Table Of ContentPHARMACOLOGY
OF THE HYPOTHALAMUS
PHARMACOLOGY
OF THE
HYPOTHALAMUS
Proceedings of a British Pharmacological Society
International Symposium on the Hypothalamus
held on Thursday, September 8th, 1977
at the University ofM anchester, U.K.
Edited by
B. COX, I. D. MORRIS
and
A. H. WESTON
Department of Pharmacology, Materia Medica and Therapeutics
University ofM anchester, U.K.
M
© B. Cox, I. D. Morris and A. H. Weston 1978
Softcover reprint of the hardcover 1st edition 1978 978-0-333-22606-3
All rights reserved. No part of this publication may be reproduced or transmitted,
in any form or by any means, without permission.
First published 1978 by
THE MACMILLAN PRESS LTD
London and Basingstoke
Associated companies in Delhi Dublin
Hong Kong Johannesburg Lagos Melbourne
New York Singapore and Tokyo
Typeset by Reproduction Drawings Ltd, Sutton, Surrey
British Library Cataloguing in Publication Data
International Symposium on the Hypothalamus,
University ofM anchester, 1977
Pharmacology of the hypothalamus.
(British Pharmacological Society. Symposia).
1. Psychopharmacology-Congresses
2. Hypothalamus-Congresses
I. Title II. Cox, Barry, b. 1937
III. Morris, I. D. IV. Weston, A. H.
V. Series
615'.78 RM 315
ISBN 978-1-349-03508-3 ISBN 978-1-349-03506-9 (eBook)
DOI 10.1007/978-1-349-03506-9
This book is sold subject to the standard conditions of the Net Book Agreement
The generous financial contributions of the following organisations are gratefully
acknowledged:
Allen and Hanburys
Astra Chemicals
Ayerst Laboratories
Boehringer lngelheim
Ciba Laboratories
Geigy Pharmaceuticals
Hoechst U.K.
ICI Pharmaceuticals Division
Janssen Pharmaceuticals
Leo Laboratories
Organon Scientific Development Group
Sandoz Products
Schering AG
Smith Kline and French Laboratories
Stuart Pharmaceuticals
Wellcome Trust
Winthrop Laboratories
Symposium speakers
W. Feldberg, National Institute for Medical Research, Mill Hill, London,
NW7 1AA, UK
B. Halasz, Second Department of Anatomy, Histology and Embryology,
Semmelweis University Medical School, Tuzolt6 u. 58, 1094 Budapest,
Hungary
K. Fuxe, Department of Histology, Karolinska Institutet, Stockholm, Sweden
J. S. Kelly, MRC Neurochemical Pharmacology Unit, Department of Pharmacology,
Medical School, Hills Road, Cambridge, CB2 2QD, UK
A. S. Milton, Department of Pharmacology, University Medical Buildings,
Foresterhill, Aberdeen, AB9 2ZD, UK
E. Fluckiger, Biological and Medical Research Division, Sandoz Ltd, Ch-4002 Basle,
Switzerland
A. V. Schally, Endocrine and Polypeptide Laboratory, Veterans' Administration
Hospital, 1601 Perdido Street, New Orleans, Louisiana 70146, USA
G. M. Besser, Department of Endocrinology, St. Bartholomew's Hospital Medical
College, London, ECIA 7BE, UK
L. Martini, Universita di Milano, Instituto di Endocrinologia, Via A. del Sarto 21,
20129 Milano, Italy
Contents
Bodies from whom financial support was received v
Symposium speakers vi
Preface iX
Introduction. W. Feldberg 1
1. Functional anatomy of the hypothalamus. B. Halasz 5
2. The transmitters of the hypothalamus. K. Fuxe, T. Hokfelt,
K. Andersson, L. Ferland, 0. Johansson, D. Ganten, P. Eneroth,
J.-A. Gustafsson, P. Skett, S. I. Said and V. Mutt 31
3. Pharmacology of the hypothalamic neurones. J. S. Kelly and
L. P. Renaud 63
4. The hypothalamus and the pharmacology of thermoregulation.
A. S. Milton 105
5. Ergot alkaloids and the modulation of hypothalamic function.
E. Fhickiger 137
6. Hypothalamic peptide hormones and their analogues.
A. V. Schally, D. H. Coy, A. Arimura, T. W. Redding,
A. J. Kastin, C. Meyers, J. Seprodi, R. Chang, W.-Y. Huang,
K. Chihara, E. Pedroza, J. Vilchez and R. Millar 161
7. Evaluation of clinical disturbances of the hypothalamus.
G. M. Besser 207
8. The hypothalamus as an endocrine target organ. L. Martini 227
Author Index 247
Subject Index 264
Preface
When Ian Morris proposed that a symposium on the pharmacology of the hypo
thalamus should be held during the September, 1977 meeting of the British
Pharmacological Society in Manchester the idea was immediately accepted, since
recent advances in this field suggested that the theme would be of widespread
interest.
In the time available it was impossible to include all aspects of hypothalamic
function and so a programme was selected which attempted to stress new develop
ments and to relate experimental findings to potential therapeutic applications.
Interest in this research field and its importance was emphasised by the fact that
some 500 people attended the symposium. Moreover the editors note with pleasure
the award of the Nobel Prize in Medicine to one of the contributors, A. V. Schally,
shortly after the meeting. No causal relationship is claimed!
We gratefully thank all the organisations (listed earlier) who provided generous
financial support and also the academic, secretarial and technical staff of the
Department of Pharmacology at Manchester University without whose help neither
the symposium itself nor this publication would have been possible. We are grateful
to L. Martini, who chaired the afternoon session, for providing an additional
chapter and we also thank the speakers themselves whose stimulating contributions
played such an important role in the success of the symposium.
Manchester, 1978 B.C.
I. D. M.
A.H.W.
Introduction
W. Feldberg*
A good way to explain present-day politics is to go back to Adam and Eve, to
show how they looked upon their problems and then how the problems have
developed over the centuries. Although the hypothalamus is one of the most
ancient parts of the vertebrate forebrain, speaking phylogenetically, we need not
go quite as far back as that in order to explain its functioning. Physiologists can
stay in the twentieth century. For instance, in the 1900 edition of Schaefer's
famous textbook of physiology, the hypothalamus is not mentioned at all, either
in the index or in the chapter which deals with the parts of the brain below the
cerebral cortex. This chapter was written by no less a person than Sherrington.
The anatomist has to go a little further back in history because in 1865 a brain
atlas was published by Luys in which the hypothalamus is described as the
nucleus of Luys.
The first evidence for a physiological function of the hypothalamus was
obtained in 1909 by Karplus and Kreidl (1909). They showed that its electrical
stimulation caused a discharge in the cervical sympathetic nervous system which
led to pupillary dilatation, opening of the eyes and withdrawal of the nictitating
membranes. Later, it was shown that practically every effect mediated by the
sympathetic nervous system can be reproduced by its electrical stimulation. The
sympathetic nervous system is, as we say today, represented in the hypothalamus.
Recently, Wei and I (Feldberg and Wei, 1977; 1978), analysing the cardio
vascular effects of morphine, have been able to influence selectively the sympath
etic discharge from the hypothalamus to one organ, the heart. Injected into the
third cerebral ventricle of anaesthetised cats, morphine produces pronounced
cardio-acceleration without signs of a sympathetic discharge to other organs, for
instance, to the muscles of the eye, to the pupils or nictitating membranes.
The upper record of figure 0.1 shows the morphine tachycardia. On injection
at the arrow of 400 J.lg of morphine into the third ventricle, heart rate rises from
200 to 330 per minute. The lower record shows the associated pressor response
resulting from the cardiac effect because after removal of both stellate ganglia,
both tachycardia and pressor response are abolished. Morphine thus induces,
probably through an action on the paraventricular nuclei, a sympathetic dis
charge to the heart alone without even affecting vasomotor tone.
But to return to the early history. We go back to 1914 because in that year
Isenschmid and Schnitzler (1914) found that the chief mechanism for the con
trol of body temperature was localised in the hypothalamus. But it was not
until 1932 that Keller and Hare (1932) demonstrated that without its hypo-
*National Institute for Medical Research, Mill Hill, London, NW7 1AA
1
2 W. Feldberg
340
320
300
~ 280
::!:
c;;-
!;:{ 260
w
a:l
~ 240
<{
w
:::c 220
J'\
120
Cl
:::c 100
E
E
c.. 80
a:l t
60
30 60 90
Min
Figure 0.1 Pulse rate per minute (top record) and mean arterial blood pressure
(bottom record) from a cat anaesthetised with chloralose. A Collison cannula was
implanted into the third cerebral ventricle and the aqueduct cannulated. At the
arrow, injection of 400 pg of morphine sulphate into the third ventricle. (After
Feldberg and Wei, unpublished observations)
thalamus the rabbit had lost completely its ability to maintain constant temp
erature, and that it was unable to shiver. It exhibited, however a remarkable
release of the heat-loss mechanism: merely pressing the tail elicited typical
panting.
This early anatomical dissociation between the sites for heat-producing and
heat-eliminating mechanisms is of particular interest to those who study the
pharmacology of body temperature and use the method of injecting drugs into
the cerebral ventricles. Many drugs applied in this way appear to be unable to
discriminate between the synapses: they produce strong shivering with a rise in
body temperature, but at the same time panting.
In the 1920s and 1930s our knowledge of the hypothalamus advanced rapidly.
In 1940 a symposium was held in the USA entitled The Anatomy, Physiology and
Ginical Significance of the Hypothalamus. From the title it is evident that the
