Preclinical Psychopharmacology

479 Pages·1985·7.339 MB·English

by  D.G. Grahame-Smith (Eds.)

PSYCHOPHARMACOLOGY 2
A critical survey
of recent literature
1985
ELSEVIER, Amsterdam - New York - Oxford
Part 1:
PRECLINICAL
PSYCHOPHARMACOLOGY
Editor:
D.G. GRAHAME-SMITH
Associate editor:
P.J. COWEN
MRC Clinical Pharmacology Unit,
University Department of Clinical Pharmacology,
Radcliffe Infirmary, Oxford, UK
1985
ELSEVIER, Amsterdam - New York - Oxford
© Elsevier Science Publishers B.V. 1985
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ISBN 0 444 90350 χ
ISBN Series 0 444 90294 5
Notice The editors and publishers of this work have made every effort to ensure that the
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Contributors
S. CASTELLANI B.D. GREENBERG
Department of Psychiatry Department of Psychiatry
University of Kansas School of School of Medicine
Medicine-Wichita University of California
1010 N. Kansas San Diego
Wichita KS 67214, USA
La Jolla CA 92093, USA
E.H. ELLINWOOD
Department of Psychiatry and W. HAEFELY
Pharmacology Pharmaceutical Research Department
Duke University Medical Center F. Hoffmann-La Roche & Co. Ltd.
P.O. Box 3870 CH-4002 Basel, Switzerland
Durham NC 27710, USA J.P. HUIDOBRO-TORO
Laboratory of Pharmacology
J.P.M. FINBERG Department of Physiological Sciences
Faculty of Medicine Faculty of Biological Sciences
Technion - Israel Institute of Catholic University of Chile
Technology Casilla 114-D
12 Haalyah Street Santiago 1, Chile
Haifa, Israel
B.L. JACOBS
G.M. GOODWIN Program in Neuroscience
MRC Clinical Pharmacology Unit Department of Psychology
University Department of Clinical Princeton University
Pharmacology Princeton NJ 08544, USA
Radcliffe Infirmary
Woodstock Road S. KNAPP
Oxford OX2 6HE, UK Department of Psychiatry
University of California School of
A.R. GREEN Medicine
MRC Clinical Pharmacology Unit La Jolla CA 92093, USA
University Department of Clinical
Pharmacology B.E. LEONARD
Radcliffe Infirmary Department of Pharmacology
Woodstock Road University College
Oxford OX2 6HE, UK Galway, Ireland
ν
H.J. LITTLE D.S. SEGAL
University Department of Department of Psychiatry
Pharmacology School of Medicine
South Parks Road University of California
Oxford OX1 3QT, UK San Diego
La Jolla CA 92093, USA
A. METZ
MRC Clinical Pharmacology Unit E. LEONG WAY
University Department of Clinical Department of Pharmacology
Pharmacology School of Medicine
Radcliffe Infirmary University of California
Woodstock Road San Francisco CA 94143, USA
Oxford OX2 6HE, UK
D.R. WING
D.J. NUTT University Department of
MRC Clinical Pharmacology Unit Pharmacology
University Department of Clinical South Parks Road
Pharmacology Oxford OX1 3QT, UK
Radcliffe Infirmary
Woodstock Road M.B.H. YOUDIM
Oxford OX2 6HE, UK Faculty of Medicine
Technion - Israel Institute of
R.G. PERTWEE Technology
Department of Pharmacology 12 Haalyah Street
University of Aberdeen Haifa, Israel
Marischal College
Aberdeen AB9 IAS, UK
R.M. RIDLEY
Division of Psychiatry
Clinical Research Centre
Watford Road
Harrow
Middlesex HAI 3UJ, UK
vi
Introduction
Sometimes it is not too wise to examine closely the meaning of words which have
by usage become accepted into the language. Psychopharmacology is one of these
words. We know it has something to do with drugs and pharmacology and that
somehow or other, mental processes are affected by drugs, but what the word does
not tell us is that between the drugs and the mind is the brain (at least, that is the
conventional scientific wisdom and here is not the place for a philosophical discus-
sion on that).
It is a fact that most of the drugs effective in the treatment of mental illness were
discovered by serendipity with subsequent trial and error as to indications and full
evaluation of a place in therapeutics. It seems likely that this empirical approach
to the development of psychopharmacological therapy will continue for some time.
There are so many gaps in the knowledge necessary to allow a straightforward
rational approach to the design of molecules which will predictably alter human
psychological processes. First, our knowledge of the (human and non-human)
brain's integrated function is still rudimentary. Second, our knowledge of the
molecular processes in the brain underlying any of the major psychiatric illnesses
is essentially nil. Third, however much we may protest, there is no reliable animal
model for any of the psychiatric illnesses afflicting man. These three factors make
predictable and rational progress in the therapeutic aspects of psychopharmacology
extremely uncertain.
Drugs are important though, not only as medicines but also as a means of
probing brain function (another sphere of activity of the psychopharmacologist).
Drugs are exogenous molecules which interact with endogenous molecules to
set in train a sequence of events by which a biological process is manipulated.
When this molecular interaction is put to therapeutic ends a disordered physiolog-
ical process is either returned to normal or altered in such a way that the symptoms
or manifestations of the illness are ameliorated.
Two points follow from this that are relevant to the biology of normal and
abnormal mental function and which, although self-evident, are nonetheless worth
stating.
1. Whatever the rationale for the use of the drug in mental illness, if the drug
can be shown by properly conducted clinical trial to produce benefit, then at some
level a potentially definable biological process is involved.
2. It is likely that an understanding of the action of a drug from studies in man,
animals, intact organs, cells, particles, or at the molecular level might provide
some insight into the pathological process involved in the mental illness. A similar
line of reasoning can be adopted for those drugs which mimic certain manifesta-
tions of mental illness, for instance reserpine and α-methyl-p-tyrosine producing
ix
depression, hallucinogens producing anxiety and hallucinations; or even simple
mental changes, e.g. morphine producing tranquillity, euphoria and analgesia.
These 'symptomatic' changes produced by drugs must tell us something about the
physical basis of mental processes.
There is, however, a trap for the unwary in all this, which frequently claims
victims. An analogy with physical illness is useful here. Suppose we knew as little
about the pathophysiology of heart failure as we do of brain function in mental
illness. Suppose too that by serendipity a powerful diuretic was discovered and
used empirically and with benefit in this uncharted syndrome of 'heart failure'. If
the mode of action of this drug was then investigated, the investigations would
reveal that its action was on the kidney and the conclusion would be drawn quite
wrongly that the syndrome of 'heart failure' was due to a primary disturbance in
renal tubular sodium excretion. We know, of course, this renal tubular functional
change is a 'normal' response to the altered hemodynamic state produced by the
heart failure, and although a renal abnormality is involved, excessive and undi-
vided attention upon it would distract from the primary cause of heart failure.
Consider schizophrenia in this light. There is a very impressive correlation be-
tween the ability of phenothiazines and other neuroleptics to block the actions of
dopamine in the brain and their antipsychotic potency. In addition, the similarity
between amphetamine psychosis and paranoid schizophrenia, coupled with the
actions of amphetamine in releasing brain dopamine, also fits into this picture.
This has led to the proposition of a 'dopamine hypothesis' for the causation of
schizophrenia. It is difficult to be sure exactly what is meant by 'the dopamine
hypothesis' of schizophrenia except that it implies that somehow or other a distur-
bance or 'an overactivity' of dopaminergic neuronal function is involved. This may
be so but it would be naive at this stage to consider it a primary disturbance.
The neuroleptics could equally well be acting at a secondary level. Considering
that curare would prevent any physical violence ensuing from a schizophrenic
paranoid delusion, it would be foolish therefore to invoke a 'peripheral cholinergic
hypothesis' as the cause of paranoid schizophrenia. There is nothing in the indirect
evidence culled from drug studies that implicates dopaminergic mechanisms in
schizophrenia which convincingly shows that an abnormality in dopaminergic
function is a primary etiological factor. Indeed, just as the kidney during heart
failure responds in a normal physiological manner to the change in the
hemodynamic state produced by heart failure, it might be that the dopaminergic
systems in the brain are functioning as a normal response to some other more
fundamental disturbance. The neuroleptics would then dampen down this over-ac-
tivity without affecting the primary disturbance. So before drawing too firm conclu-
sions from the clinical effects and pharmacological actions of drugs, this point
should be borne in mind.
This is not to say that a knowledge of drug action does not allow 'a way in'. It
certainly does, and if there is an entry into the problem of brain dysfunction in
mental illness, even at a secondary level, then this can be a starting point from
which progress can be made.
With many psychopharmacological treatments, therapeutic responses may be
delayed, e.g. with antidepressants; side effects may ensue from chronic treatment,
χ
e.g. tardive dyskinesias with chronic neuroleptic therapy. It is becoming more
apparent that a number of the important effects of psychotropic drugs may result
from adaptive pharmacological changes occurring in the brain as a result of drug
treatment. The contributions in our book show that this is proving a fertile field
for exploration.
This first volume on preclinical psychopharmacology has been constructed with
all the above points in mind. The contributors are all fully aware of the importance
of preclinical psychopharmacology to its clinical application, and we hope that this
discussion of the preclinical pharmacology of psychotropic drugs with its bias to-
ward clinical relevance will be useful both to practising psychiatrists, to help hem
understand the basis of their drug therapy, and to neuropharmacologists, in their
appreciation of the link between basic neuropharmacology and clinical psychophar-
macology.
P.J. COWEN D.G GRAHAME-SMITH
xi
Introduction
to the second volume
The first volume of Psychopharmacology was well received and we have therefore
maintained the same format for the second volume. All the chapters have been
entirely re-written to take full account of the rapid developments in preclinical
psychopharmacology. In addition, we are pleased to include in this volume a chap-
ter on cocaine by Drs Castellani and Ellinwood; we also welcome Drs Goodwin
and Metz, who have this time contributed the chapter on neuroleptics, and Drs
Greenberg and Segal, who co-authored the chapter on hallucinogens.
In the first volume we noted the trend for studies of psychotropic drugs to
concentrate more on the adaptive changes in the brain produced by longer term
drug treatment. This focus of interest has continued and is well represented in the
present volume where a number of valuable insights, particularly concerning the
mechanism of action of antidepressant drugs and neuroleptics, are discussed. In
addition, there is increased awareness of the importance of the interaction between
different neurotransmitter systems in both functional and biochemical conse-
quences of repeated drug administration. This seems likely to lead to an increasing
sophistication in our knowledge of how psychotropic drugs affect the brain.
Clinically one cannot help but be reminded of the limitations of present-day
psychotropic medication. A major reason for investigating the fundamental
mechanism of action of psychotropic drugs is to assist in the development of new
pharmacological methods of treating psychiatric illness. In this respect we believe
that the accounts given in this volume of both peptide transmitters and novel
ligands for the benzodiazepine receptors offer particular promise for the future.
As with the first volume, the present publication has been designed to be of use
to neuropharmacologists and practising psychiatrists, and it is our hope that both
groups of workers will gain as much from the book as we have in compiling it.
P.J. C.
D.G. G.-S.
xii
1. Antidepressants
A.R. Green and DJ. Nutt
INTRODUCTION
In the previous volume (1) we pointed out that studies on the biochemistry and
pharmacology of antidepressant treatments were increasingly using longer-term
administration of drugs (14-21 days) since the results obtained were more likely
to have clinical relevance. This trend has continued and the majority of the studies
reviewed in this chapter have examined the consequences of longer-term drug
administration. The use of radioligand-receptor binding studies has further in-
creased, although knowledge of the relevance of the reported binding site to a
physiologically or pharmacologically relevant receptor has sometimes been mini-
mal. This problem is discussed further in other parts of this chapter.
We have arranged the chapter in the same way as that in the previous volume;
again with the proviso that this is for ease of discussion and not because the
biochemical and pharmacological changes induced in any one neurotransmitter
can be considered in isolation, a point which becomes apparent in some sections
examining neurotransmitter interactions (see page 22). General comments and
criticisms are made in the final section.
C A T E C H O L A M I N ES
EFFECTS OF ANTIDEPRESSANTS ON NOREPINEPHRINE
METABOLISM
As stated in the previous review (1), there is relatively little work being performed
on the effect of antidepressant drugs on norepinephrine (NE) metabolism.
Miyauchi et al. (2) have demonstrated that acute and chronic antidepressant ad-
Psychopharmacology 2, Part 1: Preclinical Psychopharmacology
D.G. Grahame-Smith, editor
© Elsevier Science Publishers B.V., 1985
1