Already published in this series: OLFACTION AND TASTE Edited by Y. Zottcrman, 1963. LIGHTING PROBLEMS IN HIGHWAY TRAFFIC Edited by E. Ingelstam, 1963. THE STRUCTURE AND METABOLISM OF THE PANCREATIC ISLETS Edited by S. E. Brolin, B. Hellman and H. Knut son, 1964. TOBACCO ALKALOIDS AND RELATED COMPOUNDS Edited by U. S. von Euler, 1965. MECHANISMS OF RELEASE OF BIOGENIC AMINES Edited by U. S. von Euler, S. Rosell and B. Uvnäs, 1966. COMPARATIVE LEUKAEMIA RESEARCH Edited by G. Winqvist, 1966. THE FUNCTIONAL ORGANIZATION OF THE COMPOUND EYE Edited by C. G. Bernhard, 1966. OLFACTION AND TASTE II EditedbyT. Hayashi, 1967. MAGNETIC RESONANCE IN BIOLOGICAL SYSTEMS Edited by A. Ehrenberg, B. G. Malmström and T. Vanngard, 1967. STRUCTURE AND FUNCTION OF INHIBITORY NEURONAL MECHANISMS Edited by C. von Euler, S. Skoglund and U. Soderberg, 1967. GROUND WATER PROBLEMS Edited by E. Eriksson, Y. Gustafsson and K. Nilsson, 1968. PHYSIOLOGY AND PATHOPHYSIOLOGY OF PLASMA PROTEIN METABOLISM Edited by G. Birke, R. Norbergand L.-O. Plantin, 1969. THE POSSIBILITIES OF CHARTING MODERN LIFE Edited by S. Erixon and Assisted by G. Ardwidsson and H. Hvarfner, 1970. EVALUATION OF NOVEL PROTEIN PRODUCTS Edited by A. E. Bender, R. Kihlberg, B. Lofqvist and L. Munck, 1970. VESTIBULAR FUNCTION ON EARTH AND IN SPACE Edited by}. Stahle, 1970. THE STRUCTURE OF METABOLISM OF THE PANCREATIC ISLETS Edited by S. Falkner, B. Hellman, and I. B. Taljedal, 1970. HUMAN ANTI-HUMAN GAMMAGLOBULINS Edited by R. Grubb and G. Samuelsson, 1971. STRUCTURE AND FUNCTION OF OXIDATION - REDUCTION ENZYMES Edited by A. Äkeson and A. Ehrenberg, 1972. CERVICAL PAIN Edited by N. Emmelin and Y. Zotterman, 1972. ORAL PHYSIOLOGY Edited by N. Emmelin and Y. Zotterman, 1972. CIRCUMPOLAR PROBLEMS: HABITAT, ECONOMY AND SOCIAL RELATIONS IN THE ARCTIC Edited by G. Berget al., 1973. DYNAMICS OF DEGENERATION AND GROWTH IN NEURONES Edited by K. Fuxe, L. Olson and Y. Zotterman, 1974. THE FUNCTIONAL ANATOMY OF THE SPERMATOZOON Edited by B. A. Afzelius, 1974. BASIC MECHANISMS OF OCULAR MOTILITY AND THEIR CLINICAL IMPLICATIONS Edited by G. Lennerstrand, Paul Bach-y-Rita, C. C. Collins, A. Jampolsky, and A. B. Scott, 1975. ANT1PSYCHOTIC DRUGS: PHARMACODYNAMICS AND PHARMACOKINETICS Edited by G. Sedvall, B. Uvnäs, and Y. Zotterman, 1976. GASTROINTESTINAL EMERGENCIES Edited by F. R. Barany and A. Torsoli, 1976. SENSORY FUNCTIONS OF THE SKIN IN PRIMATES Edited by Y. Zotterman, 1976. PHYSICAL WORK AND EFFORT Edited ftyGunnar Borg, 1976. NEUROGENIC CONTROL OF THE BRAIN CIRCULATION Edited by C. Owman and L. Edvinsson, 1977. DOPAMINERGIC ERGOT DERIVATIVES AND MOTOR FUNCTION Proceedings of an International Symposium held in The Wenner-Gren Center, Stockholm July 24-25, 1978 Edited by Kjell Fuxe Karolinska Institute Stockholm and Donald B. Calne N1H, Bethesda PERGAMON PRESS OXFORD · NEW YORK TORONTO · SYDNEY · PARIS · FRANKFURT U.K. Pergamon Press Ltd., Headington Hill Hall, Oxford OX3 OBW, England U.S.A. Pergamon Press Inc., Maxwell House, Fair view Park, Elmsford, New York 10523, U.S.A. CANADA Pergamon of Canada, Suite 104,150 Consumers Road, Willowdale, Ontario M2J 1P9, Canada AUSTRALIA Pergamon Press (Aust.) Pty. Ltd., P.O. Box 544, Potts Point, N.S.W. 2011, Australia FRANCE Pergamon Press SARL, 24 rue des Ecoles, 75240 Paris, Cedex 05, France FEDERAL REPUBLIC Pergamon Press GmbH, 6242 Kronberg-Taunus, OFGERMANY Pferdstrasse 1, Federal Republic of Germany Copyright © 1979 Pergamon Press Ltd. All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers. First edition 1979 British Library Cataloguing in Publication Data Dopaminergic Ergot Derivatives and Motor Function (Conference), London, 1978 Dopaminergic ergot derivatives and motor function. -(Wenner-Gren Center. International symposium series; vol. 31). 1. Extrapyramidal tracts - Diseases - Chemotherapy - Congresses 2. Ergot - Congresses I. Fuxe, Kjell II. Calne, Donald Brian III. Series 616.8 RC385 78-41333 ISBN 0-08-024408-4 In order to make this volume available as economically and as rapidly as possible the authors' typescripts have been reproduced in their original forms. This method unfortunately has its typographical limitations but it is hoped that they in no way distract the reader. Printed in Great Britain at William Clowes & Sons Limited Beccles and London LIST OF PARTICIPANTS Walter H. Aellig Roger C. Duvoisin Experimental Therapeutics Department Mount Sinai School of Medicine Sandoz Ltd 5th Avenue and 100th Street CH-4002 BASEL NEW YORK, N Y 10029 Switzerland USA Luigi Agnati Edward V. Evarts Department of Human Physiology Laboratory of Neurophysiology University of Bologna National Institute of Mental Health Italy 9000 Rockville Pike BETHESDA Michael J. Brownstein Maryland 20014, USA National Institute of Mental Health 9000 Rockville Pike Stanley Fahn BETHESDA College of Physicians and Surgeons of Maryland 20014, USA Columbia University 630 West, 168th Street Donald B· Calne NEW YORK, N Y 10032 National Institute of Neurological and USA Communicative Disorders and Stroke National Institutes of Health Bertil Fredholm Building 10, Room 6D20 Department of Pharmacology BETHESDA Karolinska Institute Maryland 20014, USA S-104 01 STOCKHOLM Sweden Thomas N. Chase National Institute of Neurological and Kjell Fuxe Communicative Disorders and Stroke Department of Histology National Institutes of Health Karolinska Institute BETHESDA S-104 01 STOCKHOLM Maryland 20014, USA Sweden Valerie B. Domesick Richard B* Godwin-Austen Mailman Research Center Department of Neurology McLean Hospital Nottinghamshire Area Health Authority 115 Mill Street South Nottingham District General BELMONT Hospital Massachusetts 02178, USA NOTTINGHAM NG1 6HA England Donald F.H. Dougan Department of Clinical Pharmacology Menek Goldstein St Vincents Hospital New York University Medical Center SYDNEY 2010 Room H 544 Australia 550 First Avenue NEW YORK, N Y 10016 USA ix X List of Participants Robert W. Griffith Harold L· KLawans Biological and Medical Research Department of Neurologic Sciences Sandoz Ltd Rush University CH-4002 BASEL 1725 W. Harrison Switzerland CHICAGO Illinois 60612, USA Ulla Gr^n Hyrdeengen 363 Edmund C. Kornfeld DK-2620 ALBERTSLUND Lilly Research Laboratories Denmark Eli Lilly and Company INDIANAPOLIS Hartmut Hauth Indiana 46206, USA Sandoz AG CH-4002 BASEL Christer Köhler Switzerland Astra Läkemedel AB S-151 85 SÖDERTÄLJE Edwin Hedman Sweden Lilly Research Laboratories William N. Wishard Memorial Louis Lemberger Hospital Lilly Laboratory for Clinical Research 1001 West Tenth Street Wishard Memorial Hospital INDIANAPOLIS INDIANAPOLIS Indiana 46202, USA Indiana 46202, USA Reinhard Horowski Abraham N. Lieberman Schering AG 566 First Avenue Klinische Forschung NEW YORK, N Y 10016, USA Müllerstrasse 178 D-1000 BERLIN 65 Dieter M. Loew Westgermany Biological and Medical Research Division E. Anthony Jones Sandoz Ltd Liver Unit Kohlenstrasse National Institutes of Health CH-4002 BASEL BETHESDA Switzerland Maryland 20014, USA Maynard H. Makman JohnW. Kebabian Department of Biochemistry National Institutes of Health Albert Einstein College of Medicine BETHESDA 1300 Morris Park Avenue Maryland 20014, USA BRONX, N Y 10461, USA Procerfina R. Kebabian C. David Marsden National Institutes of Health Institute of Psychiatry BETHESDA De Crespigny Park Maryland 20014, USA Denmark Hill LONDON SE5 8AF, England Wolfgang Kehr Schering AG Marcello M. Nardini Department of Neuropsychopharmacology Department of Neurology Müllerstrasse 170-178 University School of Medicine D-1000 BERLIN University of Siena Westgermany Piazza Duomol 1-53100 SIENA Italy List of Participants xi John L. Reid Michael O. Thorner Department of Clinical Pharmacology School of Medicine Royal Postgraduate Medical School University of Virginia Medical Center Ducane Road Box 252 LONDON W 12 CHARLOTTESVILLE England Virginia 22901, USA U.K. Rinne Marco Trabucchi Department of Neurology Institute of Pharmacology University of Turku University of Milan SF-20520 TURKU Via Vanvitelli 32 Finland 1-20129 MILAN Italy Robert Schwarcz Department of Histology Urban Ungerstedt Karolinska Institute Department of Histology S-104 01 STOCKHOLM Karolinska Institute Sweden S-104 01 STOCKHOLM Sweden Ellen K. Silbergeld National Institutes of Health Denis Wade BETHESDA Department of Clinical Pharmacology Maryland 20014, USA University of New South Wales St. Vincent's Hospital Pier F. Spano Darlinghurst Department of Pharmacology SYDNEY University of Milan Australia 2021 Via Vanvitelii 32 1-20129 MILAN Judith R. Walters Italy National Institutes of Health BETHESDA Gerald Stern Maryland 20014 University College Hospital USA LONDON WC1E 6AU England Adrian C. Williams National Institutes of Health Carol Tamminga BETHESDA National Institute of Neurological and Maryland 20014 Communicative Disorders and Stroke USA National Institutes of Health BETHESDA Maryland 20014, USA PREFACE On July 24th and 25th, 1978, an international· symposium on "Dopaminergic Ergot Derivatives and Motor Function" was held at the Wenner-Gren Center, Stockholm. Forty-two participants presented thirty-eight papers. The first day was devoted to laboratory studies and the second to clinical research. The purpose of the meeting was to review the current state of knowledge of dopaminergic mechanisms involved in motor function in the central nervous system. Ergot derivatives were chosen as a starting point in this endeavor since these compounds have proved so useful in elucidating dopaminergic synaptic events in recent years, and they have been employed for the practical application of new knowledge to a clinical setting - the treatment of extrapyramidal disease in man. Topics covered on the 24th of July included the anatomy, physiology, bio chemistry and pharmacology of dopaminergic pathways in the brain. Also the mechanism of action of ergot drugs at monoamine synapses was extensively discussed. Perhaps the most important conclusion to be drawn from this session was the contribution that ergots are making to the identification of different cate gories of dopaminergic receptor. On the 25th of July clinical studies with dopa minergic receptors were reported in Parkinsonism, Huntington^ disease, the Shy-Drager syndrome and the Steele-Richardson-Olzewsky syndrome. Observa tions on both therapeutic activity and toxicity were considered; while it was generally agreed that dopaminergic ergots are potent antiparkinson agents, there was a rather wide range of views on their therapeutic usefulness. One theme discernible throughout this symposium was a conviction that the meeting was taking place at a time when the subject of the meeting was still evolving. Many new ergoline and ergopeptine compounds were being synthesized and undergoing early development; it is probable that when these agents become freely available for laboratory and clinical study, they will help to resolve many of the questions which could not be answered in the summer of 1978. It will be of great theoretical and clinical value if among these new ergot compounds drugs can be developed with a high selectivity for various types of dopamine receptors. We wish to thank the following for their generous financial support which allowed this symposium to be held: — The National Institute of Neurological and Communicative Disorders and Stroke; The Swedish Medical Research Council; The Wenner-Gren Center Foundation; Sandoz Ltd; Schering AG; Eli Lilly and Company. K. Fuxe D.B. Calne Karolinska Institutet National Institute of Neurological and Stockholm Communicative Disorders and Stroke Bethesda xiii THE ANATOMY OF THE EXTRAPYRAMIDAL SYSTEM WALLE J.H.NAUTA and VALERIE B. DOMESICK Massachusetts Institute of Technology, Cambridge, Ma 02139, USA, and Mailman Research Center, McLean Hospital, Belmont, Ma 02178, USA INTRODUCTION The term, extrapyramidal system, introduced by S.A.K. Wilson (94) in 1912, has never been adequately defined anatomically. Although literally the term can be interpreted so as to denote all of the brain's effector mechanisms that do not involve the pyramidal tract, convention over the years has made it very nearly synonymous with the basal ganglia and their efferent connections. The much older term, basal ganglia, originally referred to all of the gray masses at the base of the cerebral hemisphere, including even the thalamus, but gradually became restricted to the corpus striatum (striatum and pallidum) and only recently has come to include also two smaller structures, the subthalamic nucleus and substantia nigra, both linked to the corpus striatum by reciprocal fiber connections. On a solid basis of clinico-pathological evidence it can be assumed that the basal ganglia are involved first and foremost in skeletomuscular mechanisms (Ref. 21). The efferent connections of the basal ganglia are compatible with this notion at least in part, but neither physiological nor anatomical findings thus far have offered a ready explanation for the peculiar nature of the movement disorders resulting from pathology of the basal ganglia. In the following sections of this contribution the neural circuitry of the basal ganglia is reviewed in some detail, with no more than occasional reference to the neurophysiological and neurochemical evidence discussed in other chapters of this volume. STRIATUM It is appropriate to begin a survey of the extrapyramidal circuitry at the striatum, for it is this structure, rather than the pallidum, that receives the principal extrinsic afferents of the corpus striatum. In all primates and many non-primate mammals the striatum is subdivided by a plate-like internal capsule into two districts, the dorsomedial caudate nucleus and the ventrolateral putamen. In other mammalian forms, including the rat, the anterior part of the internal capsule passes through the striatum in the form of a brush rather than a plate; in such forms the striatum lacks clear subdivision and is therefore often referred to as caudatoputamen. All districts of the striatum exhibit basically the same cytoarchitecture: throughout its extent more than 98% of its neurons are small to medium-sized while the remaining 1-2 percent is made up of large multipolar cells with we 11-developed Nissl bodies (Ref. 60). Most of the smaller cells probably correspond to the so-called spiny neurons reported from studies by the electron microscope and the Golgi method (Refs. 49,50,53,30). These neurons are characterized by numerous dendritic spines on all but the most proximal dendritic segments. A much smaller number of small cells, the so-called spidery neurons 3 4 W.J.H. Nauta and V.B. Domesick (Ref. 32) have smooth dendrites, but are distinct by their small size from the large 'aspiny neurons' which correspond to the large multipolar cells seen in Nissl preparations. It was initially assumed that efferent connections of the striatum originate exclusively from the large aspiny neurons (Ref. 32), whereas the smaller cells were thought to be intrinsic striatal neurons. This notion, dating back to C. and O. Vogt (88), seemed supported by evidence that all of the principal striatal afferent systems terminate largely in contact with spiny striatal neurons (Refs. 2,50,53,30,32,1). The results of more recent retrograde-labeling experiments, however, suggest instead that most striatofugal fibers to the globus pallidus and substantia nigra originate from medium-sized rather than large neurons (Refs. 38,23,9,5). Afferent Connections of the Striatum The striatum, appropriately considered the main neural entrance portal of the basal ganglia, receives three major projections arising from, respectively, the cerebral cortex, the intralaminar thalamic nuclei, and the substantia nigra. The corticostriate connection. Fiber-degeneration studies have demonstrated that virtually all regions of the cerebral cortex project to the striatum in a pattern that is topographically organized so that it by and large preserves the topology of the cortical mantle (Refs. 92,93,11,12,52). The mosaic of the projection is, however, not sharply defined, and the degree of overlap is such that few if any parts of the striatum are projected upon by a single cortical area. The projection from the sensorimotor cortex, most widely distributed, may be the only corticostriatal projection that is bilateral (Refs. 12,56). The scheme of corticostriatal topography inferred from findings in fiber-degeneration studies may require some revision. Recent autoradiographic studies have shown that the precentral cortex of the monkey projects almost exclusively to the putamen (Ref. 56) rather than to both putamen and caudate nucleus as previously reported (Ref. 52), and that the frontal cortex projects to the entire length of the caudate nucleus rather than exclusively to the latter's caput (Ref. 35). Future autoradiographic studies may reveal additional inaccuracies in current schemes, but are unlikely to invalidate the notion that all cortical regions project to the striatum in a reasonably well-defined topographic pattern, and that all parts of the striatum receive corticostriate fibers. Nucleus accumbens. The preceding statement needs a proviso for the nucleus accumbens. Unlike the rest of the striatum, this anterior region of the fundus striati, "leaning against the septum" and extending ventrally as the small-celled core of the olfactory tubercle, receives its telencephalic afferents not from the neocortex but from the hippocampus (Refs. 80,11,72). Since it is also projected upon by the amygdala (Ref. 22), the nucleus accumbens appears as that part of the striatum which is associated with the limbic system rather than with the neocortex. Its ventral extension, the parvicellular core of the olfactory tubercle, likewise receives projections from the amygdala, but may receive further telencephalic afferents from the olfactory cortices at the base of the cortical mantle. Thalamostriate connectjons. The only thalamostriate projections known thus far originate from the intralaminar or non-specific thalamic cell groups, in particular from the parafascicular nucleus and centrum medianum (together forming the so-called CM-PF complex). That CM-PF projects to the putamen was observed first by C. and O. Vogt (89) in the human, and confirmed later in experimental animals (Refs. 68,71,63,47). The topographic pattern of the thalamostriate projection has not been elaborated in detail, but The Anatorny of the Extrapyramidal System 5 several of the aforementioned studies suggest that the more rostral intralaminar nuclei project to more rostral parts of the striatum; the nucleus accumbens, for example, receives its thai ami c afferents from the parataenial nucleus (Refs. 19,82). The nigrostriatal projection. The existence of a massive nigrostriatal projection had been suspected since the beginning of the century from observations of rapid cell-atrophy in the substantia nigra following extensive destruction of the striatum, but attempts to demonstrate the connection directly by fiber-degeneration methods succeeded only after the introduction of the Fink-Heimer method in 1966. Already several years earlier, however, Anden et al. (3) by the monoamine-histofluorescence method had provided the first direct evidence of a nigrostriatal fiber system originating from the dopamine neurons of the substantia nigra. The observations of Anden et al. were confirmed in numerous subsequent histofluorescence studies. The anatomical trajectory of the nigrostriatal projection was charted in detail by Lindvall and Bjorklund (58). Hokfelt and Ungerstedt (45) reported evidence that nigrostriatal fibers end in axon terminals containing small granular vesicles; other electron-microscopic studies showed that these terminals synapse with dendritic spines (Ref. 50) as well as with cell bodies of spiny neurons and dendrites of spidery neurons (Ref. 32). As to the topographic organization of the nigrostriatal projections, Anden et al. (4) and Ungerstedt (87) subdivided the nigrostriatal dopamine system into I. a nigrostriatal system from the dopamine neurons of the substantia nigra's pars compacta sensu strictori (ceTT group A9 of Dahlstrom and Fuxe (20)) to the larger part of the striatum, and 2. a component, called mesolimbic system by Ungerstedt (87) from dopamine cell group AlO to the nucleus accumbens and olfactory tubercle. Cell group AlO in the rat forms a large, dorsomedially oriented, curved-wedge-shaped mass of dopamine cells protruding from the medial half of the nigra's pars compacta into the ventral tegmental area of Tsai. A smaller dorsal excrescence of the pars compacta at more caudal and lateral levels of the nigra, connected with AlO by cell bridges (Refs. 87,70,65), forms dopamine cell group A8 of Dahlstrom and Fuxe (20). Both AlO and A8 lie embedded in the mainstream of the medial forebrain bundle, and thus seem likely to receive major inputs from the preoptic region, hypothalamus, and substantia innominata (Ref. 65). Their direct continuity with the pars compacta plainly identifies AlO and A8 as outlying components of the substantia nigra, and the projections of these cell groups to the striatum should therefore be viewed as part of the nigrostriatal system in the wider sense, despite the subdividing terms, nigrostriatal and mesolimbic. The general principle of nigrostriatal topography stated by Anden et al. (4) and Ungerstedt (87) could be confirmed and somewhat amplified in more recent anterograde- and retrograde-labe ling studies in the rat (Refs. 25,27,67,7). In these studies, the heaviest projection from AlO was found to involve not only the nucleus accumbens and olfactory tubercle but the entire length of the fundus striati (of which the accumbens forms an anterior part). Moreover, the AlO projection in gradually diminishing volume extends dorsally from the fundus region so as to involve almost the entire medial half of the overlying caudatoputamen, in overlap with the nigrostriatal projection from the medial half of the pars compacta. Observations in this laboratory indicate that nigrostriatal fibers originating from A8, although avoiding the medial part of the nucleus accumbens, likewise are distributed in greatest number to the fundus region; this projection likewise spreads dorsally from the fundus, but its spread involves largely the lateral half of the caudatoputamen where it overlaps the projection from the lateral half of the pars compacta. Thus, the nigrostriatal projection from the outlying nigral cell groups AlO and A8, although distributed in greatest volume to the fundus striati, overlaps the nigrostriatal projection from the pars compacta throughout most of the larger rest of the striatum. The converse, however, is not true: in the rat the fundus region lying anterior to the temporal limb of the anterior commissure and composed largely of the nucleus accumbens and olfactory tubercle, in contrast to more posterior fundus regions, receives nigral afferents almost exclusively from AlO and A8 (Ref. 67,7). The nucleus accumbens and