Dopaminergic Ergot Derivatives and Motor Function. Proceedings of an International Symposium Held in the Wenner–Gren Center, Stockholm, July 24–25, 1978

422 Pages·1979·17.909 MB·English

by  Kjell Fuxe and Donald B. Calne (Eds.)

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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
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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