to be at the hypothalamic rather than the anterfor pltultary leve1 (GanonB I 1980). Cortlsol 1s released fron the adrenal cortex under excltatory control of ACTH.

As ACTII 1s comparatlvely dtfficult to measure directly by radiolmmuno assay, most in vlvo studies assay glucocorticold (.cortisol ) orrtprrt; Thlch has been assumed to provlde a satisf actory lndex of ACTIT secretlon (Ganong, 1980). [Iowever there i s recent evidence that the corti sol leve1 can be affected independently; for example the cort,i so1 rl se following meEhylampheEamlne may not be assoeíated wít.h a correspondtng ríse ín ACTH secretion (pehm et aIr 1984).

l. The role of dopamine pa thway s ln ACTH and cortisol release

Dopamine pathways do not appear Eo be involved 1n the control of ACTH release in experirnental animals (t"tu11er et aL, I977lal) or ín corlisol release in man (Coltu et a1, 1975; llillcox et â1, 1975; Leebaw eE aI , I97B; Checkley, 1980). 186

1f. The role of noradrenaline pathways 1n ACTH and cortlsol release

In vitro studles

Earller in vlLro evldence suggested that corticotrophln releasing factor h¡as sEimulated by acetylchollne (nlcotinic) and lnhtbited by alphanoradrenerglc influences (Jones et 41, 1976; Bucklngham and llodges, I979) . Thls view has been dfsputed by Fehm eÈ aI ( 1980) who observed that noradrenaline stlmulated corticoErophin releaslng factor, an ef f ect whlch q/as blocked by 'phent,olamine.

Anlmal studies

Evidence from animal studies suggest that alphanoradrenergic pathbrays may exert an inhlbitory role ín the regulaÈ1on of ACTH release, part,icularly st.ress-induced release (Martln eE a1, I977; i"tu11er et al , L977[a]; Ganong, 19S0). Mu11er er a1 (tglTlal) in a comprehensive revlew of dlfferent experíments in aníma1s in which a varíety of procedures had been used, concluded Ehat noradrenergic

pathhrays appeared to have an ínhíbíÈory role in ACTI{ release, particularly in rats and dogs.

Ganong ( 1980) demonstrated thaE clonidine caused an tnhibition of stress induced ACTH secretion and concluded thaE noradrenaline acts posEsynapÈically to inhibit L87 corÈ1coÈrophin releasing hormone secretion. Furthermore Ganong et al ( I9S2) gave evldence that ln dogs, thls lnhtbitlon occurs at posE synaptic alpha 2 receptors.

Studles ín humans

An inhibitory role for the alpha noradrenerglc systen on stress lnduced ACTH secretion has been ProPosed by Lancranjan er al (tgl 9[a] ) following the findíng that guanfacine, an alpha adrenoceptor agonist reduced ACTH secretlon stimulated by insulln-lnduced hyPoglycaemla; a flndlng consístent wlth that of llilcox et a1 (1975) that noradrenalíne lnfuslon decreased ACTIT and cortlsol 1eve1s.

The bulk of evidence from human studies in which a variety of different experimental procedures have been used (Rees et a1, I970; Nakai et 41, L9731 Jezova-Repcekova et a1, 7979;

Checkley, 1980) suggests that ACTH and cortí so1 secretion i s under stlmulat,ory alpha noradrenergic control and tnhibitory beta noradrenerglc conErol. For exanPle, the rise in cortisol secretion f ollowing I14 methylamphetamine I¡ras attenuated by thymoxamine and accentuated by propranolol (nees et aI, 1970).

iii. The anterior pituitary axls and affecÈive disorder

Cortisol 1eve1s are elevated in depressed patients, particularly in the evening, and t.hese 1eve1s return to normal following recovery (Ctreckley, 19E0; 1982[b]; Johnson, 188

1982). Many endogenously depressed and manlc patients show a failure of suppresslon of cortlsol secretion followlng dexamethasone, which uSually returns to normal upon recovery ( Graham et â1, 1982 Carroll eÈ aL, I982; Johnson, L982) . These observatlons hollever do not a11ow any lnference about the role of the catecholamlne pathways in affecÈ1ve disorder.

The corttsol response to insulin induced hyPoglycaemia 1s reported t,o be reduced in endogenous depres sion, an effect that may be medlaEed by alpha noradrenergic pathways ( Siever et aI, 198I). The cortlsol response to methylamphetamine is decreased ln patlents r.rlth endogenous depresslon but reEurns to normal following recovery ( Checkley and Crammer r I977; ). ftre authors proposed that thls observation supported the hypothesis of alpha noradrenergic hypofunction in some patients with endogenous depression. 189

b. Results

i. The effects of the blocking drug s alone

Plmo ztde

Pfmozlde lnduced a dose related non signlflcant fa11 with placebo pimo zLd'e 4 mg belng the difference from followlng ' -184.S(+-66.3) nmols / tttre, (p <.1) at 3 hours. See f f gure 2.7 .

The estlnates of the areas under Ehe curve are as follows:

placebo: -195.1 (+- 224.5) PYtz ? nez -403.0(+-80.4) Prlz 4 mgz -796.8(+-149.2) net lncremental area under the curve following PllZ 4 mg: -601.6(+-338.9), P <.2.

Thymoxam ine

Thymoxamine also lnduced a relatlve fa11 in cortisol levels when compared wlÈh placebo which hras most noticeable at one hour when Èhe differences were as f o11ows:

Thymoxamine B0 mg: -107(+-48.5) nmols / 1ítre, P <.2

Thymoxamine 160 mg: -82.8(+-55,7) nmols /LLt,re, P <.3

See flgure 2.8 190

100

J o o L -100 o ø +. L o o -20,0

-30 rl rl

o 1 2 3 4 5 hours

Eigure 2.7 Mean (t SEM) incremental plasma cortisol (nmol/L):

p lacebo frrrr r rr rrr

PMZ 4ng ¡lrrrrr

I L9T

10

o J o ]s.,[-..-- E -100 lllìl ì-'-' rl.___r o ì\r\,r\..\ .t Ë -200 o I u -300

o 1 2 3 4 5

d rùt

Figure 2.8 Mean (I SEM) incremental plasma cortisol (umoLlL)z

p lac ebo l}rrrrrrrrrrr TMX 80mg f-.-.- TMX 160mg lrrrrr

f I

;

t L92

Estlmates of area under the curve measures are as follows:

Placebo: -278.1(+-260.7) l TMX 80 mg: -ss6.0(+-239.9) TMX 160 mg: -3s3.1(+-176.0)

ne E lncremental area under the curve followlng TMX 160 mg:

-278.1(+-I32.r), P <.2

11. The effecÈs o f p lmo zlde and thymoxamine pretreatment on the neuroendocrine response Eo oral dextroamphetamlne

In both experimenEs B and D plasma cortlsol levels fe11 steadtly throughout, reflectlng the diurnal drop 1n corti so1

secretlon 1n t.he evenlng. Dextroamphetamlne lnduced a

-11 :tîil

apart from t hour 1n experlment B

Plmo zlde pre trea tment wa s Íri thou t tnf luence on the cortlsol response to dextroamphetamlne. See figure 2.9

Area under the curve estlmates are as fol1oürs:

Placebo: -384.s(+-176.6)

dAMP 20 mg: +6t6.6 (+-83.7)

Pl"lZ 2 ng + dAMP 20 mg: +s86.0(+-82.9)

PÌIZ 4 ng + dAMP 20 mg: +s40.6(+-s8.9)

Thymoxarnine pre Erea tnent on the other hand, had an ttI , lnconslsEent effect. The 80 mg pretreatment dosage caused

Ì 193

600

J 400 o E

o .9 f L oo 200

t\l I È s3n o.

1 2 3 4 hours

Figure 2.9 Mean (l Snu) net incremental pLasma cortisol (nmoL/L) response to oral dAMP 20mg given at 0 (1800) hours demonstrating the effect of. PNIZ 4mg given 2 hours earlier:

PY1Z placebo - dAMP 20mg PMZ 4mg - dAMP 20mg f rrrr

l¡ t

I 194

an accentuaÈion of the lncrease fn cortlsol secretfon lnduced by dextroamphetamine which reached statistical slgnificance at one and tü¡o hours. The differences between t.he means plasma cortfsol 1evels following the thymoxamine 80 mg - dextroamphetaml-ne 20 mg and thymoxamlne placebo dextroamphetamine 20 mg combinatlon were +102.3(+-41.5) nmols/lttre (p <.05) and +116.3(+-37) nmols/1itre (p <.01) at one and two hours respecEively. See fígure 2.L0. Pretreat,ment by the higher dose of thymoxamlne tended to reduce the cortisol response to dextroamphetamine, though

only modesEly and 1ate. The maxlmum attenuation hlas at 4 hours when the difference beLween the mean leve1s following

the thymoxamine f 6 0 mg - dextr oarnphe tamine 20 mg and thymoxamine plaeebo - dextroamphe t,amine 20 mg combinaEion

ü¡a s -42.1(+-28.4) nmols/1itre (P <.2).

Area under the curve estimates are as follows:

placebo: -256. s(+-101.2)

dAMP 20 mg: +323. 3 ( +- 90 .4)

Tl{X 80 mg + dAMP 20 mg: +539.3(+-75.s)

TMX 160 mg+ dAMP 20 mg: +264.6(+-86.7)

Net lncremenEal changes following TMX 80 mg and TMX 160 mg pretreatment compared with dAMP alone: +216.0(+-96.6) (P <.05) and -58.8(+-82.4) (l{S) respectively. lr 195

600

I ll

J 400 o o o

L 200/ + o o

.ú o llt ct 0

- 100

o 1 2 3 4 hours

Figure 2.10 Mean (l SnU) net incremental plasma cortisol (nmol/L) response ro oral dAMP 2omg given at o (1800) hours demonstrating the effect of TÙ4X SOmg and TMX 160mg given t hour earlier:

TMX placebo - dAMP 20mg TMX 80mg - dAMP 2Omg ¡}rrrrt TMX 160mg - dAMP 20mg !rr-rr

Difference induced by TMX on the dAMP response' -k-r

c. Df scusslon

The rlse ln cortlsol 1evels following admlnistratlon of oral dextroamphetamine is consistent with a variety of studles uslng amphetamlne derfvatives (Besser eÈ ãI , I969; Rees et al, 1970; Checkley, L979) . ( See 2.1. ) . It had been assumed thaÈ this rise reflected an increase 1n ACTII secretion. As mentloned earlier ( 2.3.3. ) Èhe work of Fehm et a1 ( I984) has cast doubt on thls assumPtion. In their study, ln contrasE wiÈh the earlfer study of Besser eL a1 ( 1969) , the rise ln corÈ1so1 leve1s followfng intravenous meEhylamphetamlne rrraS not associated with a comparative rise ín ACTH. Fehm et a1 ( 1984) conclude that the rnethylanphetamine induced rlse 1n corElsol 1eve1s ra¡as independenÈ of ACTH. C1ear1y, caution is required J.n interpretlng the current results as reflecEing ACTH actlvity rather Èhan the effects on the secretlon on corEisol secretion alone, until these questions are resolved.

Dopamíne pathhrays

The absence of influence of pimozíde on the dextroamphetamíne stlmulated increase in corLisol secretion impl les no lnvolvement of dopamlne pathways in AcTH corttsol secretion. The nodest net drop in incremental plasma cortisol following pimozide alone may be a reflection of the drugs general sedating and anxiolytic effect and not a direct effect on the hypothalamo - adrenal axis. r97

Noradrenallne pathways

Oral thynoxamine glven prlor to dextroampheEamlne dld not produce the same effect as lntravenous thymoxamlne r¡hlch attenuated the lncrease 1n plasma cortlsol lnduced by intravenous methylampheEamlne (nees et a1, 1970) . The reason for this discrepancy is not c1ear. As both studles srere conducted 1n the early evenlng, it cânnoÈ be due to the dlurnal variatlon 1n cortlsol secretion.

Furthermore no clear cut explanaEfon for t.he difference 1n the effect of the Ewo doses of thyrnoxamine can be given. 0ne posslble explanatlon 1s that thymoxamine may be exerting responses at eiÈher pre- or postsynaptíc adrenocePt.or sites

epending on lts dose. [1 owever, until it can be shown Eha thymoxamine has presynaptic alphanoradrenergic blocking activíty, such a suggestlon must remain conjectural.

A possible explanatlon for the reported dlfferences in the effect of thyrnoxamlne may depend on whether or noÈ the response belng measured is stress-relaEed or not. The alpha noradrenerglc pathürays may inhibit cortlcotrophín releaslng factor and sEress-induced stimulatíon of ACTH, whl1e exerting a physiologically stírnulating role on Ehe secretion of ACTIl whlch is noÈ stress related.

It ís not possible to elucidate how much the rlse 1n cortisol 1n thís experlment was a stress response or due to

Ehe dlrect s Eimulation by the caEecholamlne paEhways 1n the hypothalamus, anterior pituítary or at, the level of lhe 198 adrenal cortex.

The role of the alpha noradrenerglc pathways fn the cont,rol- of ACTII cortlsol' secretlon ln humans Eherefore renains unresolved, wlth experimental evldence for both an exci tatory and an tnhtbl tory role . See llterature review 2.4.2.a.

Affective í11ness

Pharmacological challenge lnvestlgating the cortfsol response in depresslve 111ness has been taken to imply central alpha noradrenerglc hypofunctlon 1n endogenous depression (Cfreckley, 1980; 1982[b]; Slever eE ,a1, 1981; Johnson, L982) . Some of these concluslons have rested on the assumpEions trhat changes ín eortisol secÊetion refleeted central acEivity in Ehe hyPothalamo anterior pitui Èary adrenal axis and Èhat the alphanoradrenerglc pathh¡ays exert. a stimulatory actíon in the control of ACTH and cortlsol release. It can be seen Èhat these conclusions are open Eo question.

In conclusion, the resulÈs of this sLudy give support. t,o

the view thaE dopamine pa Ehh¡ays are not involved 1n the

control of cortisol release in humans. As far AS

thymoxamine is concerned, t.he lack of a dose response

relaEionship makes t.he f índings difficult Eo lnEerpret. 799

2.4.3. Prolactln

a. Li terature review.

Prolactln secretlon from the lactotroph appears to be released autonomously (Hall, 1984), but 1s under predominantly inhlbltory control by the hypothalamus. Transectlon of the pítuitary stalk causes a ríse 1n prolactln secreElon. The inhibitory control, vla Prolactin Inhlbltory Fact,or, lnvolves the tuberoinfundlbular dopamlne system. There is conslderable evidence thaÈ dopamine itself acts as the maJ or physiologlcal prolactin ínhíbitory faetor, having a direcE effect on t,he pítuitary lactoÈroph (¡lu11er et ãI, t977[al; Martln et aI, 1977; Scanlon et a1, 1979la]; Gudelsky, 1981).

The same mechanísm appears to act 1n humans (Besser et aI , 1980).

i. The role of Èhe dopamine pathways 1n the release of prolactin release

In vitro and animal studies

As mentloned above, there i s good evidence thaE dopamlne physlologically ínhibits prolacEin release. Dopamine neurones of the Euberoinfundibular system originate in the arcuate and periventricular nuclei of the hypoEhalamus and project axons to the external layer of the medlan eminence 200 hlhere they terminate 1n close proxlmi ty to the hypophyslal portal vessels. Dopamlne released lnto the hypophysial portal vasculature has a dfrect acute inhlbi tory effecE on the anterior pltuitary lactotroph, inhibiEing prolact,ln

release (ltuller et â1, I977la); Clemens et a1 , 1979 3 Gudelsky, 1981; Gudelsky et â1, 1984). Increased dopamine 1eve1s over a perlod of tlme leads to a decrease in prolactln synthesls, an lncrease ln prolactln degeneratfon and a reduction 1n ceIl divt slon by the lacÈotroph ( Cronln, 1982). This latter actlon is lmportanE 1n t,he clinfcal use of bromocrlptlne (a dopamlnergic agonlst) in the treatment of prolacEin secreting tunours (lfartin et aI, I977, Scanlon et a1, 1979 [a] ) . Increased prolactín 1eve1s 1n turn lead Èo an activation of tuberolnfundibular dopamine neurones and an increase in dopamine secretion 1n the medfan eminenee ( Moore and Johnston , 1982; Gudelsky 1981, Ha11, 1984).

Oestrogens and progesterones appear to modulate Èhe activí ty of Èhe tuberolnfundibular dopamlne neurone s. Progesterone and oesEradiol respectíve1y íncrease or decrease the concentraEion of doparnine in the pítuitary portal plasrna (Cu¿elsky, I981). In addltlon to interactlng oestrogens r./ith the dopamine control of prolactin release ' rnay exert a direct stímulatory action on the lactotroph (t1oyd et aI , 1973; Scanlon et 41, 1979[a]). 20r

Human studles

There is good evfdence that the mechanfsm of controlllng prolactln secretlon by dopamlne ls the same in humans ( Scanlon et aL, tgTglal; Besser et a1, 1980). As mentloned above thi s f s reflected in the c1lnica1 use of bronocrlptine in Ehe treatment of prolactln secret.ing pltuitary adenomas.

11. The role of noradrenergic pathwa s fn the control of prolactfn secretlon

Anlma1 studies

The role of the noradrenergic pathhrays in prolactin release remains to be clarlfted. In their comprehensive

revlew Mu11er et a1 (tgl 7 [a] ) report evídence that noradrenergic pathways may exert an inhlbltory action on t.he restlng secretion of prolactln as the alpha noradrenergic blocking drugs phentolamine and phenoxybenzarnine, and the beta blocker propranolol increased serum prolactin levels 1n prlmates (Quadrí et a1 1976). Mu11er et a1 (L977lal) propose too that betanoradrenergic pathbrays may exert a stímulaEory action on t,uberoínfundlbular dopamine neurones.

Human studies

Few s tud ie s have been performed and the role of noradrenergic pathr¡¡ays ín the control of prolacÈin release 202

1n humans remains uncer t.ain ( Checkley, 1980 ) . Lancran j an e t,

a1 (tgl 9 tbl ) reported that although neither clonldine or guanfacfne (both alpha noradrenerglc agonisÈs) affected restlng prolactln 1eve1s, guanfacfne lnhlbfted the prolactln rl se followlng lnsu1 ln lnduced hypoglycaemla.

Prolactln and affective disorders

Basellne prolactln leve1s have been reported Èo be wft.hln Ehe normal range or elevaEed ln patients with depresslon (Ctreckley, 1980; 19AZIb]; Johnson, 1982). The prolactin response to TRII in depressed patienÈs has been reported as belng reduced or enhanced (Johnson, 1982). They may also how an augmerrted reductlon of prola-ctln secretlon following apomorphíne challenge ( Insel and Slever, 1981 ) . Checkley ( 1980) concluded that evldence from studles investfgating prolactin secretion ln depresslon probably 1mp11es normal " f.unctioning of the dopamlne receptors. 203

i b. Results

1. The tnfluence of Ehe bloeklng drug s a1 one

Nelther dose of thymoxam lne exerted any lnfluence on serum

prolactin 1eve1 s . Plmo zLde admlnl sÈratlon caused a dose related rise 1n serum prolact, ln secretfon 1n the latter part

of the experlment. See flgure 2.IL. Ar 5 hour s Post

pimo zLde admlnl stration, the dlfference s from placebo were;

pimozlde 2 ng +335.0(+-8f.8) mU/L' P <.05

pimozLde 4 mg +997.0(+-I38.5) mU/L, P <.01

Estlmates of the mean (+-SnU) areas under the curve.

PÍmozldez

plaeebo: +7 2.8 ( +-88 .6 )

PltZ 2 ng z +491.2(+-103.5) PllZ 4 rng: +r476.2(+-539.8)

Net lncremental 1eve1s f ollowin g PYlz 4 ng z +I403 . 5 (+-4 63.9) , P <.1

Thymoxam lne :

placebo: +98 . 4(+- 70. s ) TMX B0 mg: +82. s(+-s3.4) TMX 160 mg: +107.5(+-84.9) 204

a +

J 400 t

=E

.-'-t-' J o ...L l\t o b-' e o

o 1 2 3 4 5 hou rs

Figure 2.11 uean (1 SEM) ner incremental serum prolactin (mU/L) following Pl'12 2mg and PMZ 4mg:

PYIZ 2mg [-r-.r

Pl"lZ 4mg ¡----r

Difference versus placebo. tP <.05 *r;p (.Ql I

I

I

l 205

11. The effects of Pretreatment by plmo zLde and thymoxamine on Èhe prolacEln resPonse to dextroamphe tamine

Ptmoz!de pretreatment 1ed to a large dose related rise 1n serum prolactln Ievels. This fncrease hras htghly slgnlflcant when one comPares boÈh pimozLde preÈreatment comblnations v¡1th the placebo - placebo and placebo pimozLde - dextroamphetamlne 20 mg at all tímes (apart from the readlng at one hour followlng pimozide 2 ng pretreatmenÈ). see f igure 2.72. At 3 hours ( s hours post pirno zide adminlstration) the net incremental serum prolactin levels from placebo I¡Iere:

PimozLde 2 ng pretreatment: +88.6(+-109.4) nIJ/L, P <.001

Plmozíde 4 ng pretreatment: +I221.9(+-I34.4) mu/L, P <.001

The net lncremental serum prolactín 1eve1s comPared with amphetamíne alone at the same time hlere:

Pimozlde 2 ng pretreatment: +827.4(+-133.9) mU/L, P <.001

Pimozlde 4 ng pret,reatment: +1160.8(+-135.1) mU/L, P <.001

The increase after 4 rng plmozíde pretreatmenE rtas greater lhan af.Eer 2 mg and occurred earlíer. At th¡o hours the dif f erence betÍ¡een the thro r¡¡as 401.3(+-1lrB.6) mU/L, P <.025. 206

+ * * +

:} :} ----_ 1 200 I ï a * J ) -t-t-'- ù 800 I J I f I Ia a + I a ; I o 400 a 3! I a o t t- o. I Ia a E I L o o o

-200

o 1 2 3 4 hou rs

rígttre 2.12 Mean (+ SEM) net incremental serum prolactin (mU/L) response lo oral dAMP 2Omg given at 0 (1800) hours demonstrating the ef f ect oÍ. Pl4Z 2mg and PltlZ 4mg given 2 hours earlier:

PYIZ placebo - dAMP 20rng PÞ12 2mg - dAMP 20mg ¡!r-rrr PNIZ 4mg - dAMP 20mg l-----

Difference induced by P\12 on the response to dAMP' rk-/rP ''rP (.025 <. OO1 207

Estlmates of the mean (+-SnU) areas under the curve are as follows:

Placebo: +10.7(+-100.3)

dAMP 20 mg: +208.3(+-6s.3) Pl"lZ 2 ng + dAMP 20 mg : +203 7 . 0 ( +- 259 .8)

PYIZ 4 mg + dAMP 20 mg: +3094.5(+-252.4)

The lncreases in mean area under Ehe curve following both doses of plmo zLde urere htghly signíflcant ( P <.001)

Thymoxamlne pretreatment dld not lnfluence the sma11 increa se in serum prolactln lnduced by dextroamphetamine. See figure 2.I3. The mean (+-Snu) area under the curve estimat,es are as fo11oqrs.

plaeebo: -23.3(+-4s.1)

dAMP 20 ng: +65.3(+-s2.r)

TMX 80 rn õ'o* dAMP 20 mg: +77.0(+-64.0)

TMX 160 mg+ dAMP 20 mg: +108.6(+-63.7) 208

80

J

=E

o 40 tÉ o L o. Þ

L. o râ o

-40

o 1 2 3 4 hou rs

Figure 2.13 Mean (l SeU) tt"t incremental serum prolactin (mU/L) response to oral dAMP 20mg given at 0 (1800) hours demonstraring the effect of TMX 160mg given t hour earlier:

TMX placebo - dAMP 20mg TMX 160mg - dAMP 2Omg Jrrrr 209

c. Dlscussfoo.

Dopamlne blockade by Pimozlde considerably increased the serum 1eve1s of prolactln 1n both the basal state and after dextroampheÈamlne. Thymoxamine preÈreatment on the other hand hras without âny consisÈent effect. These ffndlngs are consistent with other studies lnvestigating the role of the cat.echolamlne pathways in prolactin release whích denonstrate that the dopamine pathways act in an lnhibl Eory manner in prolactln release and which lmp1y thaÈ noradrenergic pathways are probably not lnvo1ved.

A significant observaElon from the study investlgating the effect of plmozLde alone (flgure 2.II . ) ts !hat dopamlne blockade does not begln unt,i1 at least 2 hours af ter oral pimo zIde. This is importanÈ ln the interpretation of the tnfluence by pirno zlde on dextroamphe tamine lnduced arousal. Any reduction in arousal occurring 2 hours after plm ozLde (predextroamphetamtne) observed in Part I of Èhis study ís not 1íke1y to be due to dopamine blockade.

The results do not lnfluence conclusíons about the acÈlvlty of the caLecholanine pathways 1n affecEíve disorder fron pharmacological challenge of neuroendocrlne activlty. 270

2.4.4. Growth hormone

a. Llterature revfew

Growth hormone releasè from t.he somatotrophs 1n the anterlor pituitary 1s under posftlve control from the hypothalamus via growth hormone releaslng factor. The hypothalamus also secretes an inhlbitory tetradecaPeptlde ' gro.wth hormone ínhiblEory factor or somaÈostatln (Cryer and Daughaday, Lg77; Martln eÈ ãL, L977; tr'lass, 1983; Martln' 1983). Secretion of grohrth hormone ín nonstressed hu¡nans is at basal 1eve1s, although significant fluctuations can occur wlth spontaneous surges of growth hormone secretion occurring at lnterval s regularly throughout the day. The largest peak is usually obse rved dur ing Èhe first tr.ro hours of sleep (Martín, 1983).

The catecholamine conÈro1 of groh¡th hormone secretion

appears to be relaEively complex and lnterspecies differences have been reporEed (t'tu11er et a1, I977tal).

i. The role of dopamine PathwaYs in growth hormone secretlon

Animal studies

In the rat, l{u11er et. a1 (I977 [b]), observed that dopamine pathü¡ays appeared to exert a sEimulatory influence on growth

hormone secretlon 1n the ner^¡ born rat but an inhibitory 2TT

1nf1 uence ln the adulÈ. In the mouse dopamine pathways appear Èo be tnhlbitory (Uu1.1er et al, I977[a]), whl1e 1n the dog, haloperidol and pimo zLde reduced t,he growth hormone releasing effecE of nomlfenslne ( Casanueva e E a1 , 198r) lmplytng a stlmulatory role for the dopamine pathways.

In baboons, lntravenous dopamlne lnfuslon e1 eva te d gr owth hormone secretion, the elevation being suppre s sed by phentolamlne. However, micro tnJ ectlons of dopamlne fnt,o the hypothalamus lowered basal growth hormone leve1 s (Stelner et aL,1978).

Human studles

Invltro studles using human pltuitary cel1s demonstrated a suppresslon of growth hormone release from both normal and adenomatous ce11s by dopamine or bromocrfpÈ1ne which was blocked by haloperldol, metoclopramlde and sulpiride ( lstrlbashi and Yamaj i, 1984).

In vivo studies show a variable response by dopamine pathhrays on growth hormone release. Doparnine (Leebaw et a1, 1978; lJoolf et a7, I979; Ferrari et a1, 1981) and Ehe dopamíne agonists, apomorphine (l,at et a1, L975), lergoErí1e and piribedal (Thorner et aI , L97B) produce a rlse in growt.h hormone, which can be blocked by the dopamine antagonísts metoclopramide (lnorner et a1, L978) and chlorpromazine (tat et al, I975). (See also Scanlon et al, 1979[a]; Checkley, 1980). PirnozLde reduced arglnine and exercíse lnduced growth 2t2

hornone release ( Schwlnn e t a1 , L97 6) . 0n the oÈher hand I, growth hormone secreÈlon 1s lncreased by metoclopramfde 1n hypogonadal and adolescent boys (Cohen et al, L979 [a] and tbl).

I,Ih11e dopamtne fnfuslonr'âs menÈloned above' stlmulated growth hormone secretlon, lt lnhlblt.ed the growth hormone response to lnsultn lnduced hypoglycaemfa and L dopa (Leebaw et al , I978; lloolf et aL, I979). Dopamlne lnfusLon, bromocriptlne and L dopa give rlse to a fal1 1n growth hormone secretlon 1n acromegaLy (¡lul1er et 41, tgzTIb]; Parkes et a1, 1978; Roelfsema et a1, L978; Scanlon et al ,1g79lal).

In the light of this apparenÈ1y confllcting evldence, lE ll Èt has been suggested that dopamine pathú¡ays play a dual role 1n grohrth hormone release: sElmulating basal growth hormone secretlon but reducing sttmulated growth hormone release

(Leebaw et a1, 197B; Scanlon et al, 1979 [ a] ) . Martln ( 1983) proposed thaL the lnhibitory effect of dopamine is at the

pl tui t.ary leve1 .

r 213

it. The role of noradrenerglc pa thway s 1n growth hormone secretion

Anlmal studles

Most sÈudies 1n anlmals suggest that the a1 pha noradrenergic sysÈem sElmulates the release of growth hormone while the beta noradrenerglc sYSten f s probably inhibltory.

Both Itypothalamlc lnfusion and intravenou s noradrenal lne glve an elevatlon of growth hormone secret.íon ( Steiner et a1, 1978; Martín, 1980) as does L dopa and clonidine, the rise lnduced by L dopa being blocked by phentolamlne or rl !! phenoxybenzamine in dogs and baboons (Mu11er et aL, tgTTlal; : 'I Martin, l9S0). Phenoxybenzamine also completely lnhibited growth hormone secretory episodes (l'lartin et a1, 1980) . Beta noradrenerglc pathways either exert no effect or an lnhlbiEory effect in dffferenE species (ltu11er et 41, 1977lal; Martin, 1983).

Human studies

Most evldence in human studies poínE to the alpha

noradrenergic pat,hway acting in a s Eimulatory manner while I I the beta noradrenergíc Pathblays exert an inhibitory action I on growth hormone release.

I 214

Growth hormone secretion 1s increased by the alpha noradrenerglc agonlsts clonldtne (ta1 et aL, I975) and guanfaclne (Langranjan et a1, I979 tbl ) . Stlmulatlon of grosrth hormone secretlon by L doPa r lnsulin lnduced hypoglycaemla, stress or exerclse is blocked by alpha noradrenergic antagonlsts ( ¡tackard and Heídlngsfelder, 1968; Sachar eE al, I975; Jezova-Repakova et aL, 1979; Scanlon et aI , 1,979Íal; Checkley, 1980; Martln, 1983).

Rees et al ( 1970), on the oEher hand, observed that the modest rlse 1n growt,h hormone secretion followlng lntravenous methylamphetamine hlas augmented by thymoxamlne, though Èhe difference did noE reach statistical slgnlflcance; propranolol had a greaÈer effect sígnifícantly augmenting growÈh hor mone secre tl on. Pr opranolol also has been reported to enhance Èhe growÈh hormone release lnduced by glucagon, 1nsu11n induced hypoglycaemía, vasopressin and

L dopa ( Stackard and Heidlngsfelder, 1968; Martin et aI , 1983).

Growth hormone and affectíve di sorder

A varleÈy of pharmacological challenges have been performed to examine growth hormone secretlon in affective disorder. The growth hormone resPonse to hypoglycaemia is

È Ì reporEed to be reduced in depressed and rnanic patients

¡r I (Cneckley,1980; Johnson, L982, Silverstone and Cookson, 1,982). Some workers report an abnormal response to

þ 215

anpheÈamlne (Langer et aL, 1976; Arato eE dL,1983). 0thers have reported no dlfference bet$reeri the depressed and non depressed state (checkley and crammer, L977; Checkley' I979). BoEh desipramlne and clonidine challenge rrere reported to be associated wlth a dlmlnished growth hormone response 1n depresslon (Laakman, 1980; Checkley, 1980; tg82[b] ; Siever et al, 1981; Checkley et aI, 1981; Iloner et aL, 1984). These flndlngs have been taken Èo imply a deficleney of functioning of the alpha noradrenergic pathways ln affective dfsorder (Langer and Matussek, 1977; Garver and Davls, IgTg; Laakman, I980; Checkley, L982tbl).

The GrowEh hormone re sponse to challenge by dopamine agonlsts íncluding apomorphlne and L dopa varles wlth some

üL udies reporEing no effect, a reduced or even an augmented effect 1n some depressed patienÈs ( Insel and Siever, 1981;

Johnson, I982; Checkley, IgB2tbl ) .

lr 216

b Results.

1. Influence of the blockln drug s a1 one

The changes in serum growth hormone secret,lon lnduced by plmozide and Èhymoxamine alone are difflcult Èo evaluate. In both experiments some subj eets secreted a surge of groh¡th hormone prlor to the drugs- admlnlstratlon. Therefore the reference values for estimatlng changes in secretion were not comparable. If the subjects secretlng more-than 5 nU/L at base time are excluded, there I s insufffclent remaining data to draw any concluslons.

i i . Influence of bl ockade by plmo z!de and thymoxamine on the growth hormone re sponse to dextroam he tamlne

In both experiment B and D a ri se ln growth hormone secret,ion following placebo is evident. Dextroamphetamine administratlon appears to produce an early accentuatlon, followed by a later attenuation of thís rise. These changes did not reach statistlcal significance. Pimozide pretreatment. appeared to âccentuate bot.h Èhe early rlse and the late fa11 induced by dextroamphetamlne. See flgure 2.L4 and table 2.1.

At one hour the ne t incremental serum growth hormone r i se compared with plaeebo, following 2nE and 4 ng of pimozide pretreatment (matching pairs data only) were: +8.7(+-3.4) mU/L, and 19.1(+-7.0) rnu/L, (P <.05), and at 3 hours; -6.3(+-4.5) rnU/L (NS) and -10.0(+-3.7) nulL, (P <.0s) respectlvely. 217

25

20 J f E 15 o I o

L o 10

+, 3 o I L 5 I (9 I

L ---+ o o o

-5

o 1 2 3 4 hours

Figure 2.14 Mean (t SIU) incremenral growth hormone (mU/L) demonstrating the response ro oraL dAMp 2Omg given at O (f gOO) hours and the effecr of PNIZ 4mg given 2 hours earl ier:

Pl4Z placebo - dAMP pLacebo Qrrrrrrrrrrr PltlZ placebo - dAMP 20mg tr-- Pù12 4mg - dAMP 20mg Ir--r- 2t8

The higher dose of pimo zLde 1n particular tended to augneat the fnfluence of dextroamphetamlne on serum growth hormone secretlon, with an accentuatfon of the dextroamphetamlne fnduced rlse at 2 hours and a decrease ln secretion at 4 hours. Differences (matched palred data only) at Ehese tlmes h¡ere; +5.4(+-2.5) mU/L, ( P <.1) and -4.8(+-3.9) mU/L, (P <.3) respectlvely. 219

Tabl e 2.I

Time Pl'lZ PIac Pl"lZ plac PYIZ 2mg mg dAMP Plac dAMP 20ng dAMP 20ng d AMP 2 0mg

mean change ) +2.6(+-2.8) +9.6(+-S.s) +8.6(+-2.8) +16.6(+-6.1) dlff fron plac - plac * ¿ atched prs 0 +4.7(+-3.7) +8.7(+-3.a) +19.1(+-7.0) dlff from plac - dAMP atched prs 0 -1.0(+-6.8) +8.1(+-4.9) 2h (mean change ) +1s.3(+-7.0) +9,9(+-a.7) +7.9 (+-4.5) +11.9(+-6.6) diff from plac - plac na Lched pr s 0 -2.3 (+-a. s ) -8.2(+-8.4) -8 .2(+-t .4) diff from plac - dAMP ma tched pr s U +1.2(+-r.8) +5.4(+-2.5) 3h (mean change ) +10.8(+-3.1) +4.3(+-2.2) +s.8(+-1.9) +2.7(+-2.0) diff from plac - plac ¡ mat,ched prs 0 -4.4(+-2.7) -6.3(+-a.s) -10.0(+-3.7) diff from plac - dAMP matched prs 0 -2.1(+-3.4) -r.B(+-a.1) 4h (mean change ) +I0.9(+-5.6) +4.2(+-2.7) +2.2(+-1.1) +0.9(+-0.7) diff from plac - plac natched prs 0 -1.9(+-z.i) -4.8(+-¡.2) -9.8(+-a.6) diff from plac d AMP atched prs 0 -2.9(+-¿.t) -4.8(+-3.9)

ncrenenta serum groü/t ormone eve s toget er wit di erence data following PilZ pretreatment. ^r <.05. 220

EsÈlmates of the areas under the curves revealed no signf flcant dlfferences.

Thymoxamine pretreatmenÈ partlcularly the hlgher dose, augmented t.he early rl se ln gr owth hormone wl th Ehe ne t lncremental serum groh¡th hormone level s compared wi t,h dextroa¡nphetamine alone at 2 hours was, +13.3(+-5.5) mU/L, P <.05 . See figure 2.15.

Mean (+-Sn¡l) area under the curve esÈlmates are as fo11 ows :

placebo: +2r.3(+-s.9)

dAMP 2Q mg: +8.2(+-2.3)

TMX 80 mg +

TMX 1 60 mg+ dAMP 20 mg: +26.s(+-s.1)

Difference TMX 160 mg - dAMP 20 mg v dAMP alone (matched pair dat,a on1y, n=8): +14.2(+-4.6), P <.02. 221.

25

*

^20J J E O lE o

L r10o \ \ \ 3 o L o5 \ \ tr \ L L- o o 0 -l

-5

o 1 2 3 4 hours

Figure 2.15 Mean (l SEM) incremental growth hormone (mU/L) demonstrating the response to oral dAMP 20mg given at O (1800) hours and the effect of Tl"lX 160rng given t hour ear I ier :

TMX placebo - dAMP placebo Qrrrrrrrrrrr TMX placebo - dAMP 20mg TMX 160mg - dAMP 20mg ]rrrl

Difference induced by TMX on the dAMP response. 'kP ('05 222

c. Dfscusslon.

It 1s dtfficult Eo make an lnterpretatlon of the role of catecholamlne control of growth hormone secretlon from these results. The possibly biphasfc response by dextroamphetamlne (an early stlmulaÈlon followed by lnhtbitlon of secretion), mlghE reflect an lnteraction of Èhe fnfluence of dexÈroamphetamine wlth othet factors.

Dopamlne pa thway s

The blphaslc trends fn growth hormone secretion followlng dex troamphe Èam lne hre re augmented by pimozide pret,reatmenÈ whlch falled to reach statlstlcal sígniflcancer possíb1y as the number of matchtng paírs stere too sma11. In vlew of these dlfferentlal effects, it 1s possible that dopamine pathsJays exerted both excltatory and tnhlbit.ory lnfluences hormone and by on t,he dextroamphe tamine re sPonse by growth ' impllcation, in t.he control of groürth hormone release.

The role of Èhe doparnlne pathh/ays in growth hormone release appears, from a review of Ehe literature, to be complex wlth possibly an excitatory and tnhlbitory component to its action, both in experlmental animals and ln particular in humans. Scanlon et a1 (I979[a]) has Proposed thât perhaps the dopamine pathr¡rays play a dual role in growth hormone release in that they augment basal but reduce

s tinulated growth hormone release. 223

As dopamine lnfuslon may effect both release and inhibltlon of release, an action outslde Ehe central nervous sysÈem as well as wlthln the hypothalamus ¡ appears Èo be involved (Uul1er et a1, L977 [a] ). The stimulatory effect of the dopamlne pat.hways may be central, whereas the inhibltory effect of dopamine may be a dlrecÈ effect on somatotrophs (l'tarrln, 1983).

A dual action by the dopamine pathways on growth hormone release is not lnconsistent wlth the flndlngs 1n thls s tudy .

11. The role of the noradrenerglc pathways

0ra1 Èhymoxamíne pretreat,nenE, parÈlcu1 arLy Èhe higher dose, lncreased net lncremental serum growth hormone secretlon when compared wiÈh the placebo-placebo combinatlon or the placebo - dext,roamphe tamlne comblnat.ion. Thl s suggests Èhat Ehe alpha noradrenergic pathways may have an inhibltory role in dextroamphetamíne stimulated growth hormone release.

Simí1ar1y Rees et a1 (1970) reported an lncrease in grohrth hormone secretlon fo1lowlng intravenous methyl amphetamine after intravenous thymoxamine preEreatnent, though 1n Ehat study Èhe increase did not reach staEistical significance. In the same experinenE propranolol pre Ereatment significanEly augmented the growth horrnone response to lntravenous methyl amphetamÍne.

Thymoxamine and íts metaboliCes can block both alpha 1 224 adrenoceptors and histamlne receptors. It is consldered un1lke1y Èhat lts hlstamine blocklng actlon 1s lnvolved as hlst.amine appears to be wlthout influence in growth hormone release ( Pontlrolt et a1, I973) .

Most experlmental evidence to date, both in anlmals and humans, point to the alpha noradrenerglc pathways belng stlmulatory and the beta noradrenergic PaLhvtays being inhibítory to groh¡Eh hormone release. ( See llterat,ure reviel^r 2.4.4,a).

It has been proposed that lhe slte of noradrenerglc stlmulatlon of growth hormone release is withln the central nervous sysEem as release assoclated wlth extra hypothalamlc (eg, arnygdala) stimulatlon can be prevented by alpha noradrenerglc bloekade ( Scanlon eE â1, l,979lal; Martin, 1980). However as noradrenallne infusíon and nethoxamlne can stimulate growth hormone release, it seems 1ike1y that there are some receptors outside the blood brain barrier in

addi tlon ( Ctreckley, 1980 ) .

The role of pre- or posEsynaPtlc recePEors are of particular relevance 1n clarifylng the role of noradrenergic pathways in growth hormone release from pharmacological studies. For example, the noradrenergic agonlsts used in È.he studles in humans include both clonldlne and guanfacíne both of whích are alpha 2 toradrenergic agonists (Doxey, I979). These drugs may exert an acÈion at either pre- or postsynaptic sites depending on the dosage and the funcEion beíng invesEígated (Anden et aI, L976) . This is importanÈ. 225

because 1f the agonist used was 1n facE acÈing preferentlally at presynaptlc receptors, ir woul d be exertlng an inhfbl Eory fnfluence on the noradrenerglc pathway. See Part I ( t .3.4. b. ) .

This lssue has been addressed 1n studles ln exPerimental animals. Clonldlne lnduced growth hormone secretlon was blocked by yohimblne raEher than Prazosin or phenoxybenzamlne 1n rats, implying an alpha 2 site of actlon

( nrttsson eÈ â1, 1982) . But as reserpfne pretreatment did noE abolish the clonldine response, Erlksson et a1 ( 1982) suggested that clonldlne uras actlng aE a postsynaptic alpha adrenoceptor slte. In an extenslve study lnvesEigatlng the relatlve roles of alpha 1 or alpha 2 adrenoceptors 1n growth hormone secretlon ln the rat, Kru c et a sugges that both pre and Postsynaptic alpha noradrenerglc recePtors may be lnvolved in t.he release of growth hormone with the

alpha 1 receptor being inhibitory and the alpha 2 adrenoceptor lnvolved ín sustainlng a t,onic drive on secretion as well as pulsatile secretlon.

Cel1a et a1 (1983) interpreted t,he flndings of slmllar studies in Èhe dog (which they belleve more closely resembles the situatlon in humans)r as showlng that

clonidlne acts at presynaPtically sÍ tuaEed alpha 2 adrenocepEors, in stimulating the release of groutth

hormone . In their vlew clonidine, s timulated growth hormone release by lnhibiting noradrenaline release onto postsynaptic sit.es, lndicaEing that these Postsynaptic 226

receptors e¡ere exertlng an lnhibltory actlon on the secretlon of the hormone.

In a subsequent study Cel1a et. a1 ( 19S4) demonstrated, again in Èhe dog, that activation of alpha I noradrenerglc receptors was lnhfbltory to both tonic and stlmulaÈed grot.tth hormone release.

If the previously noLed rise 1n growth hormone followlng alpha noradrenerglc stimulatíon in studies in humans, for example by clonídlne, is manifesÈ through an action by presynaptlc stimulatlon, then noradrenallne may be exerting an lnhlbltory influence at postsynaptie sites. The results of this experimenÈ and that of Rees et al (1970) would be 1n keeping wlth that.

It ls lmportant that these issues are resolved ín the human sltuatlon. Clonidlne has been used as a stimulant to test neuroendocríne and hence catecholamine act,ivity in psychlatrlc lllness. It has been reported that depressive patíents showed a dimlnished response ( Checkley et â1, 198f; Sievers et al, 1982; Iloner et al, t9B4). Thls has been int.erpreted as reflecting a defect 1n functlon of central alpha noradrenergic receptors in depresslon.

I'laking lnferences from other studies investigating noradrenerglc functlon in aftective disorder usíng

pharrnacologieal challenge is beseÈ wiEh problems. Change s

in secreflon followlng amphe tamlne are not always reproducible. FurÈhermore the effecE of placebo conditions 227

musÈ be consldered. Thls apPears to be particulacr.y relevant when measurlng the effect of amphetamlne challenge. Flnally, concluslons of hypo or hyPer functlon of the noradrenergic pathways fn depresslon, by lnvestlgatlng the growth hormone resPonse to challenge of the alpha noradrenergic pathways, w111 requfre resolutlon of the questlon of whether they exert an lnhibltory or excltatory actlon 1n growth hormone secretlon ln humans.

I

I i

I 228

2.4.5. Thyrotrophin

a. Literature review

Thyrotrophin ( lSH) seeretlon from the thyrotroph in the anterlor pitultary is under posiEive control by the hypothalamus vla thyrotrophln releasíng hormone ( TRH) . TSH 1n turn stlnulates the producÈlon and release of thyroxlne and trilodoÈhyronine ( t¿ and T3) whlch in turn exert a negatlve feedback on TSH release at the pltuiEary 1evel (Martin et aI, 1977; Scanlon et alrlglglal),

i. The role of Èhe dopamine pathways

Evtdence f rom ínvitro, anlmal exPeriments as u¡e11 as studles 1n hunans, poínt. to t,he dopamÍne pathways exerting an inhlbl tory influence on TSIt release.

Invf tro studles

TSH secretion from cultured ce11s was stimulated by dopamlne antagonists (ttatt and Meites, 1981 ) whereas dopamlne ltse1f reduced TSH release (Peters et a1, 1983).

Animal studies

The dopamíne agonists apomorphíne, ptribedal and bromocriptine have been observed to reduce TSH secreEíon in experímental anlmals (rttu11er et ãL, 1977[al1, Krulich et aL, 229

I977; Krullch, 1982). Mueller et a1 (1976), reported that haloperidol blocked the effect of apomorphlne. Apomorphlne also reduced the cold stimulated rlse 1n TSH secretlonr âû effect that was reversed by haloperldol, pimozide and sulpirlde (Mannisto, 1981; Kru1lch, 1982).

IIuman s tud ie s

In humans, earlier studles lnvestigatíng the role of

( dopamlne pathways hrere inconclusive Co11u et a1 , 197 5 1 Thorner et, a1, 1978) . More recent sÈudles have clearly esEabllshed an lnhiblEory role for the dopamine pathways 1n TSII release (Scanlon et ãI , 1979[b]; Morley, 1981; Kru1lch, 1982). TStl rglea=e ls stlmultted by a varie ty of different dopamlne blocking drugs fncluding metoclopramide ( Scanlon et aI , I977; L979la) and Ib]; 19S0[a] and tbl) and sulpiride (t'tassara et â1 , I978[a]), haloperído1 and plmozlde (Oetttala et ãI , 198I) while TSH secretlon or the TSII resPonse to TRH ü¡as lnhíbited by dopamíne infusion (Scanlon et aL, I977; tgTgLal; Massara et a1, 1978[b]; Leebaw et aL, I978). The stimulating response to dopamine blocking drugs is greaÈer ln hypothyroid patlents (Scanlon eÈ aI , 1980[b]) and l¡¡omen (Scanlon et aI, 1977; Massara et al, 1978[a]). 230

ff. The role of the noradrenallne pathways

Invitro studles

Noradrenallne causes a release of TRIt from hypothalamic tlssue (Grimm and Reích1tn, I973) and of TSH from pltultary - hypoÈhalamo coincubations whlch can be blocked by the alpha noradrenerglc blocker, phentolamine but not Èhe beta blocker propranolol (ttat1 and l'1eit,es, 198I). Noradrenaline also caused a release from anterior pltuitary ce11s alone (Peters et al, 1983).

AnimaI stu d fes

Experiments 1n animals polnt !o a stlmulatory role for the alpha noradrenergic pat.hways in TSII release (Uu11er et a1, I977lal; Kru11ch, 1982).

Basal TSH 1eve1s r,¡ere f ound to be reduced by phentolamlne and by dopamíne beta hydroxylase lnhibition (Krulich et 41, I977). Sím11ar1y the stimulatory response by TSH to cold ín the rat $ras blocked by dopamine beta hydroxylase inhibitlon, phentolarnine and phenoxybenzamlne and augmented by cloníd ine (Krulich et a1, 1977, Montoya et aL, 1979) . Krutich (1982) concludes that the noradrenergic pathh/ays appear to act via

the release of TRI{. 23t

Human studies

The role of the noradrenergic pathways 1n TSH release has been relatively 1itt.1e studied. Investigatlon of the lnfluence of clonldtne (Lat et a1, L975) or the influence of a variety of noradrenerglc agonlsts and ant,agonlsEs on the TSH response to TRII (Lauridsen eE aI, 1976 ) led to the conclusion thaÈ noradrenerglc inechanisms were of llttle importance. ZglLczynski and Kaniewskl, 1980) found Èhat

phentolamlne but not propranolol reduced both basal TSII 1eve1s and the TSH response to TRH, lmplying a st,imulatory role f or the alpha noradrenergf c pat,hways.

TSH and affective dlsorder

In some patients with either endogenous depresslon or nania, the TSH response Èo TRII is reduced (flrkegaard et aI,

L97 5; I97 8; Johnson, 19B2; Checkley , 1982 t b I ) . The se observations do not a11or.¡ any concluslons abouE catecholamlne actlvlt.y to be drawn. Furthermore there appears to have been no dlrect study or pharmacological challenge of TStl secretion to investigate the roles of the catecholamines in affective disorder. 232

b. Results

t. The effect of the b1 ocklng drugs a1 one

PfmozLde 4 ng caused a modest nonsignlffcant rf se in TSH secretion. See figure 2.16. At 2 hours the dffference from placebo üras +0.7 (+-1.04) nU/L.

Mean (+-SEM) estlmates of the areas under the curve are as f o11ows.

placebo: -0.21 (+- I.20)

PtfZ 2 ng: +0 .25(+- 0 . 17 ) Pttz 4 ng: +1 .38 (+-I.24) ( Trends observed did not reach sÈatistical significance) rl 9 Thymoxaníne alone appeared not t,o influence TSIt secretíon.

11. The effects of pimozlde and thymoxamlne blockade on the TSI{ response to dextroamphetamíne

Pimo z!de 4 ng pre treatment accentuated the rl se 1n serum TSI{ secretlon induced by dextroampheÈamine, whereas thymoxamine pretreatment att,enuaEed tt.

Pimozlde 4 mg pretreatment caused a statistically signíficant increase in net incremental serum TSH secre Èion in all four readings. Dífferences in changes of neans are I as follows; +0.43(+-0.i7) mrJ/L, +0.76(+-0.I7) mU/L, +0.85(+-0.17 ) mU/L,and +0.75(+-0.16) mU/L (one hour P <.05 two, three, and four hours P <.001). Pimozide pretreaEment

þ l 233

I rl

I

I

o

0.6

0.4 J f o-2 E ,

a / l T .¿t^ Ø / I Þ o \'-'

-o.2

0 1 2 3 4 5

!t hou rs H

Figure 2.16 Mean (l SnU) ner incremental TStt (mU/L) following PMZ 2mg and PMZ 4mg:

PNIZ 2mg V-D-r- PMZ 4mg Àrr¡¡¡

¡

r 234

accentuated the effect of dextroamphetamfne on serum TSH, the net fncremental serum TSIt levels compared wl th

dextroamphe tamlne al one sra s max 1ma1 at three hours (+-0.63[+-0.2 mU/r) (P <.01). see figure 2.L7.

Estl¡nates of Èhe mean (+-SEM) areas under the curves are as follows:

placebo: -0.2r(+-0.37)

dAl,lP 20 mg : +0.85(+-0.s1)

Pl'(Z 2 ng + dAllP 20 mg: +0.66(+-0.51) PþlZ 4 mg + dAMP 20 mg: +1.9s(+-0.21)

Difference PMZ 4 mg - dAMP 20 mg v Placebo dAMP 20 mg: I.1(+-0.5), P <.05.

i In experlment D the elevatlon of serum TSll secretfon

1 j following dAMP uras smaller than in Experiment B.

Pretreatment with thymoxamlne 160 mgr but not thymoxamlne 80

mB s reduced the TSII re sPonse to 1 r igni flcantly ri 11 dextroamphetamine at three hours when the dtfferences of changes of means e¡ere -0.28(+-0.11) mU/L (P <.025). See f lgure 2.L8.

I

I I l¡

r 235

+ 1.o

J -, E o.5 I Ø F

L o o

0 1 2 3 4 nou rs

Figure 2.17 Mean (t Se¡l) net incremental serum rSu (mU/L) response to oral dAMP 20mg given at 0 (180O) hours demonstrating the effect of Pþ12 4mg given 2 hours earlier:

PMZ placebo - dAMP 20mg PMZ 4mg, - dAMP 20mg þrrrrr

Dif f erence induced by PI4Z on the dAMP response. -i.-P <. 01 236

0.8

o J Ð E

.L Ø t- o \\\\\

L o .t

* - o'4

o 1 2 3 4 hours

Figure 2.18 Mean (l SEM) net incremental serum TSH (mU/L) response to dAMP 2Omg given at O (1800) hours demonstrating the effect of TMX l60mg given t hcur earller:

TMX placebo - dAMP 20mg TMX 16Omg - dAMP 2Omg þr-rr

Dif ference induced by TMX on the dAMP- response. ìkP <.025 237

EsÈlmates of mean (+-SnU) areas under the curve are as f o11ot¿s:

placebo: +0.42(+-0,23) dAMP 20 mg: +0.66(+-0.36)

TMX 80 mg + dAMP 20 mg: +1.02(+-0.64)

TMX 160 mg+ dAMP 20 mg: +0.1 8 (+-0.41 )

Difference TMX 160 mg dAMP 20 mg v placebo dAMP 20 mg: -0.48(+-0.29), P <.2 238 c. Dlscussfon

The observed augmentatlon of the dextroamphetamlne fnduced increase in TSIl secretlon by plmozLde 1mp11es an lnhibltory role for dopamfne pat,hways, whilst the attenuatlon by Èhymoxamlne lmp11es a stfmulatory role for the alphanoradrenergic pathways. These results conflrm prevlous flndlngs concerning t,he roles of the dopamine and noradrenallne 1n the control of TStt in euthyrold subj ects .

Doparnlne pathways

Considerable evidence has no$r accumulated demonstratíng an

lnhibitory role of the dopanine pathways 1n TSH release from

invitro studles and st.udies in experimental anlnals and human subjects.

As dopamlne infuslon can lnhlbit TSH release which rnay be reversed by domperldone, a si E,e ouÈside the blood brain barrier appears to be lnvolved ( Scanlon er a1, I979 [ a ] ) .

Ilowever recent evidence from experimental anlmal s, a1 so implicates â central 1eve1 vía t,he hypothalamie projections of the nigrostriatal dopamine system (Mannisto et a1, 19Bl) or via inhibition of TRH release (Morley er a1, 1981).

Noradrenergic pathways

A1 though the role of noradrenergic pathways in lSH release 239

has not been so extenslvely studled, parÈ1cu1ar1y ln human

subJects, the alpha noradrenergic system appears to be stlmulatory.

The questlon arises whether t,hese pharmacologfcal studfes lmply actlvlty at pre- or post synaptic alpha noradrenergic receptors. Krulich et al (1977) reporÈed that

phenoxybenzamine ( a specific alpha 1 noradrenergic blocker) , but not phentolanlne (a less speciflc noradrenerglc blocker, actlve at both alpha 1 and alpha 2 sftes) depressed TSH release in raÈs, lmplying fnvolvemenE of postsynaptic alpha adrenoceptors. More recent investigatlon by Krullch and his colleagues (Krultch et â1, I982) into the role of the alpha I or alpha 2 receptors in the secretion of TSIt 1n the rat

conclude that the alpha 2 noradrenerglc system i s irnporÈant in the stlmulation of TSH release whllst the alpha I receptors are posslbly lnhibitory.

Studies 1n hunans have not yeE ylelded sufficient information to a11ow any conclusions to be drawn about the

roles of pre- or post synapElc adrenoceptors ln TSIt release. As thymoxamlne and its metabolites have predomínantly an alpha I noradrenergic blocklng actlon

(Drew, I976; Drew et a1, L979; Roquebert et a1, 19Bl I b] ) , the inhibitíon of TSH release by thymoxarnine would suggest that the alpha I noradrenerglc system is in parÈ at least facilltatory in the release of TSI{ ín rnan. The 1eve1 of actíon of noradrenaline on the hypothalamo pituitary axis in TSIt release is uncertain although there is evldence to 240

suggesE 1t acts vla the stlmulaEion of TRII ln t.he hypothâlamus ( Grfmm and Relchlf n, L973>.

Inferencei cannot be made as yet on the posslble role of the catecholamL.ne paÈhways ln affectlve dlsorder as pharmacologlcal challenge of TSH secretlon 1n affectlve 111ness appears not to have been studied. 24r

2.4.6. Gonadotrophlns

a. Lf terature review

The gonadotrophins, lutelniztng hormone ( fn) and fol1lcle stimulating hormone ( FSH) , are released from the anterior pitultary under posftive control of the hypothalamus vla the

ínfluence of gonadotrophin releaslng hormone ( Cnnn) . GnRH, a decapeptide, is released f n a pu1satlle manner (t'tartln eÈ aL, I977; Gallo, 1930). Indeed If. GnRII ís lnfused continuously, LIl and FStt secretfon 1s diminlshed. LH and to a less obvlous extent, FSII , ls also released in a pulsatile manne r ( Martin e t al , L977) . GnRH appears, in primate specles at least, to acÈ ln a permlssive manner, primlng g ona do n secret íon ba t ep u aty ce s to the

ínfluence of oe s trogens , proge s terone and testosterone ( gelchetz, 1983) . Sex steroids appear to exert a feedback influence prímarÍ1y at the pltultary 1eve1. 0esErogen feedback on Lt{ secretfon may be either negaEive or positive depending on the phase of the menstrual cycle (Nakal et aL,

L973) and oest,radiol can also reduce the amplitude of LH release (nelcheEz, 1983). Progesterone on Ehe oEher hand appears to act centrally, slowíng the frequency of GnRII secret.ory epísodes 1n the lutea1 phase. Testosterone also slows LIt pulses ( Selchetz, 1983) .

llost of the studies performed to date have been limited to subprimate specles. Interspecies differeûces are apparent in the control of gonadotrophln secretion, however, and care 242

must be taken when extrapolatlng experimenEal evldence partlcularly from subprlmate specles to the human situatfon (ca11o, 1980; Belchetz, 1983).

Exper fnental work has been dlrected prfmarlly towards an understanding of the release of LH rather than FSH. ConErol of FSH release 1s Èhought to be símilar but not so dependent,

on catecholamine s . The control of its release appears more dependent on other fact.ors, eg, oestrogen negative feedback (Ni11ius, I977).

i The role of dopamine pathways 1n gonadotrophtn secret,ion

Most experimental evldence point,s to the dopamfne pathways being of secondary ímportance ln gonadotrophin secre tlon. Their ro1e, 1n the light of studies uslng experlmenÈa1 animal s and humans, remain unclear.

Invitro studies

InviÈro studies usíng rat hypoEhalamlc tlssue demonstrated Èhat dopamlne caused an increase 1n GnRI{ release whlch could be blocked by phent,olamine and oestradlol (McCann eE a1, 1977). This observation together wiEh an earlier fínding t.hat intraventricular dopamine caused LH release ( Schneider and McCann, l97CIa] and Ib]), led McCann and his co,lleagues to conclude that dopamlne pathr¡¡ays r^rere responsible for triggerlng GnRH release (McCann et a1, 1977) . Orher studies 243

have conflrmed a stlmulatory effect of dopamlne on GnRII release from hypothalamtc tissue (Negro-vi1ar et aI, I979;

Robblns and Reichlln, 1982) .

Anlmal studles !

Although some studíes suggest that the dopamine pathways lncluding play a stimulatory role 1n gonadotrophtn release ' other both the pu1 satlle release and the Preovulatory surge ' studies lmply either that there ls no lnvolvement or thaÈ they exert an lnhlblEory action. Indeed mosÈ evidence polnts to an inhlbitory role (Muller et a1, l977la); Sawyer, IgTg; Ga11o, 1980; Barraclough and t^llse, 1982) perhaps by l eminence rl,l axo-axonal lnfluence in GnRH release 1n the median

't:, 'I ( Sawyer and Cllfton, 1980) .

Barraclough and I,¡ise ( 1982) conclude that one mechanism by whlch progesterone exerEs lts negative feedback 1s via suppresslng hypothalamic noradrenaline and lncreaslng dopamlne activity thereby extinguíshing LIt and FSH surges.

Sarkar and Fink ( t gA t ) provide experimental evidence that in Èhe rat, dopamlne paEh$¡ays may have a dual role in that the LI{ secretory surge could be lnhlbi t.ed or sEimulated by dopamíne, the former effect being blocked by pímozi'de or domperidone and the latter by ha1oper1dol.

Ì

I

t 244

Studles ln humans

Data from experlmenÈs ln humans are 1 lkewl se lnconclusfve. Leebaw et al ( 1978) rePort that dopamlne lnfuslou did not alter basal LII or FSII release but tt blocked the lncremental response of LH to GnRH fn no rmal male s . The FSIt re sponse to GnRI{ was unchanged .

Judd et al ( 1978) found ln normal women that Ehe lnhibltory effeet of dopamlne tnfuslon on LII and FSII secretion ütas substantial on day fourteen of the menstrual cyc1e, whereas the effect of dopamlne lnfusfon at other times of the cycle gave a sma1l drop 1n LII on1y.

Martin et a1 ( I981) also reported thaE dopamlne lnfuslon l owered LIl level s and reduced spontaneous LII fluctuatlons in nornal women.

Ferrari et al ( 19BI) ln a simllar study,. reported that doparnine lnfusion caused a drop 1n Lfl 1eve1s but not FSH leve1s 1n normal women and those with hyperprolactlnaemia, amenorrhoea and ovarlan dlsease.

Dopamlne lnfuslon also reduced the nal oxone lnduced

I nc remen t s of LIl 1n !romen ln the rnid 1utea1 phase (Ropert et ãI , 1984).

IIo et a1 ( 1984) however reported no change in LIt or FSH

secretion ln normals with dopamine infusíon but, a rise in secretion in hyperprolact,inaenlc patlents. Connell et a1 (1984) likewíse reported no alt,eration ln LH secretion 24s

followlng dopamine lnfusion ln normals.

Experlments wlth dopamlne agonists and anÈagonists have ylelded simflarly inconclusive resul ts . The agonl sts lergotrile and apomorphlne appear to be r¿ithout fnfluence on LH or FSIt secreÈ1on (l,at et aI , 1973; Thorner et a1, 197S). BromocrfpÈ1ne on Èhe other hand has been reported to increase Ltt 1eve1s 1n a patient wlth hyperprolactlnaemia

(Porter et â1, 1980) . Martln et al ( teat ¡ also observed a slight lncrease 1n LH 1eve1s following bromocriptine 1n normal women and suggested that thl s mtght be due to a preferential stimulatlon of presynaptic receptors.

Co11u et a1 (1975) reported that pimoz!de appeared to reduce the secreEion of LH and testosterone in young men.

LeppaluoEo et aI (1976) also reported a drop ín midcycle LH

(but not FSH) ln norrnal women. Metoclopramide produced an abrupt lncrease 1n LIt leve1s in women ln the mldluEeal phase but not in the early or late follicular phase (nopert et aI , re84).

Ho et a1 (1984) reporred EhaÈ monoiodotyrosine (which blocks central dopamíne synthesi s ) díd not alter LH or FSIl release in normal subjects but it 1ed to a release in hyperprolactinaemlc r"romen. 246

tt. The role of Ehe noradrenerglc pâEhe¡ays in gonadotrophin release

Invltro studies

In Ehe fnviEro studies and the invfvo studies uslng an intravenÈricular cannula, 1n whlch dopamine appeared to be exerElng a stlmulatory effect on GnRH release noradrenallne appeared to have no effect (Schne.lder and McCann, L97 0[a] and Ib]; McCann et al, I977). Negro-Vllar et a1 (I979) observed that both noradrenaline and dopamlne evoke the release of GnRIt f rom rnedlan emLnence f ragments; these responses r¡Jere blocked by phentolamine and plmozLde respectively.

Animal studies

The bulk of evidence from animal studies since the pioneering work of Sawyer in the 1940-s suggest Èhat alpha noradrenergic pathqtays exert a primary physiologíca1 action ín pulsaEile gonadotropHin release and ln t.he preovulatory surge. ( ltuller et al , 1977 Îal; Sawyer, 1979; Sawyer and Clifton, 1980; Barraclough et aI , 1984).

Extensive anlmal research, principally usiag the rat, has

confirrned an excitatory role for the alpha noradrenergíc paÈhhrays in gonadoErophín release via the central

noradrenergic bundle, pre sumably via the release of GnRH. 247

This research has fnvolved pharmacologlcal apProaches, fnjecting noradrenallne lntraventrlcularly, making leslons and investlgatfng the turnover rates of eatecholanlnes (t'tu11er et aI , I977lal1' Barraclough and lJfse, L982; Sawyer, and Cltfton 1980; Ga11o, 1980; Sarkar and 1979; Sawyer ' Flnk, 1981; Kinoshita et â1, l98I; Barraclough et 41, 1984).

Ga11o (1980) proposed that 1n the rat there may be a dual noradrenergic conÈro1 over epi sodic Ltt release, a domínant exciEatory role and a less donlnant noradrenergic system that can suppress pulsatlle LH secretion. In a subsequent study, Gal1o ( f 984) reported t,hat t,he reductlon in LII release following prolonged intraventrlcular lnfusion of noradrenallne was caused by a supPresslon of LIt pulse frequency. Furthermore, Ehe steroid background (or different s Eages of the menstrual cycle ) of the animal appeared to det,ermine the dírection of GnRH and LII response to noradrenaline (Ga11o, 1980).

S tud ie s in humans

Few studies have been conducted investigating the role of the norâdrenaline pathr¡rays ín humans. Nelther clonidine (l,at et ãL, L973), nor guanfacine (l,ancranjan and Marbach 1977), influenced gonadoErophin secretion. In a more recent

study, nei Eher phenoxybenzamíne nor alpha me thyldopa

influenced naltrexone induced increase in pulsatlle LH release (Vet¿huts et aI ,1983). 248

Fusarlc acld, a dopamlne beta hydroxylase lnhfbltor, was reported to reduce midcycle ttt leve1- s , ( Leppaluoto et 41, I976) , bur tr 1s not clear 1f Ehls reflected lEs actlon of lncreaslng dopamlne or of lowerlng noradrenallne actlvlty.

Gonadotrophlns and affecElve disorder

Very few studles have been perforned examlnlng gonadotrophfn release 1n affective dlsorder. Altman et a1

(L97 5 ) reported that LH secretfon may be reduced 1n depressed patlents whlch was taken to lmp1y noradrenerglc hypofuncEion in depresslon. This findlng awafts dupllcatlon (Checkley, I980). 249

c. Results.

t. The effects of the b1 oeking drugs a1 one

Both plmozide and thymoxamine caused the serum 1eve1 s of LH to drop. Nei Eher thymoxamfne or pimo ztde had any conslst,ent effect on FSIt secretfon.

P im o zide

The effect of plmozlde on LH secretlon was greatest at 4 hours when the dlfferences from placebo were as fo11 orirs .

Pimoztde 2 ng, -3.1(+-2.9) Il/L (US)

Pimo zlde 4 mg, -3 . 2(+-0.9 ) Il /L, P < .05.

See f igure 2 . L9. and tabl e 2.2 . There r¡¡aS some reduCtiOn

1n the mean areas under the curve of LH and FSIt secretlon

following pirnozLde, the reductlon in LH secre t,ion reaching statistical slgnlftcance.

Table 2.2

LH FSH placebo: +/+.0(+-2.1) placebo: +0.40(+-2.10) Pl{Z 2 mg: -6.6(+-s.a) PMZ 2 ng: +0.34(+-2.38)

PMZ 4 mg: -3.0(+-2.s) PllZ 4 mg: +0.06 (+-0.68 )

Mean +-SEM estinates o t e areas un er t e curve o Ltl and FSH secretlon fo11owíng Pl4Z. Difference (ln¡, pMZ 4 ng v plaeebo: -7.0(+-2.5), p <.1 250

2

o

J Ð \.

I .-.-t-' J

o 1 2 3 4 5

hours

Figure 2.19 Mean (1 SSM) ner incremenral serum LH (U/L) fotlowing Pl(Z Zmg and Pl{Z 4mg:

PYIZ 2mg !rrrrrr

PNIZ 4mg ¡!r¡r¡¡ 25r

Thym oxam f ne

The effect of thymoxamine on LH secre Elon was not so

conslstent. The greatest ef f ect, by the htgher dose eras at 5 hours when the dlf f erence f rom placebo r¡ras -3.88(+-1 .56) U/L

( p <. t ) . See figure 2.20. The effect of thymoxamlne on LH and FSH secretlon as estfmated by the mean areas under the curve are shown ln table 2.3.

Tabl e 2 .3

LH FSIT placebo: +2.8(+-2,a) placebo: -0.21(+-0.81) TMX 80 me: TMX 80 ms: ¡ -1.0(+-6-3) -o-??(+-ô-5Á) I TMX 160 mg: -0.5(+-5.2) TMx 160 mg: -I.02(+-0.56)

ean +-SEM est mates o t e areas under t e curve fo1lowlng TMX.

None of these dlfferences were sÈaÈ1stfca11y slgnlficant.

11. The effect of blockade by plmozLde and thyrnoxamlne on

the LH and FSIt response to dextroamphetamiåe

LH

Pímozíde preÈreatment 1ed to an early dose-related reduction in the dextroamphetamlne stimulated LIt release. The dlfferences 1n serum 1eve1s at r artd 2 hours are gfven ln table 2,4, and illustrated graphically 1n figure 2.2I. 252

2 J :f

'¿

-4

o 1 2 3 4 5 hours

.J !l Eígure 2.2O Mean (l SnU) net incremental serum LH (U/L) following TMX 80mg and TMX 160mg:

TMX 80mg tsr-.- TMX 160mg r---a

I

I 253

5

4

3 J f

1 I 5 2

.l J il

1 L o ttt I

hou rs

Figure 2.21 Mean (1 SnU) net incremental LH (U/L) response to dAMP 20mg given at 0 (1800) hours demonsrrating rhe effecr of PNIZ 4mg given 2 hours earlier:

Pl4Z placebo - dAMP 2Omg Pl[Z 4mg - dAMP 2Omg þrrrr

Dif ference induced by PltlZ on the dAMP response. :.p (.02

t I lr

Ì 254

Îab1 e 2.4

Time PllZ Plac Pì72 Plac Pl{Z 2ng PMZ 4mg dAMP Plac dAMP 20mg dAMP 20ng dAMP 20ng

I c hang e of means ) -0,29 +2.58 +I.18 +0.30 (+-0.74) (+-0.76) (+-0.74) (+-0.4e) dlff fron plac - plac +2 .97* +7 .47 +0.59 (+-r.12) (+-0.e4) (+-0.8r) diff from plac - dAMP -1.40* -2.29** (+-0.s6) (+-0.79) 2h ( change of means) -0.75 +3.15 +2 .0I +1.93 (+-0.75) (+-0.47) (+-0.41) (+-0.4e) dlff from plac - plac +3.90*** +2.7 6** +2 .68 (+-0.94) (+-r.01) (+-r.4s) diff from plac - dAMP -1.14 -t .22 (+-0.58) (+-0.90)

Incrementa +.SEM serum LIt eve s at, an our s 0=180 r together with neÈ increment.al (+-SEM ) 1eve1s compêt€! srÍ Eh the placebo - placebo combinatlon and placebo - dAMP 20ng combination * P <.05, ** P <.025, *** P <.005.

Mean (+-Se ¡t) estirnates of areas under the curve: Placebo: -1.87(+-2.37) dAMP 20 mg: +7.70(+-1.37)

P\12 2 ng + dAMP 20 mg: +5.38(+-1.41)

PllZ 4 mg + dAMP 20 m8: +4.47(+-1.99)

Difference, Pl'12 4 mg dAMP 20 mg v placebo dAMP 20 mg; -3 .23 ( +- r .52) , P <.1.

Thymoxarnlne pretreatment, partlcul arry at Ehe htgher dose,

i augmented the ri se in LH secre t i on induced by r dextroamphetamlne, most markedly Èowards the end of the lr experíment. The ne t i ncremental serun LH leve1 s induced by the thyrnoxamlne 160 mg - dextroamphetamíne 20 mg compared

I 255 erith the placebo placebo comblnatlon at 3 and 4 hours nere +2.05(+-0.84) Ull" and +2.72(+-0.88) tJ/L, P <.05 and P <.02 respectively. The dtfferences lnduced by thymoxamlne 160 mg pretreatmenÈ compared wfth the thymoxamfne placebo dextroamphetamine 20 mg conblnatlon at 3 and 4 hours srere +L.26(+-0.69) Ult and +1.94(+-1.1) tJ/L, P <.I and P <.2 respectlvely. See figure 2.22.

Estlmates of the mean (+-SEM) areas under the curve:

placebo: -0.20(+-r.63) dAMP 20 mg: +2.58(+-1.82)

TMX 80 mg + dAMP 20 mg: +4.2s(+-r.70) TMX 160 mg +

(There krere no statlstlcally slgntficant differences).

FSH

Pimo z!de pretreatment, partlcularly the hlgher dose, gave rlse to an early reduction ln the dextroamphetamine induced increase ln FSII secretion. Thyrnoxamlne on the other hand appeared to be without ínfluence on FSH secretfon. See figure 2.23. and 2.24,

The effect of pimqzlde pretreatment on the dextroamphetamine lnduced FSH response hlas maxlmal at t hour when the dlfference between increnents ín serum FSH hias 2s6

4

3

2

J \ = ¿. 1 J E L o to 0

o 1 2 3 4 hou rs

EÍ-gure 2.22 Mean (1 SnU) net incremenral serum LH (U/L) response to oral dAMP 20mg given at 0 (1800) hours demonsrrating the effect of TMX 160mg given t hour earlier:

TMX placebo - dAMP 20mg

TMX 160mg dAMP 2Omg Il---r 257

1.O

o.8

J 0.6 f I Ø l¡ o.4

L o o-2 6 * o 1 2 3 4 hours

Figure 2.23 Mean (1 S¡U) net incremenral serum FSH (U/L) response to dAMP 20mg given at 0 (1800) hours demonstrating t.he effect of. PYIZ 4mg given 2 hours earlier:

Pl"lZ placebo - dAMP 20mg PMZ 4mg - dAMP 2Omg b----¡

Diff erence induced by PYIZ 4mg on the dAMP response. :.p (.05 2s8

1

o.8

J J 0.4 ! Ø l¡

E t o o o

- o-2

o 1 2 3 4 hours

Fígure 2.24 Mean (l SEM) net incremental serum FSH (U/L) response to oral dAMP 20mg given at 0 (1800) hours demonstrating the effect of TMX 160mg given t hour earlier:

TMX placebo - dAMP 2Omg TMX 160rng - dAMP 20mg l--r-r 2s9

-0.29(+-0.12) u/t" (p <.os).

Estlmates of t,he areas under Èhe curves did not, demonstrate any slgnlflcant changes fnduced by elEher bloeking drug on Ehe dextroamphetamfne lnduced lncrease 1n FSH secretlon. 260 c. Dfscusslon.

0ra1 dextroamphetamine r¡ras an effectfve sEimulant for the secretlon of both LH and FSH.

Dopamine pathways

Plmoztde pretreatment Ied Èo a fall ln the dextroamphetamlne induced rLse ln LH secretlon, which 1s seen to a lesser degree ln FSIt secretfon as we11. Thfs r¿ould 1mp1y that in human male s , dopamlne may have a sÈimulatory role ln their release, partlcul arJ-y of LII. Furthermore pimozlde appeared to cause a drop ln the non-stimulaced LH levels. Thfs 1s conslstent with Ehe reports by Col1u eÈ a1 (1975) and Leppaluoto et, a1 (1976).

Evldence from invitro or anlmal studies tmply that

dopamine has an inhibi tory role 1n the release of LIi. See llteraEure revtew. Sarkar and Flnk (tgAt) hohtever rePort the apparent presence of t$ro dopamine receptors that may be facilitatory or lnhiblÈory in Èhe release of LITRII and LH in the raÈ.

It is posstble Ehat, the dopamine pathktays may also Play a dual role 1n humans. Thls would help to explain some of the apparently inconslstent experlmenÈa1 findlngs. llost of the experlnents uslng dopamine infuslon, rePort a fa11 in Lll release, particularly in the mtd lutea1 phase in normal women, as well as a fa11 in secretion 1n $¡ornen wlth ovarian 261

dfsease (.¡u¿d et al, L978; Ferrarl et â1, I981; Martin et a1 , 1981). The LH resPonse 1n patlenÈ s wl t.h hyperprolactinaemia to dopamlne lnfuslon, was a fa11 ln one serles (Ferrarf et al, 1981) and a rlse in ano the r (tto eÈ a1, 1984).

The reported response to dopamlne blockers llkewlse appears lnconsistenE. Plmozide caused a drop (Cottu et aL, 1975; Leppaluoto et a1, I976), whl1e metoclopramlde Save a rise in LIt secreEion (Ropert eE aL, 1984). The dopamlne agonlst bromocrlptine hlas rePorted to cause a rlse 1n LH secreEion ln a patlent wlt.h hyPerprolactlnaemia (Porter et al, 1980) and in normal r^¡omen (Martin et a1, 19BI).

Perhaps the central dopamlne pathways in humans have a dlfferent effect from Èhose outside the blood braln barrler.

An al E,ernaÈ1ve explanation í s that Èhe dopamlne pathhrays exert at least part of their actlon on LIt secretlon via thelr effect on prolacEln secretlon. As prolaetln excess is known to be accornpanied by reduced LIt level-s (Smith 1980)' iÈ is posslble that the LII depressant effect of plmozide and Ehe LII stimulanL effect, of bromocriptine and dopamine in hyperprolactínaemia is secondary to t,heír lnfluence ln stimulatlng or ínhiblttng prolactln release.

The effect of t.he dopamine pathh¡ays on FSH release seems s1lght , Lf. anythtng they would appear to exerE a stimulaEory action. 262

Noradrenallne pathways

In Èhl s s tudy thymoxamine caused a modest accentuation of

LH relea se and no effect on FSH release. Thts would lmp1y an lnhtbit.ory role for the alphanoradrenerglc pathways in basal Ltt release.

There 1s good evidence from anlmal studies to suggest that pathhtays f tate release both the alpha noradrenerglc acil i LfI ' of the preovulatory release and surge and of basal secretion (i"tu11er et aL, 1977lai; Sawyer, 1979; Sarkar and Fink, 1981; Barraclough and LJise, 1982; Barraclough et aI , 1984) wlth some possiblllty of a secondârY, less domlnant r central

IIO radrenergic system thât inhibits LttRIt and henc€i LH release (ca11o, 1980).

Control of FSH release has been thoughÈ Èo be simí1ar, though not so Ínfluenced by change s ln noradrenaline acÈivlty as is wlth LH release. FStt release appears to be more dependent on other factors for example oestrogen ' negative feedback ( nt111us, I977) .

Studles invesÈigatlng Ehe role of noradrenalíne pathways in gonadotrophin release ln humans are few. Neither Èhe alpha noradrenerglc agonlsÈs clonídlne (l,at et â1, I973 ) nor guanfacine (l,ancranjan and Marbach, L977) nor the antagonist phenoxybenzamlne (Vet¿huls et aI, 1983) influenced secretion. Clearly further studies are required before any concluslons on the role of the noradrenergic paEhway on 263

gonadotrophin release ln humans can be made.

There I s fnsufficfent experlmental data to draw any concluslons about the role of catecholanfne pathways fn affectfve dlsorder uslng pharmacologlcal challenge of gonadotrophln secretlon. Thts lack of experimental lnvestfgation 1s surprfsfng ln vfew of the close reratlonshlp between affectlvç: fllness and the reproductlve system seen in puerperal depresslon and manla, and fn the mood changes assoclated wlth rnensÈruaÈion and menopause. 264

2.4.7. Conclusfons.

Pimozrde and thymoxamlne exerted dtfferent effects on the responses of the dlfferent ant.erlor pltuitary hormones to dextroampheEamfne. The lmplfed role of the catecholamlne pathLrays fn the hormonal response to dextroamphetamine can be compared r¡1th other experlmental evldence for the role of Èhe dopamfne and noradrenallne pathways fn Lhe control of the secre t I on of the se hormone s .

The maln flndlngs of the present sÈudy can be summar!zed as f o11oürs.

Dopamlne pathways do not appear to be involved in the control of corti so1 secretfon. The role of the alpha noradrenergfe pathúJays 1s dtfflcult Èo lnterpret as a dose response relationshfp hras not observed following thymoxamLne pretreatment. The most, substantlal effect., accentuation of cortlsol secretlon, mlght lmply that they exert an inhibftory action.

As far as prolactin 1s concerned, as expected,

conclusions about the role of the dopamine and noradrenallne pathways 1n dextroanphetamlne lnduced growth hormone release are difficult to make from these results as other facÈors 1n the experlment ínfluenced growÈh hormone 265

secretlon. A case could be made for an enhanclng and an inhfbltfng effect by the dopamlne paÈhways and an lnhlbltory role for the alpha noradrenallne pathways.

A dual but opposing fnfluence by the two catecholamlne pathways was manlfest ln the release of TSII induced by dextroamphetamine admlnistratlon. Dopamine p'aEhhrays exerted an fnhfbitory actlon and the alpha noradrenergic pathways probably exerÈed a stlmulatory actlon.

conversely dopamfne pathways appeared to be stimulatory 1n LH release whereas the alpha noradrenergic pathhJays are lnhlbltory.

The results suggest that the dopanine pat,hways may play a ro1e, albei t a minor one, in stimulating Èhe release of FSH.

These results are generally 1n keeping nlth other experlmental evldence related to the role of the dopamfne and alphanoradrenergic pathways 1n the control of the secretion of the differenE anterior pÍtuitary hormones.

ExperlmenEal evidence for the role of the alpha noradrenergic pathways in cortisol secretion ls conflicting. Although the bulk of evídence poinEs to a stimulat.ory role 1n humans, other studíes suggest an inhíbltory actíon.

Controversy remains too, over the roles of t.he ca techolam ine pa thr¡rays in growth hormone anrl LH release.

In recent, years there has been increasing use of 266

pharmacologlcal challenge to the neuroendocrfne system fn I

I I the Lnvestlgâtlon of the blology of a varlety of psychiatric

I dlsorders. As far as affective dfsorder 1s concerned, the secretlon of cortisol and growth hormone, and to a lesser degree prolactln, has been studled. Abnormalfttes may also exlsE 1n the secretlon of TsH and LH in affectlve disorder.

In many of these studies, assumptlons have been made

regardlng the central neurochemtcal control mechanl sms lnvolved 1n the control of anterLor pltul Eary hormones fn maklng hypotheses regardfng the pathophysiology of affective 111ness. 0n the who1e, workers have concluded that these lnvesÈigatlons have demonstrated hypofunctlon of the alpha noradrenerglc pat,hways and probably normal funcÈfoning of

t e resu so e pre sent s tudy

fndicate how complex these control mechanlsms are 11ke1y Eo be, and Eherefore how cautlous one nust be in attenptfng to draw any firm concluslons. PART III

DEXTROA}IPITETAMINE INDUCED AROUSAL AS A PIIARMACOLOGICAL MODEL FOR MILD MANIA. Page 3.1. IntroducElon 269 3.1.1. IntroductorY comments 269 3.I.2. Pharmacological models 272 a. Models 1n PsYchlatrY 272 b. Criterla for acceptance of a model 273 c. Ilunan versus animal models 274

3 . 1 .3 . Phenomena of manla and the re sPonse to amPhetamlne 276 3.1.4 Blologlcal correlaÈes of manfa and dextroamphetamine 279

a Btologlcal changes 1n manLa 279 b. Bfologlcal correlates of ampheÈamine arousal 281 3.1.5. Responses to pharmacologtcal manipulatfon 283 3.1.6 The role of dopamlne and noradrenallne fn the biology of mania. 284

2 et o 289 3 3 Results

3 3 .1. A phenomenological comParison 289 293 3 3 .2. A psychophyslologlcal comParl son

3 3 .3. A pharmacologieal comParlson 297

3 4 DlscussLon 301

3 4 A phenomenologlcal comparison ,o .1. 1 305 3 4 .2. A psychobiologlcal comparl son

3 4 .3. A pharmacologlcal comParlson 307

3 4 .4. Impllcatlons for the role of the catecholamine PathwaYs 1n the bíology of manla 313 3.4 .5. Concluslon 316 269

3.1. Introductlon

3.1.1. Introductory comneûtg

Studylng the btology of manla poses parElcular dffficultles. The hyperactlvlty of patlenEs sufferlng from the fllness can make experlmentatlon very dlfflcult. and tt may be lnpossible for the patient, because of thefr lack of Judgment when 111, to be able to glve informed consent for sclentfflc study. These problems become manffest when one revfews the 1iÈerature on the bfology of manla. There 1s a surprlsing lack of lnformaElon on mania derived from studles on manic paÈ1ents. Because mania can only be researched 1n manlc patients with dtfffculEy, other research strategies have to be consldered.

Pharmacological model s have provlded a useful avenue of

sclenEiflc investlgat,lon 1n psychiatry. They provide a stimulus for Ehe generatlon of neur hypoÈheses whlch can, in

turn, be tested in t.he disease state. In the past, a variet,y of anlmal models have been proposed for the affectlve dlsorders buL these suffer from a number of

limitatlons. As animal sEudles do not a 11o r¡ any lnvestigaEion of mental state, extrapolation to the human conditlon may be unwarranted. If a human model of nania can be developed whlch fulfils the necessary crlteria for

va1ldiEy, 1t would act as a valuable tool for further psychoblological research fnto mania. 270

Since the lntroduction of amphetamlne derlvat,lves lnLo c1lnfca1 and research use, experimenters have descrlbed tn detail the amphetamfne response in humans. There are many slmllarlties 1n the descrlptlon of amphetamlne arousal and the phenomena of mania. These sfmflarltles have been observed 1n the locomotor response t,o amphetamine derivatlves in experimental anfmals (no¡blns and Sahakian, f9B0) as well as the psychological responses ln humans (eotd and Byck, 1978).

The presenE study attempt,s to extend the compari son from

the subj ec t lve and symptomatic 1eve1 to the psychobiological and pharmacologlcal 1eve1 s .

It has beeã belleved for sorne t ime thaI e catecholamfnes, dopamlne and noradrenallne r Play an irnportant role in the blology of manla. In recenE years t,he

lmportance of dopamlne has become increaslngly clear 1n thi s connection, whl1e that of noradrenallne is less so. Dextroamphetamine is belteved Eo act by releasíng newly formed dopamine and noradrenallne from the presynaptlc neurone and preventing theír reuptake ( Carlsson, 1970; Scheel-Kruger , I97 2; Chieuh and Moore, 197 5; Grove s and Rebec, 1976), See Part I. I-f. dextroamphetarnine can be shown to fulf i1 the criterla for a valid pharmacologíca1 model for rnanla, 1t would provide an avenue for lnvesEigatlng the

possible roles of the dopamine and noradrenaline pathways 1n this condltlon. 277

The psychologlcal and psychoPhyslologlcal responses Èo oral dextr'oa¡nphetamlne have been presented 1n Par t I and the neuroendocrfne responses r{ere presented tn Part II. Thls sectlon will compare some of these ftndfngs 1n detall wlth the known sequelae of nanla. 272

3 .L .2. Pharmacologfcal model s

a. Models 1n psychlaÈry

Oplnlons vary on the value of models fn the study of psychiatrlc i11ness. Crftlcs of animal models emphasise that no lesion or fnduced state ln anfmals ls homologous to any nenEal 111ness in hunans; the unlqueness of the human experlence, so much a feature of menEal i11ness, being of necessiÈy ignored (Strepherd et aL, I968). 0n the other hand, anlmal models have proved valuable in t.he study of the aetlology and nature of a rânge of l11nesses as well as 1n the evaluatlon of new t,herapeutically active drugs. For example, behaviour therapy was developed from animal models of learning. Similarly the butyrophenone derivatlve s vtere ,ll !J 'i introduced as neuroleptie drugs following examinatlon of their effect, on an arnphetamine rnodel of psychosis (Kumar,

re7 e) .

Animal models, have the additional advantage Èhat Èhey afford the opportunlty to carry out experlmenEal procedures which would be ethically unacceptable 1n human subj ects. Such models also a1low control of and simpllf ication of the experimental environmenE, thereby allowlng more vigorous control of Ehe variables to be Eested (RoUbins and Sahaklan, 1980).

I s I Thls greater control is obtained at a price ; many model

are an oversimplifícatlon of a complex situation. Furthermore iE ls unjusEified Eo assume that brain function

* 273

1s directly comparable ln dtfferent specfes (notblns and

Sahaklan, 1980). As a result, it is usually unwise Eo extrapolat,e the ffndings from one specles to another.

In psychoblologlcal research, the maln value of models fs

to provlde an experlmental sltuatlon in u¡hlch ldeas can be tested 1n a simplfffed settlng. The hypotheses so generated may, 1n turn, be tesÈed 1n the human pathologlcal state.

b. Cri teria for acceptance of a model

A model of psychiaÈr1c lllness should conform to a number

of criterla before 1t can be consfdered a useful tool 1n psychoblologfcal research. Four crfterla were inftially

proposed by McKfnney and Bunney ( 1969) , ( see also McKl nne y ,

these have gafned general acceptance (Robbtns and sahakian, 1980). These three criteria are:

i. The model should exhlblÈ close stmflarities ln experiential and behavloural terms to the illness fn question.

ii. rt should have psychophyslological and biologlcal correlates.

i-1í. rt should respond to pharmacologlcal manipulation in the same h¡ay as the naÈura11y occurrlng conditfon (¡lcrrnney and Bunney, r969; McKlnney, rg7 4; Robbins and sahaklan, I r980). lr

The more the model satisfies t.hese comparlsons, the

t 274

greater fEs relevance to psychlatric research. The power of the model 1s further enhanced if matching can be establtshed 1n features that are relattvely speciflc to the illness in guestlon.

Earlfer wrlters clted a fourth criterfon (McKfnney and

Bunney , L969 i McKlnney, I 97 4) , thar the underlying neuroblological mechanlsms 1n Èhe model and in the illness in questlon should be the same. As the neuroblology of Psychlatrlc illnesses ls largely unknown, thls criterlon

cannot usually be answered wl th any conffdence. It I s

nevertheless an important question Eo keep in mind when considerlng if the model 1s of relevance to t.he írlness in questlon. A pharmacological model is parElcularly useful if

thê knor{n ae t1ón of the drug use d SS m ar o f e pathophyslology in qu estfon, for exanple, tf its mechanism of act. lon involves th e same neurotransnltter pathways that are thought t.o be invo lved 1n the illness beíng modelled.

c . Human ver su s Anlmal model s

Despite the considerable experímenÈa1 flexfbtltty they a11ow, rnodels of psychiatric 111ness uslng experirnental anímals suffer fron tqro major disadvantages.

The first criterion of validlty is difflcult to saEísfy. rt requíres that the model rnatches the illness in both experlential and behavioural terms but, psychíatrlc irlness l¡ is described and diagnosed largely on a phenomenological basis. A knowledge of mental state ís essential for arLy 275

real comparf son and thls of course fs lmpossfble ln

experiment,al anf nal s. Even a comparl son purely on

behavloural terms 1s difffcult to make âs tt 1 s often dlfflcult to know for ce r tain what. the anlnals- behavlour may nean (Kumar, 1979; Robbfns and Sahakian, f980).

the second maJ or 'difflculty wfth anfmal nodels lfes wlth the dtf.f.lculty in ext,rapolatlng from one specles to another . Not only are there maJ or problems in as suming varlous behavlours are equfvalent t,o those seen in humans, there ¿¡re also clear differences between anlmals and humans 1n the structure and function of the central nervous system

( no¡blns and Sahaklan, I 98 O ) .

A pharmacologieal model of a psychfatric llrness usin human subJeets avolds t.hese problems. [Iowever the maln drawback with human studies fs that. ethlcal and practlcal conslderations llmft the range of experimental procedures thaÈ can be used. Nevertheless, noninvaslve technlques are available whlch a1low safe and meaningful experlmentatlon. Furthermore research flndings in animals galn 1n credlbility if the underlying -pharmacologlcal model of psychlatrlc 111ness is supported by observlng similar changes using normal hunan volunteers. 216

3.f.3. Phenonena of mania and the respoose to amphetamlne

Manla as an illness goes under a number of nafnes, all of whlch refer to the same condltlon. These names lnclude the manlc phase of bipolar affectlve ll1ness, manlc dePressive psychosis, hyponanfa, major affective disorder' manic type. Kraepelln (reprint of L92I Englfsh trans1at.lon, L976) ín hls classlc study of Manic Depresslve Insanity, described a varlety of key symptoms of manla. He observed the Presence of fllght of ldeas, flck1e 1nÈere.st, grandiosity, heighÈened energy and mood , trritability, lncreased "busyness" and resElessness; he descrlbed the patlents as "belng a stranger to fatlgue". these phenomena ate sÈ111 regarded as the key

sympEoms of the 111ness (Silverstone and Cookson, 1982).

Glbbons ( 1982) recently revl-ewed 4 studles from the last 15 years recording the frequency of rnanic symPt.oms. those were: over talkativeness most frequently clEed ' overactlvity, grandiosíty, irritabí1ityr €uPhorla, lnsomnía, fllghts of ideas, 1abi11ty, hostility and distractability.

Clinlcal diagnostlc criterla published over the Past decade have further helped to define Èhe concept. There is a high degree of agreement betr^reen the different criteria that have been proposed (feighner et aI , L972; ICD9, I977: Spitzer et aL, 1978; Amerícan Psychiatric Assoclation, DSM-III, 1980). All requlre the presence of elaElon or irrtt.ability !ogether wlth hyperactivíty, distractabillty' overtalkativeness ( sometimes amounting to pressure of speech), flights of ideas, grandiose ideas and social 271 dysfuntlon (eg lnjudfclously spending money, promlsculEy or dlsrupÈlon wfEhln the home or at r¿ork).

Many of the symptoms of mania resemble those produced by amphetamine drugs. From both anecdoÈa1 reports and more recently published controlled studles, there appears to be a close resemblance be !ween the symptoms and slgns observed 1n patients suffering manla and the phenomena observed following a slngle 1ow dose of amphetamlne.

Shortly after the lntroductlon of amphetamine derlvatlves lnto clinical practice a number of central effects were noted. Reports of lnsomnia from amphetamine (benzadt tne ) overdosage and iÈs efftcacy in Ehe treatment of narcolepsy ( prinzmetal and Bloomberg, 1935) , were fo1lov¡ed by observations of elevation of mood and reduced fatÍguability

1n normal subj ects . ( ¡lathanson, 1937; Davidoff and Reifensteln, 1937). These earlier studies have been replicated by Levine eL a1 ( I948) and Lassagna et a1 ( 1955) who descrlbed elevatlon of mood or lrritability, over-talkatlveness, increase in moÈor actlvity and restlessness, a heightened sense of energy, alleviation of fatiguê, anorexia, alertness and lnsomnia ín their subjects.

Controlled experlmeûts, despite some varlabí1fty of response (Check1y, 1978), have conflrmed that amphetamine 1n relatively 1ow dosage glves a reproducible rise in mood and arousal, as measured in a variety of ways, including the

Profile of ì4oods Scale and the Lfnear MooC scale ( Smi th and 278

Davles 1977), a modlfied Mood AdJectlve Checklfst ( Brown eÈ al , 197 8 ) and vl sual analogue rating scales ( Sttverstone et â1, 1983). Hlgher or Prolonged doses glve rlse to other phenomena (nt1lnwood, L967).

Mfndful of the constralnts 1n relattng data from anlmal experlmentatlon to an 111ness in humans, lncrease 1n activlty followlng a Êelatlvely low dose of dextroamphetamlne 1n experlmental anfmals has been proposed as an anlmal model f or manla. (t'turPhY, I977; Robblns and Sahaklan, 1980). A sfmllarity $ras found between the amphetamlne induced changes in the anlmals behavlour and that seen in manla. 279

3. f.4. Blological correlates of manfa and dextroarnphetamine

a Blologlcal changes 1n manla

í. Psychophysfological correlates.

Publlshed reports of psychoblologieal changes occurring 1n manla ate few because of the experlmental dlfffcultles of working with such patients. Nevertheless sufficlent fnfornation has been obtained Èo suggesE that there are significant changes 1n functioning during a manic eplsode. For example Lake et a1 ( 1982) demonstrated t,hat manic patients had higher pulse rates and systollc blood pressures than a conÈro1 group of healthy volunteers or depressed patients. IIensley and Philíps ( 1975) 1n a longitudinal- study in one subject reported that manic episodes hrere

associated w1Èh an increase in skin conductance 1eve1 s.

There have also been some reports of observatíons on patients with a persisting 48 hour cycle bipolar affecElve i11ness. Jenner et a1 (tgAl ) ¿emonstrated that the manic phase r{as associaEed rrrith increased weight and extracellular f1uíd and a drop in mean corpuscular volume. Pulse rate, skin resistance, thyroid function tests and urinary gonadotrophins all were unaffected. Bunney eE a1 ( 1965) reported a drop ín I7 hydroxycorEicosteroids when the patient was manlc and lncreased 1evels when the patlent was depressed. 280

f1. Neuroendocrlne correlates.

Anterlor pttultary adrenocortlcal axls

A relationshlp between mania and the aetivfty of the anterlor pltuttary - adrenocorÈica1 axis ls suggested by the reports that euphoria may occur in pa!1enÈs with Cushlngs dlsease and fn patlents recelvlng systemlc cortlcosteroids (Ltshman , I978; Hal1 eE aI, I979) . Although manlc symPÈoms they are may be observed 1n patients wl th cushings d1 sease ' relatlvely infrequent (Cohen, 19S0). Studles ln manlc patlents offer further supPort for these observatlons ' For examDle. mldnleht 1eve1s of cortlsol are htgher 1n manlc patlents than 1n normal subjects (cookson et aI , 1983) and

467" of manlc patlents show an abnormal suppresslon resPonse Eo dexamethasone (Graham et 41, 1982).

0ther hormone s

There may also be some relationship between thyrold disease and mania. Klrkegaard et a1 ( I978 ) have reporEed that manic patient s exhlbit a decrease in serufn trilodothyronlne 1eve1s and a reduced response of TSIt Eo TRH. ALthough basal 1eve1s of gonadotrophlns appear to be unaltered in mania, the risk of manla 1s relatively increased tn the imnedlaEe posE partum period ( Dean and Kende11, 1981) , a time when oesÈrogeo 1eve1s are falling 281

dramatically. 0estrogen reduces dopamlne actlvlÈy; so a drop fn oesErogen may be followed by a rapid relatlve lncrease 1n dopamlne functionlng whlch lncreases the rl sk of manla (Cookson, 1981). Growth llornone appears Èo be unchanged 1n manla ( Cookson et aL, 1982; Sllverstorie and Cookson, 1982).

b. Biological correlates of amphetamlne arousal

In a wlde variety of experimental animals, amphetamlne derlvatives cause an lncrease ln locomotor actlvity. In higher do se s they produce stereotypy ( Iversen and Iversen,

197 s) .

SÈudies lnvestigatíng Ehe psychophyslologfcal response to dext.r-arnphetamlne in hunáns, reporE an eleT-tlo-of blood pressure, pulse rate (Martin eE a1, 197 I; Morselli et a1, I978; Nurnberger et a1, 1984), skln conductance leve1s (Zahn et a1,1981) and contingent negatlve varlation (Tecce and Co1e, L974).Ilowever just as the psychological response to amphetamine derivatives may be varíab1e ( see earlier) so too may there be varlabilíty in psychophysiologlcal measures (Tecce and Cole , I974; Rapoport eE a1, 1980).

Amphetamine derlvatives have been used as stimulatory agents in the investigaElon neuroendocrine sysEem functioning; both in the study of the cat,acholamine coutrol of anterlor pituitary hormone excretion (Rees et aL,1970), and as a stimulatory challenge in the invesÈigatíon of neuroendoerine function in psychialrlc i11ness. See Part 282

II. Amphetamfne drugs are rePorted to stlmulate the excretlon of corEfsol (Besser et aI, 1969; Rees et aLr 1970) and posstbly TSIt (Uorley, 1981). The growth hornone (Besser et al, Lg69) and prolactln response (van Kammen et a1, L975) 1s usually stimulatory, the former dependlng upon experlmental condltlons. The response of the gonadotrophins to dextroanphetamine challenge as has been shown ln Part II 1s also stlmulaÈory. 283

3 . f .5 . ResPoûses to pharnacologfcal manlpulatlon '

Neuroleptic drugs have Proved a mainstay 1n Ehe management of acute manla ( Shaw , LgTg) . Both the sedatlng neuroleptfcs chlorprom azlne and haloperldol ( Shaw, I979 ) and the less sedatlng drug plmozTde (Cookson et a1, 1981) have been shown has proven to be ef f ectlve. Lf t.hlum Carbonate, too ' efficacy both 1n the treatment of acuÈe manla and, ln particular, in prophylaxis ( SitversEone and Turner, 1982) .

Neuroleptics are also effectlve in reverslng Èhe effects of amphetamlne derivatives. In f act, t,he abillty to attenuate the stereotypy lnduced by amphetamÍne has been used as a biologíca1 measure of neuroleptic potential (Janssen et aLr 1965). In humans pimozLde has been shown to at Eenuate many of Èhe responses to dextroamPhe tamine

(Jonsson, L97 2; Silverstone et aI, 1980; G1111n et aI, re78 tbl ).

Slmtlarly lithium carbonate has been shown Eo attenuaÈe t.he response to anphetarníne. In animals the locomoEor stimulatory actlon of amphetamlne drugs but noi the amphetamine induced stereotypy r¡ras reversed by 1íthíum carbonate pretreatment (t'turphy, I977; Iversen, 1980; Robbins and Sahakian, 1980). Llthiurn carbonate likewise aEtenuated the amphetamine lnduced arousal response in humans (Van whlch Kammen and Murphy, Ig7 5) . Alpha methylparatyrosine ' blocks the synthesi s of both catecholamlnes, reduced the symptons of manía ( Brodle et a1, I978 ) as v¡e11 aEEenuating the response to amphetamine (Jonsson et aI , I97l)' 284

3. r .6 . The role of dopamlne and noradrenallae ln the blology of nanla

Schildkraut-s (1965) catecholamlne hypothesls of affectlve 111ness proposed that depresslon $ras associated with a relatlve deflciÈ of caÈecholamlnes, partlcularly of noradrenaline, whlle manla was associated with a T.elatíve excess.

Over the past ten years hohlever, a dlrect role of dopamlne ln the neuroblology of manla has become clearly establlshed (Randrup and Munkvad, I976; Silverstone' L978; Post, 1980; sllverstone and cooksofr, 1982) . Although there is some uncertalnty about changes 1n leve1 s of dopamine and i ts metabolites ín the blood and CSF of manlc Þafients (Post; 1980), evidence from pharmacologícal studíes ís qulte

per suas ive . l'lanf a can b e precipitated by L- dopa (Murphy et a1, 1973) and dextroamP her.amine (Gerner et aL, 1976) (both of whlch can stimulate t he actlvi ty of the noradrenerglc and

dopamlnergic pathwaYs) . It can also be PreciPitated bY the speclflc dopamlne agon lsEs ptrlbedll and bronocriPtlne

( Gerner e t al , I97 6; Brook and Cookson, 1978). Manic symptoms can be amelio rated by alpha methylparatyrosine (which blocks the for maElon of both noradrenaline and dopamine). NeurolePtic drugs have an antimanlc actlon. Those with a rnore sPecif 1c dopamine blocking action ( eg. pimozíde) have a more pronounced antimanic actlon than those neuroleptics with more mixed effect on the

neurotransrnitters, such as chlorpromazine (Cookson eE aI , 285

1981).

The evidence for a direct lnvolvement of the dopamlne pathways in the neuroblology of manla has overshadowed thaÈ of noradrenallne, the role of which has become increasfngly uncertain. Levels of noradrenaline and noradrenergfc metabolltes (MPflG) are elevat,ed tn the b1ood, urlne and CSF of manic patients (Post, I9S0). It ls unclear' however' whe ther the se change s are secondary to the lncrea se 1n arousal and motor actlvlty ( post and Goodwln, 197 3) ' pharmacological evldence about the role of Èhe noradrenallne pathways has unfortunately not helped to clarify the plcture. L-dopa and amphetamíne, which activate both catecholamlne pathnays can Precipitate mania and manic ptoms måy be reduced by alpha meEhylparatyrosine xhicl also affect,s both catecholamine pathways. Tricyclic anEidepressants are known to Precipttate mania (l'Iehr and Goodwln, I97g ) but they have a broad sPectrum of effects orr a number of central neurotransniEter Pathk¡ays. If the formaElon of noradrenaline from dopamlne í s blocked by the dopamlne beta hydroxylase lnhibitor fusarlc acid, there ís a rlse in dopamine and a drop in noradrenallne. Thís causes an accentuation of manlc symPtoms ( Sack and Goodwin, 197 4) .

llanlc symptoms are reduced by t.he alpha 2 noradrenergic agonist clonidine and rebound symptoms occur on withdrawal (Jouvent eE a1, 1980). Yohimblue an alpha 2 noradrenerglc antagonist has been reported Eo Precipltate mania ( Price eÈ â1, l9B4). The beta noradrenergic blocker propranolol-, at 286 hlgh doses, can amelforaEe manlc symPtons but as the non-noradrenerglc blocklng s Eereol somer of Propranolol al so reduces manLc symPtoms, tt 1s unllkely tha¿ the antlmanlc effect I s vla lts betanoradrenerglc actlon ( Emrlch et a1, re7 9) .

In vlew of the uncertalnÈy of the relatlve roles of Èhe dopamlne and noradrenallne pathways 1n manla, Ehe effecÈ of specific dopamlne and noradrenallne blocklng drugs on the manlc like symptoms produced by amphetamine would be 11ke1y to shed some llght on the problem. 281

3.2. MeÈhods

The subjecÈs, drugs used and experfmental design are described 1n detal1 1n Part I

Different visual analogue ratlng scales dlmensions I¡Iere chosen to measure ehanges in the subJeets mood, alertness and mental actlviEy 1n those symptoms most frequently seen 1n manlc paÈients ie. elatlon and irritabllity' arousal, restlessness, nental speed and energy. The impairnent of sleep on the nighÈ followlng Ehe experlmenÈ üras rated by subjects on a 5 polnt, scale the following day.

As the phenomena and psychophysiological sequelae of the amphetamlne response alone were being investigaÈed in this part of the study, data from experiments B and D were combined. Thus data from the placebo blocker - placebo dextroamphetanine combination from both experiments h/ere conbined as stere the daÈa from the placebo blocker dextroanphetamine 20 mg combination. This gave a total of 24 subjects. Pharmacokinetic data as described ín Part I r{ras also comblned giving 18 sub jects in all, some samples from experíment D having been 1ost.

There is a paucity of lnformaEion on the psychophysioLogical and biological concomiEants of mania, preventlng a detailed comParison with the response to dextroamphetamine. As rnania appears to be associaEed with an elevation of pulse rate, systolíc blood pressure and skin conductance 1eve1s and a rise ín daytirne plasma cortisol 288

leve1s ( see lntroduction) these measures were chosen for comparison r¿1th the response to dextroamphetamlne. Results from experlments B and D úIere agaln combtned. The effect of pimo zLde on dextroamphetamíne lnduced arousal, formlng Part of the pharmacologlcal comParlson of the two sÈates r has been described in detall fn Part I and wt11 be brfefly revlewed.

As fn Part I and II, all data has been converted to ehange values from a reference level Just prlor to the dextroamphetamine dose aE f800 hours ( the reference values were comparable within all dimensfons ) . Mean changes 1n the subjective raÈing scales hlere analysed statlstically using the I.Jillcoxon slgned rank difference Èest for palr differences. The differenc e s in t.he mean c hang e s 1n objective data r4tere exposed Èo analysis using StudenE-s t test for matching paírs. As the dírectlon of resPonse can be anticipated, the one tall test f or estimat. lng sE,aEistical slgniflcance r¡ras used. 289

3.3. Results

3.3.f . A Phenomeoologfcal conParlson

Oral dextroamphetamine 20 mg gave rise to an elevatlon 1n all the vlsual analogue ratfng scales reflecting the symptoms of manla. The subJects also rated thefr sleep Ehe nlghE followfng the experlmenL as belng sfgniffcanÈ1y dlsturbed.

The maxfmal changes for each vlsual analogue raEing scale of the mood and hyperactivity paramet.ers as well as the ratlngs of dimlni shed sleep followfng plaeebo and dextroamphetamlne 20 rng are shown fn gur e c ange s showed a statístfca11y signiflcant rise followlng dextroamphetanine admlnlstraElon, wlth the changes ln the arousal - hyperactlvlty dlmensions belng higher and the dlfference reaching a hlgher degree of statlstlcal stgníficance than the mood scores. The maxlmum differences from placebo occurred at two and a half hours af ter dextroamphetamine administration for all measures apart from Èhe restlessness dirnension when the maxlmal change t¡as at tv¡o hours.

The time of the maximal re sponse to dextroamphe tarnine I s comparable rr¡1Eh the time of l ts peak serum 1eve1, whtch occurred between Eh¡o and four hours after adminisEration. See fígure 3.2. mean change VAS ratings (mm) 290 Þ o ]\' Þ

miserable - happy

t

placid - irritable t

dr ow sy - ale r t +t I

lethargic - snorgetic i {ì

m entally slowed mind racing t *t

physically inactiY€ - restless

f

dimin ished sleep (O -5) Orlr)('¡)Þ (J|

* I I

Figure 3.1 Mean changes in VAS ralings (0 - tOOmm) following oral dAMP 2Omg (maximal change shown) plus diminished sleep (O - S scale):

p lacebo dAMP 20mg

ìkìkP -k-k;kp Dif f erence versus placebo. 'kP <.05 <.02 (.QQJ 297

50

40 ts ccD 30 ô. E E' 20 tll

ú, ,! 10 ct

o 1 2 3 4 hours

Fígure 3.2 Mean (l S¡U) plasma dAMP levels (nglml) fotlowing oral dAMP 2Omg given at 0 (1800) hours: 292

The elevatlon ln the arousal scores is accompanied by a reductlon tn the ratfng of the quality of sleeP during the nlght following attendance. The dlfference from placebo in rhe scale dlmlnlshed qualfty af sleep (5 Pofnt) stas 2.L (p <.01). 293

3 .3 .2. A psychophyslological compari son

Dextroamphe tanine 20 mg 1ed to an lncrease ln all

psychophyslologlcal and blological measures. The t lme of

maxfmal re sponse was at tvro and a hal f hour s .

The mean changes ln pulse rate and systolic blood pressure along wíEh those 1n log skin conductance 1eve1s and the

number of spontaneous fluctuations 1n skin conductance aE the tlme of maximal response are shown 1n flgure 3.3. The

mean changes (+-SEM) fn pulse rate were +1 1 . 2(+-2.0) beaEs per mlnute following dextroamphetamine and -1.3(+-1.0) beats per mfnute following plaeebo; the difference belng, +I2.5(+-2.1) beats per mlnute, P <.001. The mean changes in systollc blood pressure at the same tlme were +19.4(+-1 .3) ,.'l !l 'l:, nm Itg following dextroamphetamlne and +3.4(+-1.5) mm llg

following placebo; the dlfference belng +16.0(+-1.9) mm [Ig , P <.00r).

The change's ln log skln conductance 1eve1s vrere similar 1n direction but the differences between placebo and dextroamphetamine failed to reach sEatistical signiflcance. Thus at two and a half hours after the dextroamphetamine 20mg or its placebo, the mean change following

dextroamphetamine was +0.0 25(+-0 .024) micromhos compared Eo -0.012(+-0.021) mlcromhos followlng placebo; the dlfference being +0.042(+-0.030) micromhos, P <.1). The response in the number of spont.aneous fluctuations ln skin conductance at the same tlme r4/as greater. The meaû changes f ollowing dextroamphetamine 20mg r4ras +0.88(+-0.65) and f ollowing I pulse (beat s/ min) 294 1 ul o (rì o (¡

I 'lt

systolic BP (mm HG) lulu o ur o o(,l

I I I

log SC 1¡ mhos¡ ¡ I I I oo 9 o o óö o è À¡ O19å o I

spontaneous fluctuations .-I o ùl I (,| o C'l o (,l (¡ o

t

Figure 3.3 Mean changes (! SEM) in pulse rate systolic BP, log SC and number of spontaneous fluctuations at the maximal response following oraL dAMP 20mg:

placebo dA.MP

*ìk-/rP Dif f erence versus placebo. 'kP < .05 <.001

I

Ì 295

placebo -0.65(+- 0.64) wlth the dlfference between the t$to drug regimes being +1.56(+- 0.81), P <.05.

Dextroamphetamine 20ng gave rise to an I'ncrease ln mean plasma cortlsol 1evels when compared wfth placebo 1n a response that reflects the rlse in plasma dextroamphetamine 1eve1s. See figure 3.4. The maxlmal lncrease was ât 2 hours wlth the mean changes in plasna cortlsol- from 1800 hrs rlslng from -L02.3(+-29.3) nmols / lltre following placebo, to 249.2(+-26.4) nmols / lltre followlng dextroamphetamlne ' The dlfference betsreen the two was +351.4(+-41.6), P <.001).

See a1 so Par t II.

Thus Èhe psychophysiologieal and blological changes followfng dextroamphetamine match those few changes uhat ll E have been shown to be assoclat,ed r¿iÈh mania. .i

r 296

30

200

\ 1 o E tr U o

o .^ -100 €L o o

t\t -20, so Ê -300

o 1 2 3 4 hours

Figure 3.4 Mean changes (t SEM) in plasma cortisol (nmoL/L) folLowing oral dAMP given at 0 (1800) hours:

placebo dAMP 297

3.3 .3. A pharnacologlcal compari son

P lmo ztde has been shown to be an effectlve and relatlvely selective drug in the treatment of manla ( Post, et al, 1980;

Cookson et al , 1981).

The effect of pimo zlde on dextroamphe tamine lnduced arousal has been described 1n detail 1n Part I and will be

revlewed only brfefly 1n thl s section.

P im o zlde al one appeared no t, to influence subj ective ratings or the psychophysiological data ln any consistent

manner. The sole excePÈion hras lts effecE on skin conduct,ance 1eve1s where both doses of pimozide used caused a signiflcant drop over 5 hours. In the L2 subj ects ln

experlment B, dextroamphetamlne 20 mg gave only a m rise in elation and irrltability and plmozlde pretreaEment fal1ed to exert any significant change on them. The rlse 1n visual analogue raÈings of arousal, restlessness, mental speed and energy produced by dexEroamphetamine was rêduced by t,he higher dose of plmozide but thls attenuation failed to reach statlstical significance. See flgure 3.5. (ttre reference tírne for change comparison of changes q¡as 1700 hours in order to minimlze any effects of pimozLde on

reference value s ) . Pimo zíde pre treatment appeared noÈ to influence the effect of dextroamphetamlne on the quali t.y of sleep in the night following the experiment either. Pre treatment by pimo zLde r part,icularly the higher dose, caused a statlstically significant atÈenuation 1n the dextroanphetamlne lnduced increase in pulse rate and 298 VAS rat ings(mm) I I I ct) Þ N Þ

happiness

irritabilitY

al ertne ss

enefgy

mental speed

restlessness

Figure 3.5 Mean changes in VAS ratings (O - tOOmm) in the miserable - happy, placid - irritable, drowsy - alert, lethargic energetic, mentatly slowed - mind racing, restful - restless dimensions from 1700 hours at lhe time of the maximal response by pimozide:

PMZ placebo dA-Ì"IP placebo

PMZ pLacebo dAMP 20mg

Pl4Z 4mg dAMP 20mg 299 systollc blood pressure, the rise skln conductance leveIs and the lncreased number of sponÈaneous fluctuations 1n skin conductance. See flgure 3.6. ( reference tlme for change values was f700 hours). log SC ( pmhos ) 9 300 o o I I (¡ (Jl t\¡

spo ntaneous f luctuations

I N I o N

t:.:.:;:;3;:;:

pulse ( beats /minl I l\) Ul o ul o (¡ o

i:iilitlll¡liät!ll!!iliiilii!lll!il,x"'

systolic BP (mm Hg I o oool\)(,)Þ

Figure 3.6 Ùlean changes (1 SEM) in Log SC (pmhos) and number of spontaneous fluctuations, pulse rate and systolic BP from 1700 hours at the time of the maximal dAMP response:

PMZ placebo - dAMP placebo

PltlZ pLacebo - dAMP 20mg

Pl"lZ 2ng dAMP 20mg

PYIZ 4ng dAMP 20mg 301

3.4. Dlscusslon

3. 4. I . A phenonenonological comparl soa

An lmporEant feaÈure of the use of a pharmacologlcal model usfng human subJects, 1s that 1t a1lows a comparison between the phenomena of mania and the response t.o dextroamphetamine

1n terms of t,he mental state. As discussed earlf er, such a comparison ts only posslble using a human model. In the early anecdotal reports of the subjective response to dext.roamphetamine derlvatlves, many phenomena remínlscent of mania were descrlbed. In thf s regard one of the earlfest. reporEs by Davidoff and ReífensÈein ( 1937) noted that oral racaemic amphetamine gave ri se to lnsomnia, elevatlon of mood or increased agftation, over-talkativeness, lqcreased motor actfvity and restlessness in normal subjects. Similar f lndings r¡rere described by Nathanson ( 1937) who rePorted t.hat subjects frequenEly noted elatlon, lessened fatíBue, talkatlveness, increased energy. In some subjects a late ef f ect of depression r¡ras observed. In subsequent open studies carried out in the 1950-s similar observations I¡/ere made. These findings were confirned in double-b1ind controlled studies of the psychological response to dextroamphetamíne (Brorvn et a1, 1978; Smíth and Davis, I977; Silverstone et â1, I983).

The most common features of mani a ar e the symptoms of nood elevation and/or irritabiliEy, increased energy, physical 302

.l actfvlty and restlessness, fncreased loquaclousness and I repetitive speech, and alertness togethe'r r¿tÈh lnsomnia (CfUbons I982). All are lncluded 1n Èhe varlous dlagnostfc crlterla as being necessary for Ehe diagnosls of manla (fetghner et al, L972; ICD-9, L977; Spitzer et al, I978; Amerlcan Psyehlatric AssociatLon, DSM-III' 1980).

In the presenE study the acElon of dextroamphetamfne on seven lmportant mental staÈe phenomena seen fn manla was examlned ln normal subJects in a controlled and double-b1fnd manner. The resul ts clearly show a close correspondence between the symptomatology of mtld manfa and that followlng a sfngle 20 mg oral dose of dextroamphetamfne.

The effect by dextroamphetamlne on the ratlngs of mood and lrrltabl1lty are much less than iEs effect on ratlngs measurlng arousal and increased mental activi ty. Other studies (Smttn and Davls, 1977; Silverstone et aI , 1983) have not reported such a large dlfference between ratlngs of

mood and ar ou sa1 .

In a series of manic patienÈs, Cooksoti (personal cornmunicat, lon) observed an admlxture of euphoria and irritabilttyr Dêlther of which r¡ras as promlnent as an increase in symptoms such as restlessness and increased speed of thinking. These findlngs are slmilar to those in the current study.

In addition to the above f lndings, ot,her simit.ar iEies in mental state and behaviour have been observed between the 303

response Èo amphetamlne derlvatfves and mania. SomeÈimes af ter a stngle dose, but rnore of t.en af ter a htgher dose or durlng wíthdrawal r symptoms of depression are rePorted

( Connel1, 1958; Ellinwood, 1967; Randrup et 41, I97 5) . Schildkraut et aL (1971) reports thaÈ whl1e anphetamine addlcts hrere sti11 taktng amphetamines " they r.¡ere cllnlca11y hypomanic". Within turent,y-f our to f orty-eight. hours af ter stopplng the drug they became depressed reachlng a peak forty-elght to sevenEy-Èwo hours after taking the 1asÈ dose.

Normal subJects or addlcts takfng high or contínuous doses of ampheÈamine drugs have revealed other phenomena. These have included behavloural and verbal stereotypies, increased Lhinking helghEened energy and clart Ey of ¡ ^sSEessiveness, self-confidence and hypersexuallty. Psychotic phenomena also occurred such as visual, tactile and audíLory halluclnations and persecutory deluslons ( Be11, L965; L973; Ellinwood, 1967; Ellinwood et àI , 1973), Although many workers have pointed to these phenomena as resembling

paranoid schizophrenia (Snyder, L972; I973; Snyder et aI , I97 4) , Ashcroft (I972) observed that stereotypie behaviour can be seen in manic paEients. Furthermore the presence of hallucinaEions and paranoid delusions are not inconsistent with a dÍagnosis of manla. They are reported to occur relatively frequenEly in severe cases ( Cibbons, l9B2 ) and are usually mood congruent (American Psychiat.rlc Assocíation, DSM-III, 1980). 304

Checkley ( tgZA) emphaslsed that the mental state changes wlth arnphetamine derfvatives are frequently mlxed, not only showlng dtfferences over t,lme but also aÈ the same time, rnaking measurement on a two-dirnensional analogue scale difficult. Tecce and Cole (197 4) report slgnificanÈ varlabtltty in the arousal response to dextroamphetamlne when measured subjectively as well as using the psychophyslologlcal measure of the contlngent negative varfatlon r parEicularly ln Èhe first. hour after adminlstration. Again mlxed mood states of elation and depresslon, hyper- and hypoactlvlty are noE lnconsistent wlth the clinical ptcture of mania. The lnconsistency of mood change s may account f or t.he re1at. lve1y 1ow change s in t.he visual analogue scale ratlngs seen in 'the present

experiment. It may also occur because the mood dimenslons of happlnes s and irrltabllity are to a degree opposing emoLions. 305

3.4.2. psychoblologfcal comparfson ^ The comparlson of the response Eo dextroamphetamine and manla on psychophysiologlcal and blologlcal measures I s made dlfflcult because of the paucity of lnformatlon abouÈ Ehe physlcal sequelae of manla. A comprehenslve llterature search revealed very few parameters whlch had been shown to be altered in mania and whlch could also be used in an experimental comparl son. The lack of psychophysiological and blologlcal information reflecEs the very great dlfftculty posed by patlenÈs sufferlng from manla when scientific study in this area 1s attemPted. studylng patients during and after their lllness wlthout the tnfluence of medication is rarely posslble. Leaving manic patl Onts r{j.thõTt ãEÈiv-trettrnent for prolonged p-erlods for the purpose of experiment.atlon 1s not usually ethically appropriate, nor c1lnica11y deslrable.

The reported findtngs with nania involve few patients and 1t is not certaln how representative t,hese findings mlght be. Kraepelin (reprinE of Ig2L Englfsh translation I976) suggested that, the pulse h/as raised or normal and that blood pressure also was raised, particularly 1n the more severe forms of mania. Studles in patienÈs wlth a forty-eíght hour cycle dld not demonstrate changes of pulse with mania and although the pat.ient Ì¿¡as noticed to süreat more on rnanic days, there r^ras no change ín skln galvanometry (Jenner et â1, 1967). Bunney er a1 (1965) demonstrated a negative correlatlon between manla and 17-hydroxycorticosEerold 306

level s .

More recent reports suggest t.hat pulse and blood pressure are ralsed 1n manlc patf ents (l,ake et, aI , L982) whl1st a longitudinal report fn one subJect suggested that manla correlated wtth lncreasfng skln conductance levels (ttemsley and Phf1lps, 1975) . A1Èhough thfs 1s barely satfsfactory evldence for the basis of a psychophyslologieal comParfson, ft fs the best that can be done 1n the clrcumstances.

Blologiea11y there i s evldence that cortlsol 1s generallY elevated in manla Cookson et a1, 1980; Sflverstone and

Cookson, 1982) . The pa t te rn wi th the other anEerlor

pi tui tary hormone s fn mania has not as yet been elucidated.

,l -- J ! L DOLII III LIte PÈ'y(:IIUPITy¡itUJ-9Ë,J-\;dr P¿1réurCLErÐ 4r¡s wrL¡¡ y¿oС¡¡4 cortlsol leve1s sEudled 1n this experlment,, the response by normal subj ects to dextroamphetamine closely natched those measures known to occur 1n manla. 307

3 .4. 3 . A pharmacologfcal comParl. son

Pimo zLde has been reported to exert an antimanic actlon, which may be more spectfic than other neuroleptlcs ( Post et a1, i98O; Cookson et ãI , 1981). In the experfmenE descrlbed 1n Part I, pimoztde caused at most, only a mild attenuation of the response to dext,roamphe tamlne 1n some of the psychologlcal dlmensions wit.h none of the changes reaching statistical significance. Pimozlde reduced the rise in pu1 se rate and the rf se in systollc blood pre s sure induced by dextroamphe tamine . The effects on the card I ova s cular system are dlfflcult to interpret as 1t 1s not clear how much these changes are due to perlpheral rather than cenÈra1 actions of the drugs.

Pimozide preEreatment caused a clear dose-related atÈenuation in the amphetamíne induced rlse 1n skin conducEance rneasures suggestlng that pimozlde does attenuate Ehe central effects of dextroamphetamine. Skln conductance changes are medíated by a cholinergic sympathetic pathway (Venables and ChrisEie, 1980) aud dextroamphetamine appears to have no direct action on cholinergíc neurones (Moore, 1977), This ls consistent with other studies that have demonstrated that pimozide at.tenuated the mood elevaling

ef f ect of íntravenous dexEroarnphetamine (.lonsson , I97 2) and the alert.ing and sleep reducíng effect of oral dexrroamphetamine (cittin et â1, t979[b]; Silverstone et â1, 1980).

A comparison of the effects of other pharmacological 308 agents or challenges derlved from the sclentiflc literature a1 so support the relevance of the model for manla. Alpha methylparatyroslne, wh.ich blocks the raÈe lfmited enzyme tyrosfne hydroxylase concerned with the converslon of phenylalanine to dopa thereby reducfng the formatlon of both dopamine and noradrenallne ln the presynaptlc neurone r r¡ras found Èo be effective 1n reduclng Ehe symPtoms of manla

( Brodie et â1, L97 I) . Tht s drug also aÈtenuated the affectlve response to lntravenous dextroampheEamlne ln human subJects (Jonsson eÈ a1, L97L).

Llthlum carbonate has a maj or c1 lnical role ln the treatment of mania, both in reduclng manlc sYmPtoms and as

prophylaxí s Eo prevenE relapse (Cade, 1948; Schou, 1968;

Shaw , L97 9) ; it ls Eherefore of interest that llthlum carbonat.e has been reported as attenuatfng the arousal

response Eo dextroamphetamlne in normal subJ ec t s ( Van Kammen

and Murphy, 1975; Angris! and Ger shon, 197 9) .

Consldering the observaEions made 1n the present study together with those reported by other investígators' there appears to be close correspondence between the changes produced by a sfngle dose of dextroarnphetamlne in normal volunteer subjects and those occurring during the course of a manlc illness in the t,hree critería posed to valldate the mode1. Indeed the amphetamine model clearly fulfils the three criteria required for a useful clinical model for mania. (See 3.1.2.b.) 309

t. Amphet,amlne prod'uces a state 1n whlch there are c1 o se slmllaritles ln experlenttal and behavioural term s wl th those seen fn mf1d manLa.

11. There are strlking psychophyslologfcal and biologlcal correlates between amphetamine arousal and c1lnlcal manla.

1it. The response of both amphetamine arousal and mania to the dopamlne receptor blocker pfmozlde are fn a slmllar dfrectfon. The responses to lfthlum carbonate and alpha methylparatyrosfne are similarly comParable.

See table 3.1. 310

Table 3.1 Summary of re sul Ès and ci ted reference s comparlng the symptoms physfcal changes and resPonses to pharmacologlcal challenge with the response to dextroamphetamine.

PARAMETER MAN IA DEXTRO- AMPHE TAM INE Changes fn Mental state elat,lon I I frr1tabl1lty I I alertness I I energy t I restlessness I I mental speed I I

sleep ,1, ,1, Hnyslcar unanges

pul se I ( a ) I systollc blood pressure I ( a ) I skln conductance I ( b ) I cortisol I ( c ) I Response to Pharnacological Challenge ( q¡ pimo zlde ,t ) ,1,

1íthium carbonate ( e ) ,t (r) 't alpha methylparatyrosine ,t ( o ) \t (h)

a Lake et a1, I982 b Hemsley and Phl1lps, I975 (c) Cookson et a1, I9B2 (d) Cookson et a1, i9B1 (e) Schou, f968 (f) Van Kammen and Murphy, I975 (e) Brodie et aL, 197I (h) Jonsson et a1, L97I 311

Hftherto amphetamine - tnduced states 1n humans have been almost excluslvely regarded as a model for schlzophrenia. This was based on the observatlon that when taken in hfgh or prolonged dosage amphetanine produces a paranoid psychosis slmllar to paranofd schlzophrenia ( Conne11, 1958; Be11, 1965; I973; Ellinwood, 1967; Ellinwood et a1, 1973; Snyder, 1972t L973) . However, as mentioned earller, many of the symptoms described by indivlduals taklng high doses of amphetamlne drugs can be seen in more severe forns of mania. These lnclude loquacíousness, restlessness, irrftabflity and anger, lncreased self-confidence and grandiosity, stereotypy, hallucinations and deluslons and wíthdrahral depression Ashcroft et a1, 1965; I972; Glbbons, 1982). At the tlme some workers pointed out that. t.here were subst.antial differences between paranoid psychosls induced by amphetamíne and schlzophrenla ( 8e11, I973; Snyder, 1973) .

The comparlson of Ehe amphetamine induced psychosis with schizophrenla seems to have dl s tracted r¡rorkers f rom the rather obvious comparison between the response to a sma1l dose of an amphetamíne derivative and mild mania.

One posstble reason for thls may be that at the tlme comparisons r¡rere made between amphetamine psychosls and paranoid schizophrenia the dtstlnction between schizophrenia and mania h/ere not as clearly def ined as they are noh¡. 0ver the past fif teen years and partlcularly since t.he advent of the treatnent for mania by lilhium carbonate, the dÍagnostíc críteria for the dlfferent psychoses have been sharpened. 3t2

Earller eriterfa for schlzophrenla, ln Partfcular those posed by Sehnelder, whfch $rere tn general use untll recently, have been found not to adequately dfstlngulsh manla from sehlzophrenia ( ¡rockfngham et a1, L978) . diagnostic criterfa Cllnlclans uslng the newer more refined ' have found that many patlents prevfously dlagnosed as suffering paranoid schlzophrenia should be reclassifled as sufferlng manla and are successfully treated with llthlum carbonate (Me11or, 1982). 313

3.4.4. rmprlcatlons for Èhe role of the catechoranine l:i I pathways fn the blology of nanla

The results obt,ained in the present sÈudy conffrm thaL the response Eo a sma11 dose of dextroamphetamfne glven ora11y to normal human subJects, fulflls a set of crlterla whfch establíshes that iÈ may be a valid model for mild mania. The fourth crlterfa for a model of a psychiatric illness posed by McKlnney and Bunney (1969) was that the model and

dlsease share a common aetfology or mechanism of action. As the blological aetlology of mania ls not known iE was felt best t.o consider this crlterion as a criterlon of relevance rather than of validity.

The catecholamine s are clearly fnvolved ln the ll r[! pathogenesis of nanía though thelr precise respectfve roles : have yet to be determlned. Earlf er st.udies lmplicat.ed a excess of activlty of the noradrenerglc pathways ( sctrlldkrauÈ , 1965 r97 3) . More recent evidence, partícu1ar1y from pharmacological studies, strongly suggests that an elevatlon in the activity of dopamlne pathways is of primary importance in the pathogenesi s of manla ( Randrup et

aI , I975; Sllverstone, I97B; post, 1980; Sílverstone and Cookson, 1982) . The role of noradrenal lne has become íncreasingly uncertain.

A rnodel using dextroamphetamine i s of relevance Eo a1lo¡¡ further exploration of these questions, âs amphetamine

derivaElves act as lndirect agonists of both dopamíne and noradrenaline centrally. (See \.2.5,). As dexEroamphetarnine k 3t4

lnduced symptoms are blocked by pfmozLde and other centrally actlng dopamine blocklng drugs, the nodel reinforces the

possfbllf ty of a stfmulatory role for dopamlne pathhrays 1n

mani a .

In the fnvestigaElon of the role of the alphanoradrenerglc pathways 1n the dextroamphet,amlne response r pretreatment by thymoxamine, an alpha t postsynâptlc noradrenergic

antâgonlst, accentuated the response ( see Part I). Thls riras particularly manifest wfth the higher dose of thymoxamine and was demonstrable on both the psychologlcal and i. psychophyslological effects of dextroamphetamlne.

I^¡h11e the accentuating effect by thyrnoxamine on the ,r dextroamphetamlne response could reflect a blockfng actlon q on presynapt,lc alpha 2 adrenoceptors, ie. a yohimbine 11ke ac!1on, there 1s no evldence to support such a vlew. It fs more 1ikely thaE the accentuatfon of Èhe dextroamphetamlne

response by thymoxamine eras due to lts blockfng actlon on postsynaptic recepÈors. If so r then a case can be made for the noradrenergic pathways (at least the alpha noradrenerglc pathways ) lnteractlng with dopamine paÈhh¡ays 1n the regulatlon of arousal; the noradrenergic pathways belng inhtbitory 1n states of lncreased dopamlne activíty.

If tht s is so, it poÍnts the vray to the posslbtltty of a different approach to trea tment.

Such a concluslon would be in keeping with Ehe results of the study 1n which fusaric acid, a dopamine beta hydroxylase l 315

lnhlbltor, was given to manic patlents. Thl s 1ed to a rlse in dopamine and a drop in noradrenal ine and caused an

exacerbatlon of symptoms ( Sack and Goodwfn, 197 4) .

0ther studles lnvestigatfng the role of the alpha noradrenergic pathways 1n manla have looked at clonidine and yohlmbine, âr agonist and antagonlst respectively, at pre- and postsynapÈ1c alpha 2 receptors (Anden et aL, I976; L982; Langer, 1981 ) . Clonldine admlnisLratlon reduced manic

symptoms whlch may rebound on withdrawal (Youvent et aI , 1980) whereas yohtmbine may precipttate mania (Prlce et â1, 1984). Interpretatlon of these results depend on whether the drugs are actlng preferentially aE pre- or postsynaptic sltes r¿ithin Èhe central nervous system. Clearly oËher studies aimed at resolvlng these issues would be deslrable.

t,I 316

3.4.5. Concluslon

It would appear reasonable to conclude that the resPonse

to a low dose of dextroamphetamlne 1n normal human subJects fulfils the various crlterla 1a1d down for a valíd model for mania as Èhere 1s close correlat, lon ln the various crlteria ?toposed. Thls glves credence to the use of dextr oamphe tamlne a s an anlnal model for manla (t'turphy,

1978; Robbins and Sahaklan, I9B0) . Furthermore, as dextroamphetamine acÈs as an indirect agonlst for both

dopamine and noradrenal fne , i t allows an opportunity Eo

explore and compare the role of Ehe two caEecholamines 1n thls disease. In so dolng, the model relnforce s the

proposal that hyperfunctlon of the dopamlne pathways I s lmportant in Ehe biology of mania.

If I4Ie use oral dextroamphetamine as a model for nild rnanla to lnvesÈfgate the role of the alphanoradrenerglc pathways

1n manfa, results lmp1y that the noradrenergic pathways rnay not be lnvolved in the simple sEimulatory role thaE had been previously assumed but that a more complex interactíve relatlonship wlth Èhe dopamlne pathh/ays exlsts.

As one of the main purposes in using models of illnesses 1n psychopharmacologlcal research is 1n the generation of new research hypotheses, the model described pronotes further lnvestigation of the role of the noradrenergic pathways in the biology of manla. 3r7

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