Function and Regulationof Monoamine Enzymes:

Basic and Clinical Aspects

Function and Regulationof Monoamine Enzymes:

Basic and Clinical Aspects

Proceedings of a conferenceheld at Airlie House

March 6-8 1981

edited by

EARL USDINNational Inst itute ofMental Health

NORMAN WEINERUniversity ofColorado

MOUSSA B. H. YOUDIMTechnion Faculty ofMed icine

MThis book was edited by Dr Usdin in

his private capacity. No official supportor endorsement by the NIMH is intended or

should be inferred.

Contents

Introduction xiPreface xiiiParticipants xvAbbreviations xxi

Tyrosine Hydroxylase

In situ phosphorylation of vas deferens tyrosine hydroxylase during hypogastric nervestimulation. Norman Weiner, Fu-Li Lee, John Meligeni and A. William Tank 3

A schematic model for the allosteric activation of tyrosine hydroxylase. P. R. Vu/liet andN. Weiner 15

Isoelectric focusing of tyrosine hydroxylase. John Meligeni and Norman Weiner 25

Role for tyrosine hydroxylase activation in the regulation of dopamine synthesis. B.Zivkovic 35

The control of tyrosine hydroxylase activity: Enzyme activation vs. feedback inhibition .Robert L. Perlman 45

Neuroleptic drugs modify retinal dopamine-containing amacrine cell tyrosinehydroxylase activity . Joseph Cohenand Norton H. Neff 55

Short-term and long-term regulation of tyrosine hydroxylase activity in retinal andmesolimbic dopamine-containing neurons. P. Michael Iuvone and Albert L. Rauch 65

The rapid activation and deactivation of adrenal tyrosine hydroxylase and protein kinasefollowing electroconvulsive shock . Joseph M. Masserano and Norman Weiner 75

Central noradrenergic neurons: Studies on the mechanism of the in vivoactivation oftyrosine hydroxylase. K. Gyslingand R. H. Roth 83

In vivotreatments associated with the activation of tyrosine hydroxylase in rabbitvasculature. Glenn S. Takimoto and Norman Weiner 95

Regulatory properties of tyrosine hydroxylase: Multiple forms, subunit structure andcyclic nucleotide independent phosphorylation. Joachim D. Raese, GeorgeMakk andJack D. Barchas 105

The modification of the kinetics of tyrosine hydroxylase in vitro and in vivo: a possiblerole for carboxymethylation in the regulation of Ldopa synthesis. Stephen P. Mann 115

Activating sheep antibodies to tyrosine hydroxylase. John W. Haycock and Jack C.Waymire 121

v

vi

Partial destruction of noradrenergic terminals is followed by increased tyrosinehydroxylase activity in residual terminals. M. J. Zigmond, A. L. A cheson and E. M.Stricker 131

Molecular biology of tyrosine hydroxylase induction. A. Guidotti. D. M. Chuang. K.Kumakura and E. Costa 141

Regulation of tyrosine hydroxylase by cyclic AMP and dexamethasone in mouseneuroblastoma cells. A. W. Tank and N. Weiner 149

DISCUSSION 157

2 Tryptophan and Phenylalanine Hydroxylases

Regulatory properties of pterin-dependent hydroxylases : variations on a theme . SeymourKaufman 165

In vitro and in vivoactivation of tryptophan hydroxylase in the rat brain. S. EIMestikway, S. Bourgoin. F. Artaud and M. Hamon 175

The regulation of tryptophan hydroxylase activity. Donald M. Kuhn 187

Regulation of tryptophan hydroxylase activity: Studies with slices of rat brain stem andsome in vivo treatments. Margaret C. Boadle-Biber 195

Modulation of tryptophan hydroxylase stability: A possible mechanism for monoamineenzyme regulation. Anthony Vitto 205

Calcium, cofactor and propranolol-induced changes in the kinetic variations of rat raphetryptophan hydroxylase activity . Suzanne Knapp and Arnold J. Mandell 215

3 Pterin Cofactors

The hydroxylase cofactor and catecholamine synthesis. Walter Lovenberg, RobertLevine and Leonard Miller 225

Adrenergic-cyclic AMP regulation ofbiopterin biosynthesis in the pineal gland. GregoryKapatos, Seymour Kaufman. Joan L. Weller and David C. Klein 231

Control of tissue tetrahydrobiopterin levels through GTP-cyclohydrolase : A factor in theregulation of monoamine synthesis. O. H. Viveros. M. M. Abou-Donia, C.-L. Lee. S. P.Wilson and C. A . Nichol 241

New aspects in biopterin biosynthesis. H.-Ch. Curtius, M . Hdusermann ,A . Niederweiser,W. Endres and M. Viscontini 251

Sepiapterin (6-lactyl-7, 8-dihydropterin) is an intermediate in biopterin biosynthesis in acell-free preparation from rat striatum. Gregory Kapatos, Setsuko Katoh and SeymourKaufman 263

Striatal tyrosine hydroxylase : The role of cofactor concentration in the scaling of enzymeperiodicity and behavioral stereotypy. Arnold J. Mandell and Patrick V. Russo 271

DISCUSSION 281

4 Monoamine Synthesis and Metabolism in Intact Systems

Transynaptic regulation of adrenal tyrosine hydroxylase in tracing central autonomicpathways. Jean-Pierre Gagner. Serge Gauthier and Theodore L. Sourkes 287

Hormonal involvement in footshock-induced changes in catecholamine synthesis in brainslices. Adrian J. Dunn. Neal R. Kramarcy and Richard L . Delanoy 297

Stimulant drug effects on catecholamine synthesis regulation . Robert L. Patrick 307

Transport systems for tyrosine and their relation to catecholamine biosynthesis. J.Bruinvels 315

The site of decarboxylation of exogenous L-dopa in the rat striatum. Franz Hefti andEldad Melamed 327

Regulation of dopa biosynthesis by presynaptic dopamine receptors andoq-adrenoreceptors. Menek Goldstein,Jose M. Rabey, Keith Markey , Patricia Passeltinerand Jorgen Engel 339

Neurotransmitter interactions in the median raphe nucleus . C. M. Forchetti and J. L.Meek 347

Combined immunocytochemical and radioautographic study of dopaminergic terminalsin the neostriatum. V. M. Pickel, A. Beaudet, T. H. Joh, D. J. Reis and M. Cuenod 353

Evidence for a peripheral dopaminergic neural system . Zravko Lackovic, Maja Relja andNorton H. Neff 361

The metabolism of dopamine in sheep blood . D. F. Sharman 371

Regulatory dysfunction of tyrosine hydroxylase and dopamine-J3-hydroxylase in familialdysautonomia. N. Eric Naftchi, Felicia B. Axelrod and Margaret Demeny 377

Effects of chronic amphetamine administration on behaviour and monoaminemetabolism in cats. Michael E. Trulson and Barry L. Jacobs 387

A mathematical model of central dopaminergic transmission and the dopaminehypothesis of schizophrenia. Roy King. Joachim D. Raese and Jack D. Barchas 399

S Dopamine-B-Hydroxylase

Dopamine-J3-hydroxylase : Comparison of soluble and membrane forms . NormanKirshner. Joseph P. Albanesi, Ellen C. Robinson and JacquelineReynolds 409

Semidehydroascorbate as the enzymic product of dopamine J3-hydroxylation:Mechanism and functional significance. Emanuel J. Diliberto.Jr . 421

Catecholamine synthesizing enzymes in rat pheochromocytoma PC-12 cells. EstherSabban, Jim Fong, Keith Markey, Louis Shenkman. Menek Goldstein and Lloyd A.Greene - 431

Regulation of circulating dopamine J3-hydroxylase by disposal pathways : Effects ofendocrine function. Jon M. Stolk, Jeffrey H. Hurst. Ras B. Guchhait, Robert J. Faddenand Bruce C. Nisula 435

Functional implications of dopamine J3-hydroxylase localization and norepinephrinesynthesis capacity in large and small vesicles of sympathic neurons. Richard L. Kleinand Asa K. Thureson-Klein 443

vii

viii

Isolation and purification of dopamine f3-hydroxylase from the splenic nerve and purifiednoradrenergic vesicles. Wen-Hsun Yang 453

DISCUSSION 461

6 Monoamine Oxidase

Energy of activation of MAO . TheodoreL. Sourkes and Madan M. Kwatra 465

How do MAO-A and MAO-B select their substrates? Thermodynamical aspects . E. A .Zeller and K. L. Arora 469

Catalytic mechan ism of MAO from liver. Mazhar Husain, Dale E. Edmondson andThomas P. Singer 477

Topology and lipid protein association of MAO-A and MAO-B. Rosa H. Huang 489

The processing and assembly of rat liver MAO. David Smith and Roy McCauley 503

Role of type A and type B monoamine oxidase in the metabolism of epinephrine in ratbrain . Ray W. Fuller and Susan K. Hemrick-Luecke 509

Differences in the preferential deamination of I-norepinephrine , dopamine and serotoninby MAO in rodent and primate brain. Nancy A. Garrick and Dennis L . Murphy 517

Aliphatic amines as MAO subst rates in the rat : The effect of selective inhibitors on thedeamination of n-pentylamine . Margherita Stroltn-Benedetti. Nicole Sontag, ThierryBoucher and Jean-Paul Kan 527

Oxidative deamination of trace amines in the brain . A. A. Boulton, B. A. Davis, D. A.Durden, A. V. Juorio, S. R. Philipsand P. H. Yu 539

Cardiovascular changes accompanying MAO inhibition in man. Dennis L. Murphy,Benjamin Roy, David Pickar, Steven Lipper, Robert M. Cohen, DavidJimerson, CharlesR. Lake , G. Muscettola, Juan Saavedraand Irwin J. Kopin 549

Platelet MAO activity in depressed patients. Jean C. Shih, Kerrin White, Javad Razani,GeorgeSimpson and R. Bruce Sloane 561

Anomalies in MAO assays using .!I.Az49 and.!l.O measurements with benzylamine assubstrate. R. W. Von Korffand A. R. Wolfe 565

DISCUSSIONS 575

Interaction ofacetylenic compounds with MAO active site: structure-activity andpharmacological studies . M.B. Y. Youdim,J. P. M. Finbergand M. Tenne 911

7 Aldehydereductasesand dehydrogenases

Substrate competition for aldehyde metabolism. Keith F. Tipton, Ian L. Smith, CatherineM. Ryle and A. Jennifer Rivett ·581

The structure and function of aldehyde reductases. Anthony J. Turner and Susan R.Whittle 591

Functional groups in pig kidney aldehyde reductase. T. G. Flynn, D. Fergusonand W. S.Davidson 601

Role of magnesium and calcium ions in the regulation of mitochondrial aldehydedehydrogenase. Henry Weiner and Kojiro Takahashi 611

A critical appraisal of aldehyde reductase activities in brain . Paula L. Hoffman and BorisTabakoff 621

The purification and properties of mouse brain aldehyde dehydrogenase. D. R. PetersenandN.A .Atkinson 633

Actions of amine-aldehyde condensation products. ChristineL. Melchior 643

8 Transferases

3-Substituted-4-methoxy-5-hydroxybenzaldehydes and benzoic acids as inhibitors ofcatechol-O-methyltransferase. Ronald T. Borchardt and Joan A. Huber 657

COMT-A and COMT-B: Catalytic differences and role of disulfide bonds. GiovanniMarzullo and Arnold J. Friedhoff 665

Immunohistochemical localization of catechol-O-methyltransferase in brain : potentialrole as an enzymatic barrier. Boyd K. Hartman, Gary P. Kaplan and Cyrus R. Creveling 675

Use of a catechol O-methyltransferase inhibitor to enhance cental action of L-dopa . A.Reches, D. Jiang and S. Fahn 683

Stereochemical aspects of binding of aromatic and non-aromatic substrates andinhibitors to phenylethanolamine N-methyltransferase. Gary L. Grunewaldand MichaelF. Rafferty 691

Purification of sheep pineal N-acetyltransferase. M. A. A. Namboodiri and D. C. Klein 70 I

Inactivation of pineal N-acetyltransferase disulfide exchange : A possible role ofS-Speptides . David C. Klein and M. A. A. Namboodiri 711

Investigations of the relationship between changes in neural activity and changes in tissuebiochemistry : Some criteria and the example of serotonin N-acetyltransferase. R. E.Zigmond and C. W. Bowers 723

Regulation ofphenolsulfotransferase activity in the rat . Randall K. Pearson, Timothy P.Maus, Robert J. Anderson, Lee C. Woodson, Cristoph Reiter and Richard M.Weinshilboum 735

Phenolsulphotransferase and its clinical importance. M. Sandler, GlenRein, VivetteGlover, Susan M. Bonham Carter and Julia Littlewood 743

DISCUSSION 755

9 Applications of Electrochemical Detection Techniques

The determination of catecholamine and indoleamine enzymatic activities using liquidchromatography with electrochemical detection. C. LeRoy Blank, P. Wong, M. Bulawaand P. Lin 759

Electrochemical recording of brain catecholamine and serotonin release duringbehavioral changes. P. J. Knott, P. H. Hutson, R . P. Scraggs and G. Curzon 771

Direct amperometric measurement of the rate of release of dopamine from superfusedbrain tissue . R. Mark Wightman,John N. Cavinessand Ann M. Hmelovsky 781

ix

x

10 Monoamine-Receptor Interactions

Modulation of dopamine-sensitive adenylate cyclase by calmodulin and guanylnucleotides . M. E. Gnegyand S. D. Bagley 793

Treatment with 6-hydroxydopamine or morph ine induces supersensitivity of thedopamine receptor-adenylate cyclase complex. N. H. Neff, M. Parenti, S. GentlemanandM. C. Olianas 803

Mechanisms of the internalization of beta-adrenergic receptor recognition sites. D.-M.Chuang, L. Farber, M. L. Barbaccia and E. Costa 809

Correlation of dopam ine and opiate binding with adenylate cyclase in rat striatum. SusanGentleman 817

Regulation of intracellular and nuclear metabolism by stimulation of l3-adrenergicreceptors on C6 glioma cells. Joan P. Schwartz and Pierluigi Onali 825

II Genetic and Developmental Aspects

Genetic variations in number of dopamine neurons in mouse brain : Evidence that alldopamine systems are involved. Harriet Baker and Donald J. Reis 835

Development and regulation of hypertension in the spontaneously hypertensive rat :Enzym atic and nutritional stud ies. Tom Lloyd and Brenda Boyd 843

Biochemical and genetic analysis of MAO A and B. John E. Pintar. Richard M.Cawthon, Morris Hawkins Jr., Carmela M. Castiglioneand Xandra O. Breakefield 855

Substrate and species related variat ions dur ing the perinatal development of MAOactivity. Margarethe Holzbauer 865

Transformation of catecholaminergic precursors into glucagon (A) cells in the mouseembryonic pancrease. G. Teitelman, T. H. Joh and D. J. Reis 873

Morphological changes in the adrenergic ground plexus of the iris elicited by lead.cadmium and mercury . Hdken Bjorklund. Lars Olson, ,.Ike Seiger and Barry Hoffer 885

Regulat ion of intracellular enzyme proteolysis by small-molecule cofactors. Roland D.Ciaranello 895

DISCUSSION 905

GENERAL DISCUSSION 907

Subject Index 923

Introduction

Four years ago, the First Conference on Monoamine Enzymeswas held at Steamboat Springs, Colorado. At that time, recentprogress in areas of fundamental and clinical research on mono­amine enzymes and inhibitors was discussed by many of the lead­ing investigators who were addressing these exciting topics .Emphasis was placed on the structure and function of the enzymesinvolved in biogenic amine synthesis and catabolism and on as­pects of possible ways i n which e ither abnormal i t i es in theseenzymes might be related to, or chemical modification of theactivities of these enzymes might modify , cardiovascular and men­tal diseases in humans .

Although progress in fundamental research on monoamine en­zymes has again been emphasized in this Second Conference onMonoamine Enzymes, the topics addressed and the research approachesutilized suggest that this field of research has advanced con­siderably and new levels of inquiry are attracting the attentionof scientists in this field. Emphasis has turned to examiningthe physiological regulation of the enzymes involved in biogenicamine synthesis and catabolism, the nature and functions of themultiple forms which many of the enzymes exhibit, the subcellularlocalization and tissue distribution of different forms \of theseenzymes and the genetic factors which determine the types andfunctions of the enzymes present in the organism. Genetic stud­ies, both in man and animals, of the variations in the types andlevels of the enzymes of biogenic amine metabolism and the bio­logical and clinical consequences of these variations, are re­ceiving increased attention. The roles of pterin cofactors andprotein phosphorylation in regulating monoamine synthesis inbrain and in the sympathetic nervous system - subjects which wereonly beginning to emerge four years ago - have become major fociof attention in biogenic amine research. The biosynthesis and

xi

xiich~ical characterization of pterin compounds and their possibleuse in genetic disorders of pterin synthesis have become subjectsof increasing fund~ental importance and clinical relevance. Ourincreased knowledge and understanding of isozymes of mono~ine

oxidases and the developri:lent of new, selective inhioitors ofthese isozymes are other areas of research which have progressedrapidly in recent years and where clinical applications in themanagement of certain cardiovascular and mental diseases appearto hold much promise.

As was true four years ago, leading investigators from theUnited States, Canada, Europe and Israel met to share the resultsof their basic and clinical studies on the metabolism of biogenicamines and to discuss and debate these topics in the hope thatnew understanding, new concepts and new ideas might emerge fromthese discussions . Although one cannot be certain about the ex­tent to which the aspirations of the participants were realized,it seemed apparent from the quality of the presentations and theintensity of the discussions which ensued that the purposes ofthis conference were achieved. We hope, in turn, that the pub­lished proceedings of this conference will be of similar valueto other biomedical scientists with interests in one or more as­pects of the biochemistry, physiology, and pharmacology of thebiogenic amines and of the clinical situations to which inform­ation on these subjects can be applied.

N. We1,n.eJLE. U¢cUn.M.B.H. YoucLi.m

Preface

Several elements are essential to allow a proceedings volumesuch as this to reach fruition:

1. authors/presenters. Each of the papers in this volumewas presented (in somewhat abbreviated form) at the Airlie Housemeeting on Monoamine Enzymes. Would you believe that almost everyone of these manuscripts was turned in at the meeting in camera­ready form? and that the remaining few were received by me withinten days of that meeting? I acknowledge, with thanks, this won­derful performance of the cast.

2. reporters. Many a meeting engenders the most scintillat­ing of discussions but the World knows naught of these since theparticipants' Words of Wisdom are not reported in the proceedings'volume. Many a proceedings' volume is overwhelmed by transcriptsof both Words of Wisdom and also trivia of discussion. We hopethat the summary of the discussions which is included after var­ious sections contains the wisdom and omits the trivia. Wouldyou believe the reporters (Drs. Boadle-Biber, Mandell, Sharman,Tabakoff, and Von Korff) turned in their notes before the end ofthe meeting? I must both acknowledge their feat and also ack­nowledge that I have "edited" their words: let the wrath of mis­quoted discussants fall upon my head.

3. publisher. The use of camera-ready copy allows some savingin cost and, possibly more significantly, in length of time betweenmeeting and appearance of published volume, but it creates problemsfor authors, editors and publisher. Would you believe that pageproofs were received by me less than a month after I gave copy tothe publisher? I should like to thank Macmillan for their coop­eration and, in particular, their Science Editor: Harry Holt.

4. meeting site. Much of the success (or failure) of a meet­ing is due to the ambience of the site where it is held. Would

xiii

xivyou believe that Airlie House not only provided a most pleasantmeeting room, a beautiful location, excellent food, etc., buteven superlative weather - which is not that easy in the foothillsof the Shenandoah in early March! Our thanks go to the staff ofAirlie House and, in particular, to Mrs. Westlake, the Director.

5. sponsors. Although the Monoamine Enzyme conference wasplanned as a satellite of the American Society for Neurochemistrymeeting (in Richmond) to eliminate the need for support of travelexpenses, there was need to provide room and board as well ascheese and wine at the poster sessions. Would you believe thatthere was a goodly supply of both wine and cheese after the meet­ing was over? We should like to acknowledge, with much thanks,support from the following:

American Cyanamid (U.S.)Astra Pharmaceutical (Sweden)Ayerst, McKenna & Harrison (Canada)Hoffman La Roche (U.S .)ICI Americas (U.S.)Eli Lilly (U.S.)Arthur D. Little (U.S.)E. Merck (Germany)Merck Sharp & Dohme (U.S.)Merrell-National (U.S.)Smith Kline & French (U.S.)Upjohn (U.S.)

6. secretaries. A meeting can not become a meeting nor cana proceedings' volume become a publication without the dedicatedwork of secretaries in the organizing of the meeting and in thepreparation of manuscript material. Would you believe that Ellensdid it all? Many, many thanks to Ellen Queen (in Colorado) andto Ellen Perella (in Maryland).

7. organizers/editors. Since I sign this myself, I feel thatI may express my great appreciation to my fellow organizers/editors- Norman Weiner and Moussa Youdim: the meeting could not/would not/have been held without their extraordinary capabilities. Thanks,thanks, thanks.

EaJt1 U-6cUn

ParticipantsC. LeRoy BlankDepartment of ChemistryUniversity of Oklahoma620 Parrington OvalNorman, OK 73019

Margaret C. Boadle-BiberDepartment of PhysiologyMedical College of VirginiaRichmond, VA 23298

Ronald T. BorchardtDepartment of BiochemistryUniversity of KansasLawrence, KS 66045

Alan A. BoultonPsychiatric Research DivisionUniversity HospitalSaskatoon, Sask., Canada S7N OXO

Xandra o. BreakefieldDepartment of Human GeneticsYale Univ. School of MedicineNew Haven, CT 06510

J. BruinvelsDepartment of PharmacologyMedical Fac. ,Erasmus UniversityPO Box 17383000DR Rotterdam'~The Netherlands

D.-M. ChuangLab. of Preclin. PharmacologyNational Inst. of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

Roland D. CiaranelloLab. of Devel. NeurochemistryDept. of Psychiatry & Behav. sci.Stanford Univ . School of Med.Stanford, CA 94305

Joseph CohenLab. of Preclin. PharmacologyNational Inst. of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

xv

Erminio CostaLab. of Preclin. PharmacologyNational Inst. of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

Cyrus R. CrevelingLaboratory of ChemistryNIAMDD. NIHBethesda, MD 20205

H.-Ch. CurtiusDivision of Clinical Chern.Department of PediatricsUniversity of ZurichSteinwiesstrasse 758032 Zurich, Switzerland

Emanuel J. Diliberto, Jr.Dept. of Medicinal Biochem.Wellcome Research Labs.Research Triangle Park, NC 27709

Adrian J. DunnDepartment of NeuroscienceUniv. of Florida Col. of Med.Gainesville, FL 32601

Thomas G. FlynnDepartment of BiochemistryQueen's UniversityKingston,Ont., Canada K7L 3N6

Ray W. FullerLilly Research LaboratoriesEli Lilly and CompanyIndianapolis, IN 46285

Jean-pierre GagnerMontreal Neurological Institute3801 University StreetMontreal,Que. H3A 2B4 Canada

Nancy A. GarrickClin. Neuropharmacology BranchNational Inst. of Mental HealthBethesda, MD 20205

xviSusan GentlemanSec. on Biochem. & Pharm.Biological Psychiatry BranchNational Inst. of Mental HealthBethesda, MD 20205

Margaret E. GnegyDepartment of PharmacologyUniv. of Michigan Med. SchoolAnn Arbor, MI 48109

Menek GoldsteinDepartment of PsychiatryNew York Univ. Med. Center550 First AvenueNew York, NY 10016

Gary L. GrunewaldDept. of Medicinal ChemistryUniversity of KansasLawrence, KS 66045

Alessandro GuidottiLab . of Preclin. PharmacologyNational Inst . of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

Katia GyslingDepts. of Pharmacology & Psych.Yale univ. School of MedicineNew Haven, CT 06510

Michel HamonGroupe NBINSERM U. 114College de France11 place Marcelin Berthelot75231 Paris cedex 5, France

Boyd K. HartmanDepts. of Psychiatry & Neurol.Washington Univ. School of Med.St. Louis, MO 63110

John W. HaycockDept. of Neurobiol. & AnatomyUniv. of Texas Med. SchoolPOB 20708Houston, TX 77025

Franz HeftiLab. of Neuroendocrin. Reg.Mass. Inst. of TechnologyCambridge, MA 02139

Barry HofferDepartment of PharmacologyUniv . of Colorado Health Sci. Ctr.Denver, CO 80262

Paula L. HoffmanDept. of Physiology & Biophysicsuniv. of Illinois Med. CenterChicago, IL 60612

Margarethe HolzbauerARC Institute of Animal PhysiologyBabraham, Cambridge CB2 4AT, U.K.

Rosa H. HuangDept. of BiochemistryUniv . of S. Alabama Col. of Med.Mobile, AL 36688

Mazhar HussainDept. of Biochem. & BiophysicsUniversity of CaliforniaSan Francisco, CA 94143

P. Michael IuvoneDepts . of Pharmacology & Ophthal .Emory UniversityAtlanta, GA 30322

Gregory KapatosLab. of NeurochemistryNational Inst. of Mental HealthBethesda, MD 20205

Seymour KaufmanLab. of NeurochemistryNational Inst. of Mental HealthBethesda, MD 20205

Roy KingN. Pritzker Lab. of Behav. Neuro-

chemistryDept. of psychiatry & Behav. Sci.Stanford Univ. School of MedicineStanford, CA 94305

Norman KirshnerDepts. of Biochem. & PharmacologyDuke Univ. Medical CenterDurham, NC 27710

David C. KleinLab. of Developmental NeurobiologyNatl. Inst. Child Health & Human

Development, NIHBethesda, MD 20205

Richard L. KleinDept. of Pharmacology & Tox.Univ. of Mississippi Med. Ctr .Jackson, MS 39216

Suzanne KnappDepartment of PsychiatryUniv. of Calif., San DiegoLa Jolla, CA 92093

Peter J. KnottDepartment of PharmacologyMarshall Univ. School of Med.Huntington, WV 25701

Irwin J. KopinLab . of Clinical Sci.National Inst. of Mental HealthBethesda, MD 20205

Donald M. KuhnHypertension-Endocrine BranchNatl. Heart, Lung & Blood Inst.Bethesda, MD 20205

Zdravko LackovicLab. of Preclin . PharmacologyNational Inst . of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

Tom LloydDepts. of Ob./Gyn. & Pharmacol.Milton S. Hershey Med. CenterPennsylvania state UniversityHershey, PA 17033

Walter LevenbergSec. on Biochem. PharmacologyNatl . Heart, Lung & Blood Inst.Bethesda, MD 20205

Arnold J. MandellDepartment of PsychiatryUniv . of Calif., San DiegoLa Jolla, CA 92093

Stephen P. MannARC Inst. of Animal PhysiologyBabraham, Cambridge CB2 4AT,U.K.

Giovanni MarzulloMillhauser LaboratoriesDepartment of PsychiatryNew York Univ . School of Med.New York, NY 10016

Joseph N. MasseranoDepartment of PharmacologyUniv. of Colorado School of Med.Denver, CO 80262

Roy McCauleyWayne State Univ. School of Med.Detroit, MI 48201

James L. MeekLab. of Preclin . PharmacologyNatl. Inst. of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

Christine L. MelchiorDept. of Physiology & BiophysicsUniv. of Illinois Med. CenterChicago, IL 60612

John MeligeniDepartment of PharmacologyUniv . of Colorado School of Med.Denver , CO 80262

Dennis L. MurphyNatl. Inst. of Mental HealthBethesda, MD 20205

N. Eric NaftchiLab . of Biochem. PharmacologyInst. of Rehabilitation Med.New York Univ. Medical CenterNew York, NY 10016

M. A. A. NamboodiriLab. of Developmental Neurobiol.Natl . Inst . of Child Health &

Human DevelopmentBethesda, MD 20205

Norton H. NeffLab . of Preclin. Pharmacol .Natl. Inst. of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

Robert L. PatrickNeurosci. Sec ., Div. of Biology

& MedicineBrown UniversityProvidence, RI 02912

xvii

xviii

Robert L. PerlmanDepartment of PhysiologyHarvard Medical School25 Shattuck StreetBoston, MA 02115

Dennis R. PetersenSchool of PharmacyUniversity of ColoradoBoulder, CO 80302

Virginia PickelLab . of NeurobiologyCornell Univ. Med. College1300 York AvenueNew York, NY 10021

Joachim D. RaeseNancy Pritzker Lab . of Behav-

ioral Neurochem.Dept. of Psychiatry & Behav. Sci.Stanford Univ. School of Med.Stanford, CA 94305

Avinoam RechesDepartment of NeurologyCollege of Physicians & Surgeons630 West l68th StreetNew York, NY 10032

Donald J. ReisLab. of NeurobiologyCornell univ . Med. College1300 York AvenueNew York, NY 10021

Merton SandlerB. Baron Mem. Res. Labs.Queen Charlotte's Hosp.London W6 OXG, England

Joan P. SchwartzLab. of Preclin. Pharmacol.Natl. Inst. of Mental HealthSaint Elizabeths HospitalWashington, DC 20032

Dennis F . SharmanARC Inst. of Animal PhysiologyBabraham,Cambridge CB2 4AT, U.K.

Jean Chen ShihSchool of PharmacyUniv. of Southern Calif.Los Angeles, CA 90033

Thomas P. SingerDept. of Biochem. & BiophysicsUniversity of CaliforniaSan Francisco, CA 94143

Theodore L. SourkesDepartment of PsychiatryMcGi l l UniversityMontreal,Que., Canada H3A lAl

Jon M. StolkMaryland Psychiatric Res. Ctr .Univ. of Maryland School of Med.Baltimore, MD 21228

Margherita Strolin-BenedettiCentre de Rech . Delalande10, rue des Carrieres92500 Rueil-Malmaison, France

Boris TabakoffDept. of Physiology & BiophysicsUniv. of Illinois Med. CenterChicago, IL 60612

Glenn S. TakimotoDepartment of PharmacologyUniv. of Colorado School of Med.Denver, CO 80262

A. William TankDept. of PharmacologyUniv . of Colorado School of Med.Denver, CO 80262

Gladys Te itelmanLab. of NeurobiologyCornell Univ. Med. College1300 York AvenueNew York, NY 10021

Keith F. TiptonDepartment of BiochemistryTrinity CollegeDublin 2, Ireland

Michael E. TrulsonDepartment of PsychologyUniv. of Texas at DallasPO Box 688Richardson, TX 75080

Anthony J. TurnerDepartment of BiochemistryUniversity of LeedsLeeds LS2 9JT, U. K.

Earl UsdinNatl. Inst . of Mental Health5600 Fishers Lane, Rm 9C-07Rockville, MD 20857

Anthony vittoDiv. of PharmacologyDept . of MedicineUniv . of Calif ., San DiegoLa Jolla, CA 92093

O. Humberto ViverosDept.of Med. BiochemistryWellcome Research Labs.Research Triangle Park, NC 27709

Richard W. Von KorffMichigan Molecular InstituteMidland, MI 48640

Philip R. VullietDepartment of PharmacologyUniv. of Colorado School of Med.Denver, CO 80262

Henry WeinerDepartment of BiochemistryPurdue UniversityWest Lafayette, IN 47907

Norman WeinerDepartment of PharmacologyUniv . of Colorado School of Med.Denver, CO 80262

Richard M. weinshilboumDepts . of Pharmacology & In-

ternal Med.Mayo Found./Mayo Med. SchoolRochester, MN 55905

R. Mark WightmanDepartment of ChemistryIndiana UniversityBloomington, IN 47405

Wen-Hsun YangDept. of Pharmacol. & Tox .Univ. of Mississippi Med. Ctr .Jackson, MS 39216

Moussa B. H. YoudimDepartment of PharmacologyTechnion Faculty of MedicineHaifa, Israel

E. Albert ZellerDept. of Pathology & Lab. Med.Evanston HospitalEvanston, IL 60 201

Michael J. ZigmondUniversity of PittsburghPittsburgh, PA 15260

Richard E. ZigmondDepartment of PharmacologyHarvard Medical SchoolBoston, MA 02115

B. ZivkovicBiochemical Pharmacology GroupSynthelabo-LERS31 avo P . V. Couturier92220 Bagneux, France

xix

AbbreviationsAAB = ammonium hydroxide - ac­

etic acid bufferAAAD = aromatic amino acid de-

carboxylaseACTH = corticotropinADH = alcohol dehydrogenaseADP = adenosine diphosphateALDH = aldehyde dehydrogenaseALRED = aldehyde reductaseAMP = adenosine monophosphateAMPT = a-methyl-E-tyrosineAPM = apomorphineAPUD = Amine Precursors Uptake

and DecarboxylationAR = aldehyde reductaseATHA = adrenal TH activityATP = adenosine triphosphateATP-R = ADP-ribose phosphate

B = biopterinBCEE = B-carboline-3-carboxylic

acid ethyl esterBH2 = 7,8-dihydrobiopterinBH4 = S,6,7 ,8-tetrahydrobiop­

terinBP = blood pressureBPH4 = S,6,7,8-tetrahydrobiop­

terinBPRS = Brief Psychiatric Rating

ScaleBSA = bovine serum albumin

CA = catecholamine(slCaM = calmodulincAMP = cyclic AMPCDR = calmodulincGMP = cyclic GMPCHNH = cyclohexylethanolamineCNS = central nervous systemCOMT = catechol O-methyltrans-

feraseCONH = cyclooctylethanolamineCSF = cerebrospinal fluidCST = cervical sympathetic trunk

DA = dopaminedB-cAMP = DBcAMP = (dB)-c-AMP =

dibutyryl cAMPDBH = dBH = dopamine B-hydrox­

ylase

DCNP = dichloronitrophenolDDC = dopa decarboxylaseDDEP = 2,4-diamino-S-(3',4'-di-

chl or ophenyl l - 6- met hyl pyr i mi di neDE = detergent extractDHA = dihydroalprenololDHBA = 3,4-dihydroxybenzylamineDHPE = dihydroxyphenylethanol or

3,4-dihydroxyphenylethylamineDHPR = dihydropteridine reductaseDMPH4 = 6,7-dimethyltetrahydro­

pterindopa = DOPA = dihydroxyphenyl­

alanineDOPAC = dihydroxylphenylacetic

aciddopal = 3,4-dihydroxyphenylacet-

aldehydeOTT = dithiothreitol

E = epinephrineEact = energy of activationECS = electroconvulsive shockEOTA = ethylenediamine tetra-

acetic acidEGTA = ethylene glycol bis(B-am­

inoethyl ether)-N,N,N',N'-tetra­acetic acid

EKG = electrocardiographEPI = epinephrineEPR = electron proton resonanceESR = electron spin resonance

F-Pyd-P3 = 2-amino-6-(S~triphos­

phoribosyl)-amino-S(or 6)-form­amido-6-hydroxypyrimidine

GABA = y-aminobutyric acidGABA-T = GABA transaminaseGAD = glutamic acid decarboxylaseGBL = y-butyrolactoneGC/MS = GC-MS = gas chromatog-

raphy/mass spectrometryGHB = y-hydroxybutyrateGMP = guanosine monophosphateGMP-PNP = guanylimidodiphosphateGpp(NH)p = guanyl-S'-yl-imido-

phosphateGSG reduced glutathioneGTP = guanosine triphosphate

xxi

xxii

HA = hydroxylapatite6-HDA = 6-hydroxydopamineS-HlAA = SHlAA = S-hydroxyindole

acetic acidS-HICA = S-hydroxyindole-3-car­

boxylic acidHIOMT = hydroxyindole O-methyl­

transferaseHMPG = MHPGHPLC = high performance liquid

chromatographyHR = heart rateHRP = horse radish peroxidaseHS = 3'-hydroxysepiopterinHSPLX = hemisplanchnicotomyS-HTP = S-hydroxytryptophanHVA homovanillic acid

lAA indoleacetic acidicv ICV = intracerebroventric-

ularIg = immunoglobulinIMO = immobilizationi-NAMT = iso-N-acetylmethoxy-

tyramine

KRM = Krebs-Ringer medium

LC = liquid chromatographyL.C. = phospholipase CLCEC = liquid chromatography

with electrochemical detec­tion

L.D. = phospholipase DLDV = large dense cored ves­

iclesLSD = lysergic acid diethyl­

amide

MAO = monoamine oxidaseMAOI = MAO inhibitorMCR metabolic clearance rateMDH = malate dehydrogenaseMES = multiple equilibrium states

or (2-N-morpholino)-ethane sul­fonic acid

6-MePtH4 = 6-methyl-S,6,7,a­tetrahydropterin

m-HPAA = ~-hydroxyphenylacetic

acidMHPG = 3-methoxy-4-hydroxyphenyl­

glycol

MOPEG = MHPG6-MPH4 = 6-methyl-S,6,7,a-tetra-

hydropterinu-MPT = AMPTmRNA = messenger RNAm-TA = ~-tyramine

NA = NENA-4-DMM = N-acetyl-4-desmethyl­

mescalineNAT = arylamine N-methyltrans-

feraseNDE = non-detergent extractNE = norepinephrineNe = neopterinNeH4 = D~rythro-tetrahydro­

neopterinNeH2P3 = D-erythro-dihyroneop­

terin triphosphateNeH4P3 = tetrahydroneopterin

triphosphateNGF = nerve growth factorNHCP = non-histone chromosomal

proteinsNIMH = National Institute of

Mental HealthN-Me-S-HT = Nw-methyl-S-HTNMN(H) = reduced nicotinamide

mononucleotide

6-0HDA = 6-0H-DA = 60HDA6-hydroxydopamine

O.M. = outer membraneOMD 3-0-methyldopa

PAA = phenylacetic acidPAGE = polyacrylamide gel elec-

trophoresisPAR = phenylalanine hydroxylasePAP = peroxidase-antiperoxidasePAPS = 3'-phosphoadensoine-S'-

phosphosulfatePBS = phosphate buffered salineP-6-C = pterin-6-carboxylic acidPCA = £-chloroamphetaminepCPA ~-chlorophenylalanine

PDA = phosphodiesterasePEA = B-phenylethylamine or

phenylethanolaminePGE = prostaglandinPH = phenylalanine-4-hydroxylase

spiroperidolsuccinic semialdehyde

p-HPAA = £-hydroxyphenylaceticacid

Pi = inorganic phosphatePKP=protein kinase phosphor­

ylationPKU = phenylketonuriaPNMT = phenylethanolamine N-

methyltransferasePOMS = Profile of Mood StatesPST = phenolsulfotransferasep-TA = ~-tyramine

q-BH2 = quinonoid-dihydrobiop­terin

q-NeH2P3 = quinonoid-D-erythro­dihydroneopterin triphosphate

ROC = Research Diagnostic Cri-teria

RMS = root mean squareRNA = ribonucleic acidrRNA = ribosomal RNA

SAM = S-adenosylmethionineSAPN = sympatho-adrenal pre-

ganglionic neuronsSCG superior cervical ganglionSCN suprachiasmatic nucleusSDH succinate dehydrogenaseSDR semidehydroascorbate re-

ductaseSDS = sodium dodecyl sulfateSDV = small dense cored vesiclesSHAT = super high affinity trans-

portSHR = spontaneously hypertensive

ratSpiSSA

T = tryptamineTES = N-tris(hydroxymethyl)-2­

aminomethane sulfonic acidTH = tyrosine hydro~llase

THBC = l,2,3,4-tetrahydro-B­carboline

THP = tetrahydropapaverolineTIQ = l,2,3,4-tetrahydroisoquin-

olineTN = turnover numberTpH = tryptophan hydroxylaseTPOH = tryptophan hydroxylase

TRYP = tryptamineTY = tyramine

UMP = uridine monophosphate

VDE = vesicle detergent extractVE = vesicle(s)VMA = 4-hydroxy-3-methoxymandelic

acidVTA ventral tegmental area

WKY = Wistar-Kyoto rat

xxiii