Table Of ContentPROGRESS IN BRAIN RESEARCH
VOLUME 79
NICOTINIC RECEPTORS IN THE CNS
Their Role in Synaptic Transmission
EDITED BY
A. NORDBERG
Department of Pharmacology, University of Uppsala, Uppsala, Sweden
K. FUXE
Department of Histology and Neurobiology, Karolinska Institute, Stockholm, Sweden
B. HOLMSTEDT
Department of Toxicology, Karolinska Institute, Stockholm, Sweden
and
A. SUNDWALL
Pharmacia LEO Therapeutics, Helsingborg, Sweden
ELSEVIER
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1989
0 1989, Elsevier Science Publishers B.V. (Biomedical Division)
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Library of Congress Cataloging-in-Publication Data
Nicotinic receptors in the CNS : their role in synaptic transmission /
edited by A. Nordberg . . . [et al.].
p. cm. -- (Progress in brain research ; v. 79)
Proceedings of the International Symposium on Nicotinic Receptors
in the CNS--Their Role in Synaptic Transmission, held in Uppsala,
Sweden, June 19-21, 1988.
Includes bibliographies and index.
ISBN 0-444-81088-9 (U.S.)
1. Nicotinic receptors--Congresses. 2. Nicotine--Physiological
effect--Congresses. I. Nordberg, A. (Agneta) 11. International
Symposium on Nicotinic Receptors in the CNS: Their Role in Synaptic
Transmission (1988 : Uppsala, Sweden) 111. Series.
[DNLM: 1. Neural Transmission--congresses. 2. Nicotine-adverse
effects--congresses. 3 . Receptors, Nicotinic--congresses.
4. Smoking--physiopathology--congresses. W 1 PR667J v. 79 / WL
102.8 N662 19881
QP376.P7 vol. 79
(QP364.71
612'.82 s--dc2O
[599' .0188]
DNLM/DLC 89-12034
for Library of Congress CIP
Printed in The Netherlands
V
List of Contributors
A. Adem, Department of Pharmacology, University of Uppsala, S-751 24 Uppsala, Sweden
L.Fg Agnati, Department of Human Physiology, University of Modena, Modena, Italy
A. A hlin, Department of Psychiatry and Psychology, Karolinska Hospital, S-104 01 Stockholm, Sweden
1. Alafuzoff, Department of Pathology, Karolinska Institutet, Huddinge Hospital, S-141 86 Huddinge,
Sweden
K. Anderson, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm,
Sweden
S.H. Appel, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, U S A .
S.-M. Aquilonius, Department of Neurology, University Hospital, S-751 85 Uppsala, Sweden
D.M. Araujo, Department of Psychiatry, McGill University, Montreal, Quebec, Canada H4HIR3
D.J.K. Balfour, Departments of Pharmacology and Clinical Pharmacology, University Medical School,
Ninewells Hospital, Dundee, U.K.
T. Bartfai, Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, S-106 91
Stockholm, Sweden
L. Beani, Department of Pharmacology, University of Ferrara, 44100 Ferrara, Italy
N.L. Benowitz, Clinical Pharmacology Unit of Medical Service, San Francisco General Hospital Medical
Center, University of California, San Francisco, CA 94143, U.S.A.
C. Bianchi, Department of Pharmacology, University of Ferrara, 44100 Ferrara, Italy
B. Bjelke, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm, Sweden
F.A. Bobbitt, Departments of Medicine and Pharmacology, University of Kentucky, Lexington, KY 4051 1,
U.S.A.
J . Boulter, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, CA
92138, U.S.A.
L. Brown, Departments of Medicine and Pharmacology, University of Kentucky, Lexington, KY 4051 1,
U.S.A.
N. Brynne, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm, Sweden
J . Cartaud, Institut Jacques Monod du Centre National de la Recherche Scientifique, Universite-Paris VII,
Paris Cedex 05, France
J.P. Changeux, Departement des Biotechnologies, Institut Pasteur, Paris Cedex 15, France
B. Clark, Department of Pathology, SIV School of Medicine, Springfield, IL-62794-9230, U .S.A.
P.B.S. Clarke, Departments of Pharmacology and Therapeutics, McGill University, Montreal, Canada
H3GlY6
B. Collier, Department of Pharmacology, McGill University, Montreal, Quebec, Canada H4HIR3
A.C. Collins, School of Pharmacy and Institute for Behavioral Genetics, University of Colorado, Boulder,
CO 80309, U.S.A.
J. Connolly, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, CA
92138, U.S.A.
S. Consolo, Mari Negri Institute of Pharmacological Research, 20157 Milan, Italy
E. Deneris, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, CA
92138, U.S.A.
P. DeSarno, Department of Pharmacology, SIV School of Medicine, Springfield, IL-62794-9230, U.S.A.
L. Dong, Departments of Medicine and Pharmacology, University of Kentucky, Lexington, KY 405 11,
U.S.A.
T.M. Egan, Department of Biochemistry, Brandeis University, Waltham, MA 02254-911 0, U.S.A.
P. Eneroth, Department of Applied Biochemistry, Huddinge University Hospital, S-141 86 Huddinge,
Sweden
K.O. Fagerstrom, Pharmacia Leo Therapeutics AB, S-25 1 09 Helsingborg, Sweden
L. Ferraro, Department of Pharmacology, University of Ferrara, 1-44100 Ferrara, Italy
H.C. Fibiger, Department of Psychiatry, University of British Columbia, Vancouver B.C. V6T IW5,
Canada
G . Fisone, Mari Negri Institute of Pharmacological Research, 201 57 Milan, Italy
B. Fontaine, Departement des Biotechnologies, Institut Pasteur, Paris Cedex 15, France
Vl
K. Fuxe, Department of Histology and Neurobiology, Karolinska lnstitutet, S-104 01 Stockholm, Sweden
E. Giacobini, Department of Pharmacology, SIV School of Medicine, Springfield, IL-62794-9230, U.S.A.
B.A. Giblin, Department of Pharmacology, Georgetown University School of Medicine, Washington D.C.
20007, U.S.A.
M. Goldstein, Department of Psychiatry, New York University Medical Center, New York, U.S.A.
U. Hacksell, Department of Organic Pharmaceutical Chem’stry, University of Uppsala, S-75 1 23 Uppsala,
f
Sweden
C. Halldin, Karolinska Pharmacy, Karolinska Hospital, S-104 01 Stockholm, Sweden
J . Hardy, Department of Biochemistry, St Mary’s Hospital Medical School, London, U.K.
A. Harfstrand, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm,
Sweden
P. Hartvig, Hospital Pharmacy, University Hospital, S-751 85 Uppsala, Sweden
L. Haverkamp, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
S. Heinemann, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego,
CA 92138, U.S.A.
J.S. Hendry, Departments of Pharmacology and Toxicology, Virginia Commonwealth University, Rich-
mond, VA 23298, U.S.A.
J.E. Henningfield, Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224,
U.S.A.
M. Herrera-Marschitz, Department of Pharmacology, Karolinska lnstitutet, S-104 01 Stockholm, Sweden
T. Hokfelt, Department of Histology and Neurobiology, Karolinska lnstitutet, S-104 01 Stockholm, Sweden
V. Hollt, Physiologische Institut der Universitat Miinchen, D-8000 Miinchen, F.R.G.
G. Horn, Physiologische Institut der Universitat Miinchen, D-8000 Miinchen, F.R.G.
J . Irons, Department of Biochemistry, University of Bath, Bath BA27A4, U.K.
P. Jacob, 111, Clinical Pharmacology Unit of Medical Service, San Francisco, General Hospital Medical
Center, University of California, San Francisco, CA 94143, U.S.A.
A. Jansson, Department of Histology and Neurobiology, Karolinska lnstitutet, S-104 01 Stockholm, Sweden
A.M. Janson, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm,
Sweden
J . KAhrstrom, Department of Medical Cell Research, University of Lund, S-223 62 Lund, Sweden
K. J. Kellar, Department of Pharmacology, Georgetown University School of Medicine, Washington D.C.
20007, U.S.A.
J. Kiritsy-Roy, Departments of Medicine and Pharmacology, University of Kentucky, Lexington, KY 4051 1,
U.S.A.
A. Klarsfeld, Departtment des Biotechnologies, lnstitut Pasteur, Paris Cedex 15, France
C. Kohler, Department of Neurochemistry, Astra Pharmaceuticals, S-151 85 Sodertalje, Sweden
Z. Lai, Department of Pharmacology, University of Uppsala, S-751 24 Uppsala, Sweden
B. LAngstrom, Department of Organic Chemistry, University of Uppsala, S-751 21 Uppsala, Sweden
P.A. Lapchak, Department of Pharmacology, McGill University, Montreal, Quebec, Canada H4HIR3
R. Laufer, Departtment des Biotechnologies, Institut Pasteur, Paris Cedex 15, France
P.M. Lippiello, R.J. Reynolds Tobacco Company, Winston-Salem, NC 27102, U.S.A.
R.H. Loring, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School,
Boston, MA 021 15, U.S.A.
R.J. Lukas, Division of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, U S A .
M.D. Lumpkin, Department of Biophysics, Georgetown University School of Medicine, Washington D.C.
20007, U.S.A.
G.G. Lunt, Department of Biochemistry, University of Bath, Bath BA2 7AY, U.K.
M.J. Marks, School of Pharmacy and Institute for Behavioral Genetics, University of Colorado, Boulder,
CO 80309, U.S.A.
L. Marson, Departments of Medicine and Pharmacology, University of Kentucky, Lexington, KY 4051 1,
U.S.A.
M. Mcllhany, Department of Surgery, SIV School of Medicine, Springfield, IL 62794-9230, U S A .
J.L. McManaman, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, U S A ,
T. Melander, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm,
Sweden
C. Mellin, Department of Organic Pharmaceutical Chemistry, University of Uppsala, S-751 23 Uppsala,
Sweden
L.T. Meltzer, Departments of Pharmacology and Toxicology, Virginia Commonwealth University, Rich-
mond, VA 23298, U.S.A.
VII
G. Mereu, Department of Pharmacology, St Louis University School of Medicine, St Louis, MO 63104,
U.S.A.
B.J. Morley, Boys Town National Institute, Omaha, NE 68131, U.S.A.
L. Naes, Department of Pharmacology, St Louis University School of Medicine, St Louis, MO 63104,
U.S.A.
L. Nilsson-HAkansson, Department of Pharmacology, University of Uppsala, $751 24 Uppsala, Sweden
A. Nordberg, Department of Pharmacology, University of Uppsala, S-751 24 Uppsala, Sweden
0. Nordstrom, Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, 5-106 91
Stockholm, Sweden
E. Norheirn-Theodorsson, Department of Clinical Chemistry, Karolinska Hospital, S-104 01 Stockholm,
Sweden
H. Nyback, Department of Psychiatry and Psychology, Karolinska Hospital, S-104 01 Stockholm, Sweden
R. Oppenheim, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
C. Owman, Department of Medical Cell Research, University of Lund, S-223 62 Lund, Sweden
J. Patrick, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, CA
92138, U.S.A.
H. Perry, Department of Pharmacology, St Louis University School of Medicine, St Louis, MO 63104,
U.S.A.
A. Persson, Department of Psychiatry and Psychology, Karolinska Hospital, S-104 01 Stockholm, Sweden
K. Pierzchala, Department of Medicine and Pharmacology, University of Kentucky, Lexington, KY 4051 1,
U.S.A.
H. Porchet, Clinical Pharmacology Unit of Medical Service, San Francisco General Hospital Medical
Center, University of California, San Francisco, CA 94143, U.S.A.
R. Quirion, Department of Psychiatry, McGill University, Montreal, Quebec, Canada H4H IR3
M. J . Rand, Department of Pharmacology, University of Melbourne, Victoria, 3052, Australia
C. Rapier, Department of Biochemistry, University of Bath, Bath BA2 7AY, U.K.
C. Reavill, Department of Psychiatry, Institute of Psychiatry, London SE5 8AF, U.K.
L. Romanelli, Department of Pharmacology, University of Ferrara, 1-44100 Ferrara, Italy
J.A. Rosecrans, Departments of Pharmacology and Toxicology, Virginia Commonwealth University, Rich-
mond, VA 23298, U S A .
M.A.H. Russell, Institute of Psychiatry, University of London, London, U.K.
D.W. Schulz, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School,
Boston, MA 021 15, U.S.A.
C.G. Swahn, Department of Psychiatry and Psychology, Karolinska Hospital, S-104 01 Stockholm, Sweden
G . Sedvall, Department of Psychiatry and Psychology, Karolinska Hospital, S-104 01 Stockholm, Sweden
K. Semba, Department of Psychiatry, University of British Columbia, Vancouver B.C. V6T IW5, Canada
P. Spalluto, Department of Pharmacology, University of Ferrara, 44100 Ferrara, Italy
W.A. Staines, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm,
Sweden
C.A. Stimler, Departments of Pharmacology and Toxicology, Virginia Commonwealth University, Rich-
mond, VA 23298, U.S.A.
I .P. Stolerman, Department of Psychiatry, Institute of Psychiatry, London SE5 8AF, U.K.
E. Sundstrom, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm,
Sweden
A. Sundwall, Pharmacia Leo Therapeutics AB, S-25 1 09 Helsingborg, Sweden
L. Swanson, Neural Systems Laboratory, The Salk Institute for Biological Studies, San Diego, CA 92138,
U.S.A.
S. Tanganelli, Department of Pharmacology, University of Ferrara, 1-44100 Ferrara, Italy
B. Tinner, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm, Sweden
B. Thorne, Department of Biochemistry, University of Bath, Bath BA2 7AY, U.K.
K. Vaca, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
G.R. van Loon, Departments of Medicine and Pharmacology, University of Kentucky, Lexington, KY
40511, U.S.A.
L. Vickery, Department of Pharmacology, St Louis University School of Medicine, St Louis, MO 63104,
U.S.A.
G . von Euler, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm,
Sweden
E. Wada, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, CA
92138, U.S.A.
VIIl
K. Wada, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, CA
92138, U.S.A.
T.C. Westfall, Department of Pharmacology, St Louis University School of Medicine, St Louis, MO 63104,
U.S.A.
B. Winblad, Department of Geriatric Medicine, Karolinska Institutet, Huddinge Hospital, S-141 86 Hud-
dinge, Sweden
S. Wonnacott, Department of Biochemistry, University of Bath, Bath BA2 7AY, U.K.
P.P. Woodson, Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224,
U.S.A.
C.F. Wu, Department of Histology and Neurobiology, Karolinska Institutet, S-104 01 Stockholm, Sweden
K.-W. P. Yoon, Department of Neurosurgery, St Louis University School of Medicine, St Louis, MO 63104,
U.S.A.
R.E. Zigmond, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, Boston, MA 021 15, U.S.A.
IX
Preface
The present volume constitutes the proceedings of ‘The International Symposium on
Nicotinic Receptors on the CNS - Their Role in Synaptic Transmission’ that was held
in Uppsala, Sweden June 19-21, 1988. Sweden has a long historical tradition for
research on nicotine and cholinergic mechanisms which motivated the arrangement of
the symposium in Sweden. Several international meetings have earlier been arranged
dealing with the different effects of nicotine on the human body. This symposium is
unique in that it focuses on the central nicotinic receptors and their functional role in
the CNS. In an integrative way it covers all aspects of the nicotinic receptors from
molecular to clinical approaches.
Ligand binding studies with different nicotinic agonists and antagonists have shown
the presence of several different subtypes of nicotinic receptors in the CNS. Studies on
molecular biology using expression in the oocyte model indicate that the addition of
a P2-subunit to either an a2-,a 3-,o r a4-subunit produces a receptor that initiates a
strong response to either acetylcholine or nicotine. The P2-subunit is expressed
throughout the central nervous system and the a-subunit transcripts are expressed in
separate but overlapping areas in the brain. Of special interest in the session on
radioligand binding studies was the observation that neuronal bungarotoxin (NBT) but
not a-bungarotoxin could antagonize the nicotinic receptor function in the brain.
Another interesting tool used in the pharmacological analysis was the neosurugatoxin,
a potent ganglionic nicotinic antagonist without activity at the neuromuscular junction.
The meeting clearly illustrated the important role the nicotinic receptors play in the
control of the release of monoamines and amino acids in the brain. It is evident that
the nicotinic cholinergic recognition sites predominantly belong to the terminal parts
of the cholinergic neuronal system and that these sites are especially enriched in the
reticular thalamic cholinergic pathways. New anatomical findings reported at the
meeting were the existence of neuropeptides such as galanin and GRF as well as
dopamine in the cholinergic pathways of the brain. Studies on neurotransmitter
release, neuroendocrine function and behaviour in relation to nicotine exposure reveal-
ed different types of plasticity in the central nicotinic receptor populations. Rapid
desensitization as well as resistance to desensitization are common.
Human studies also indicate the development of adaptive changes in the central
nicotinic receptors upon chronic nicotine exposure. Nicotine abstinence reveals that the
addicted heavy smokers have more severe withdrawal effects and more subjective ef-
fects after first postabstinence cigarette. Although the half-life of nicotine in brain is
short (less than 10 min) tolerance develops quickly. During the day there is an ac-
cumulation of nicotine in brain and a development of tolerance which partly can be
overcome by transiently high brain levels of nicotine. Overnight abstinence allows
resensitization mechanisms. The subjective and behavioural effects of nicotine differ
both between and within individuals due to numerous factors such as acute and chronic
tolerance, learning, conditioning and pharmacokinetic factors. Direct evidence for an
adaptive change of nicotinic receptors in human brain was reported at the meeting us-
ing positron emission tomography (PET). The question whether Parkinson’s disease
is less common in smokers than nonsmokers is still under debate. However, basic
X
animal data presented at this meeting indicated that chronic nicotine treatment, in part,
protects dopamine nerve cells in the substantia nigra from undergoing degeneration in
response to mechanical and neurotoxic injuries. In dementia disorders, such as
Alzheimer’s disease, a loss of high affinity nicotinic receptors has been found in the
brain. It was suggested at this meeting that the loss may partly be due to an interconver-
sion of high affinity to low affinity nicotinic binding sites which reduces the desen-
sitization process and opens up new aspects on therapeutic approaches in Alzheimer’s
disease.
In our opinion, the symposium finally established that the effects of smoking are
mediated by activation of central nicotinic receptors. As organizers we are indebted to
the participants for their valuable contributions. We want to express our gratitude to
the Swedish Tobacco Company and Pharmacia Leo Therapeutics AB for their finan-
cial support.
Uppsala, Stockholm and Helsingborg Agneta Nordberg
December 1988 Kjell Fuxe
Bo Holmstedt
Anders Sundwall
A . Nordberg, K. Fuxe, B. Holmsredt and A. Sundwall (Edr.)
Progress in Brain Research, Vol. 19
0 1989 Elsevier Science Publishers B.V. (Biomedical Division) 3
CHAPTER I
Neuropharmacological effects of nicotine in relation to
cholinergic mechanisms
M.J. Rand
Department of Pharmacology, University of Melbourne, Victoria, 3052 Australia
Early studies on nicotine and other drugs and system were discovered by Langley and his col-
poisons leagues (Langley and Dickinson, 1889; Langley
and Anderson, 1895; Langley, 1896, 191 1). These
From time immemorial, plant materials containing actions were useful for determining the nature of
substances that interact with cholinergic mech- the autonomic innervation and the location of
anisms have been used for hedonistic, ritual or ganglionic synapses in the nervous pathway to
magical purposes or for hunting, as well as for many organs. For example, they observed that ap-
therapeutic purposes. Such materials include not plication of nicotine to the coeliac ganglion pro-
only tobacco (nicotine), but also Duboisia spp. duced a rise in blood pressure. This and similar
(nornicotine), Lobelia inflata (lobeline), betel observations on sympathomimetic responses eli-
(arecoline), solanaceous plants (atropine, hyoscine, cited in target organs by application of nicotine to
etc.), Muscaria amanita (muscarine), esere ganglia in the nervous pathway led to the deduc-
(physostigmine), jaborandi (pilocarpine), curare tion that nicotine stimulated ganglion cells. They
(tubocurarine), and even opium (morphine), since also noted that after the administration of a large
opiates generally inhibit cholinergic transmission dose of nicotine, the response to the local applica-
in many tissues. The founding fathers of pharma- tion of nicotine to the ganglion was abolished, as
cology and toxicology investigated the actions of was the response to stimulation of the pregangli-
the crude substances and of the alkaloids isolated onic nerves; however, the response to stimulation
from them with enthusiasm and energy that was of the postganglionic nerves persisted. These ob-
eventually rewarded with the development of servations led to the deduction that nicotine block-
therapeutic substances and, most importantly, ed the excitation of ganglion cells.
with new insights into physiological mechanisms.
In the latter regard, nicotine might well hold pride Differentiation between types of acetylcholine
of place. receptors
Elucidation of physiological mechanisms arising Dale (1914) observed that a large dose of nicotine
from observations on the actions of nicotine (30 mg) abolished the pressor action of acetyl-
choline in the atropinized spinal cat: this, together
Path ways of autonomic innervation with the observation that the depressor action of
acetylcholine, like that of muscarine, was blocked
The effects of nicotine in stimulating and by atropine, led to the formulation of the concept
“paralysing” ganglia of the autonomic nervous of two different types of site of action of acetyl-
4
choline, which he termed “muscarinic and nico- Burnstock et al. (1966) noted that the smooth mus-
tinic” - a terminology that is still standard. cle of the taenia of the guinea-pig caecum was in-
nervated by neurones having their cell bodies in the
Identification of cholinergic and amino acid Auerbach’s plexus which, when excited by elec-
transmission in the central nervous system (CNS) trical stimulation or ganglion-stimulating drugs
such as nicotine or DMPP, produced relaxation
The most thoroughly understood action of nico- which was entirely different from the relaxation
tine in the CNS is inhibition of the knee-jerk produced by excitation of noradrenergic nerves. In
reflex. This effect of nicotine was first demon- a subsequent analysis of the actions of nicotine and
strated by Schweitzer and Wright (1938) in ex- other ganglia stimulants on the taenia of the
periments on cats. They produced convincing evi- guinea-pig caecum, it was confirmed that they
dence that it was in fact due to an action of acted on nicotinic receptors of both cholinergic
nicotine on the spinal cord, and that it was produc- and NANC neurones (Hobbiger et al., 1969). Fur-
ed by “smoking doses” (i.e. 5 pg i.v.) Subsequent- ther studies on NANC transmission pioneered by
ly, it was shown that inhibition of the knee-jerk Burnstock led to the acceptance of peripheral
reflex occurred in humans during the smoking of neurotransmitter systems other than the “classi-
a cigarette (Clark and Rand, 1968). cal” cholinergic and (nor)adrenergic systems (for
In the course of studies designed to prove that an historical account, see Rand and Mitchelson,
acetylcholine is a transmitter in the CNS, the ac- 1986).
tion of nicotine was investigated on a spinal
neurone, the Renshaw cell. This was the first use of Molecular biology of receptors
the technique of electrophoretic application of
drugs in the CNS (Curtis and Eccles, 1958). The The nicotinic cholinoceptors of electroplaxes from
technique, which allowed the precise application of the electric organ of the Torpedo were the first
drugs to identifiable neurones, was extended to a receptors to be isolated and characterized. The
range of other substances and led to the discovery quaternary structure and the relationship between
of the depressant action of gamma-aminobutyric acetylcholine recognition sites and functional re-
acid (GABA) and the excitant actions of glutamic sponses have been determined, and the various
and aspartic acids on Renshaw cells and other transitional states have been identified. There have
neurones (Curtis et al., 1959, 1960). Although it been several authoritative reviews on these subjects
was not at first recognized that these amino acids (Claudio et al., 1986; Karlin et al., 1986; Changeux
could be neurotransmitters, the discoveries that et al., 1987; Colquhoun et al., 1987).
sprang from studies on nicotine were of crucial im-
portance in the chain of investigations which. Location of nicotinic receptors
established that they were in fact the most common
neurotransmitters in the CNS (Johnston, 1978; The main sites at which nicotinic receptors have
Watkins and Evans, 1981). been identified are listed in Table 1. The nicotinic
cholinoceptors clearly have a functional role in
Recognition of non-adrenergic, non-cholinergic transmission through autonomic ganglionic syn-
transmission apses and adrenal medullary chromaffin cells, and
there is little new information to add to the exten-
Observations on the pharmacological actions of sive corpus of knowledge on these subjects.
nicotine contributed to a more recent development Likewise, the functional role of nicotinic chol-
in neuroscience, namely the recognition of non- inoceptors of the electroplax and motor end-plate
adrenergic, non-cholinergic (NANC) nerves. Thus is clearly established: in fact, these are the most
