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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
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