Download Dopaminergic Pathways and their

CIinical Science and Molecular Medicine (1977) 53, 303-306.
EDITORIAL REVIEW
Dopaminergic pathways and their pathophysiological
significance
J . L. R E I D
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
Key words: behaviour, dopamine, motor
system, neurotransmitter.
Dopamine as a neurotransmitter
Dopamine like noradrenaline and adrenaline
is a catecholamine possessing the 3,4-dihydroxy
(catechol) aromatic ring, and an amino group.
These three biologically active amines are
synthesized in series from L-tyrosine via
L-dihydroxyphenylalanine (L-dopa, levodopa).
Dopamine was originally considered a precursor but by the 1950s was recognized to be
pharmacologically active in its own right (for
review: Blaschko, 1973). Dopamine is now
accepted as a neurotransmitter in several
pathways in the central nervous system and
may have functional roles outside the nervous
system (Goldberg, 1972; Thorner, 1975).
Early evidence for a transmitter role of
dopamine derived from the failure of noradrenaline and serotonin to reverse some of the
effects of the monoamine-depleting drug
reserpine, and the demonstration of very
high concentrations of dopamine in brain
areas like the striatum, which had low amounts
of noradrenaline (Carlsson, 1959). In the past 10
years the criteria suggested by McLennan
(1963) to be fulfilled before acceptance of a
substance as a neurotransmitter have been
fulfilled by dopamine. These include the
presence of the enzymes necessary for synthesis
and metabolism of the transmitter, and its
release after nerve stimulation. In addition,
local application of dopamine simulates nerve
stimulation (Hornykiewicz, 1973).
Investigation of dopaminergic mechanisms
has been greatly helped by the recognition
of specific dopamine receptors in the central
nervous system and the periphery. Activation
of these receptors by dopamine is accompanied
by an increase in cyclic AMP via a dopaminesensitive adenylate cyclase (Greengard &.
Kebabian, 1974). Some drugs (dopamine
agonists) mimic the effects of dopamine on
adenylate cyclase and result in stimulation of
the effector tissue. Conversely dopaminereceptor antagonists block these actions of the
agonist drugs either competitively or noncompetitively. Some examples of drugs with
agonist or antagonist properties are shown
in Table 1. The dopamine agonist and antagonist
TABLE
1 . Drugs acting directly on dopamine receptors
Dopamine-receptor
agonists
Apomorphine
Piribedil
Bromocriptine
Lergotrile
Dopamine-receptor
antagonists
Phenothiazine
neuroleptics:
chlorpromazine.
trifluperazine etc.
Haloperidol
Pimozide
Metoclopramide
properties of these drugs have been confirmed
in several models in vim (Ungerstedt, 1971;
Goldberg, 1972). The dopamine receptorblocking action of phenothiazines and other
neuroleptics may be relevant, not only to the
extrapyramidal side-effects, but also to the
antipsychotic actions of these drugs (Snyder,
Banerjee, Yamamura & Greenberg, 1974).
The relevance of dopamine-receptor blockade to
the anti-emetic actions of metoclopramide
Correspondence: Dr John L. Reid, Department of
Clinical Pharmacology, Royal Postgraduate Medical
School, Du Cane Road, London W12 OHS.
303
304
J. L. Reid
is not established but extrapyramidal sideeffects have been described in man after
administration of this drug (Pinder, Brogden,
Sawyer, Speight & Avery, 1976).
Nigrostriatal dopamine pathway
This pathway was the first recognized, the
most extensively studied and remains the
dopaminergic system best related to a disease
state. Dopaminergic cells have their origin in
the substantia nigra of the midbrain and axons
extend to, and end in, synaptic terminals in
the caudate putamen (corpus striatum) (Fuxe,
1965).
The evidence implicating the nigrostriatal
dopamine pathway in extrapyramidal motor
control is overwhelming and has been extensively reviewed (Hornykiewicz, 1973; Calne,
1970). Destruction of the substantia nigra or
degeneration of nigrostriatal dopaminergic
neurons results in marked decreases in striatal
dopamine and, in man, a Parkinsonian syndrome (Ehringer & Hornykiewicz, 1960).
Selective destruction of these dopaminergic
pathways causes tremor in monkeys (Goldstein,
Battista, Ohmoto, Anagnoste & Fuxe, 1973)
or turning behaviour in rats (Ungerstedt,
1971). In addition, phenothiazines, which
block dopamine receptors, may cause extrapyramidal side-effects(Lader, 1970). Conversely,
levodopa, the precursor of dopamine, and
dopamine receptor agonists will reverse Parkinsonian symptoms and signs in man (Calne,
Teychenne, Claveria, Eastman & Greenacre,
1974). Although the role of dopamine mechanisms in Parkinsonism is established, the interactions of dopamine pathways with other
neurotransmitters in the brain, particularly
acetylcholine and y-aminobutyric acid and
possibly also serotonin and noradrenaline, are
less well understood and warrant further
study.
Tubero-infundibular dopamine pathway
Although the nigrostriatal pathway has historical precedence, the role of hypothalamic
dopaminergic pathways is of increasing interest
in the control of both releasing factors and
release-inhibiting factors of anterior pituitary
hormones (Thorner, McNeilly, Hagen &
Besser, 1974). Dopaminergic neurons with
cell bodies in the median eminence extend to
other hypothalamic areas and possibly to the
anterior pituitary (Fuxe, Hokfelt, Jonsson &
Lafstrom, 1973). Dopamine mechanisms in man
contribute to the control of growth hormone
and prolactin release. Prolactin secretion is
controlled by a prolactin release-inhibiting
factor. Removal of this dopamine-controlled
factor or dopamine-receptor blockade by drugs
(Table 1) causes elevation of prolactin levels
in blood and sometimes inappropriate lactation
(Thorner et al., 1974). Galactorrhoea and
infertility associated with high prolactin levels
may be successfully treated with the dopamine
agonist bromocriptine (CB 154) (Thorner et al.,
1974). This drug has also been used in the
medical management of acromegaly, where
suppression of growth hormone release is
accompanied by regression of the clinical
features (Thorner, Chait, Aitken, Bloom,
Mortimer, Sanders, Stuart Mason & Besser,
1975).
Dopamine pathways and behaviour
The role of dopamine mechanisms in motor
control has been consolidated by the demonstration of identifiable pathways such as the
nigrostriatal neurons. Although dopamine
mechanisms have been implicated in mood and
cognitive function, the evidence is less direct.
Circumstantial evidence of a disorder of dopaminergic pathways in psychosis derives from the
observation that antipsychotic and neuroleptic
activity correlates with dopamine receptor
antagonist properties over a range of drugs with
differing structures (Matthysse, 1973; Snyder
et al., 1974). In addition, amphetamine, which
releases dopamine, may provoke hallucinations and psychosis (Snyder et al., 1974), as do
levodopa and dopamine agonists (Calne et al.,
1974). It has been pointed out that it is too
simple and inaccurate to suggest that schizophrenia is a disease of dopamine overactivity
in the limbic system (Crow, Johnstone, Deakin &
Longden, 1976). However, it is possible that
functional dopamine overactivity may contribute to the clinical features of psychosis.
Animal experiments implicate dopamine in
many other behaviour patterns including
stereotypy (Costal1 & Naylor, 1975), eating
and drinking and autonomic control (Breese,
Cooper & Smith, 1974). The distribution of
Dopaminergic pathways
dopaminergic terminals in the hypothalamus
and other forebrain areas including the cortex
makes it likely that it sustains a transmitter
role over a wide range of functions (Costa &
Gessa, 1977).
Extra-cerebral dopamine mechanisms
Although dopamine is synthesized in the
periphery as a precursor of noradrenaline and
adrenaline, there is as yet little evidence of
important peripheral dopaminergic pathways.
Dopamine infusions are used in the treatment
of shock (Goldberg, 1972). Although dopamine
is not a potent alpha agonist, as compared
with noradrenaline, at high doses dopamine
causes a rise in blood pressure, tachycardia
and a positive chronotropic effect, partly by
an action on adrenergic receptors (Goodberg,
1972). After blockade of a- and &adrenoreceptors, peripheral effects of dopamine can
still be shown that are dependent on an action on
specific dopamine receptors. These receptors
are found in vascular smooth muscle, particularly in the renal and mesentericbeds, although
dopamine receptors have also been identified
in cerebral blood vessels. Dopamine receptors
have also been described on postganglionic cells
in sympathetic ganglia (Greengard & Kebabian,
1974) and on presynaptic terminals in adrenergic
nerve endings (Langer, Enero, Adler-Graschinsky, Dubocovich & Celuchi, 1976). In
these locations they appear to modify thesensitivity of the postsynaptic membrane and presynaptic transmitter release respectively.
Although dopamine receptors have been identified at these peripheral sites, dopaminergic
neurons or cells producing dopamine are not so
widespread. Small intenselyfluorescentcells(SIF
cells) in sympathetic ganglia contain large
amounts of dopamine (Jacobowitz & Greene,
1974) and may participate in regulation of
ganglionic transmission (Thorner, 1975). Although dopamine may be detectable in normal
human plasma (da Prada & Zurcher, 1976)
the absolute amount is disputed and its origin
and functional significance remain controversial. The activity of L-dopa decarboxylase
in the kidney is high and substantial amounts
of dopamine are present in urine. Dopamine
modifies renal blood flow and sodium excretion
and has been proposed as a modulator of renal
function (Goldberg, 1972). An intrarenal role
305
of dopamine in sodium homeostatis was
supported by the observation by Ball & Lee
(1977) that decarboxylase inhibition with
carbidopa reduced urinary sodium excretion.
Dopamine may participate in blood pressure
regulation not only by this mechanism but also
in other ways. Levodopa causes hypotension
by both central and peripheral mechanisms
(Reid, Calne, George & Vakil, 1972) and the
direct dopamine agonists like apomorphine and
bromocriptine also lower blood pressure
(Greenacre, Teychenne, Petrie, Calne, Leigh &
Reid, 1976). The individual contributions
of a central, ganglionic or direct peripheral
action on blood vessels have not been determined.
Although the nigrostriatal system remains
the model of a dopaminergic pathway, hypothalamic pituitary neurons, mesolimbic pathways and peripheral dopamine receptors have
extended the areas of physiological and pathological relevance of dopamine.
References
BALL,S.G. & LEE,M.R. (1977) The effect of carbidopa
administration on urinary sodium excretion in man.
British Journal of Clinical Pharmacology, 4, 11 5119.
BLASCHKO,
H. (1973) Catecholamine biosynthesis.
British Medical Bulletin, 29, 105-109.
BREESE.G.R., COOPER,B.R. & SMITH, R.D. (1974)
Biochemical and behavioural alterations following
6-hydroxydopamine administration into brain. In:
Frontiers in Catecholamine Research, pp. 701-706.
Ed. Usdin, E. & Snyder, S.H. Pergamon Press,
Oxford.
CALNE.D.B. (1970) Parkinsonism: Physiology, PharmacoZogy and Treatment. Arnold, London.
CALNE,D.B., TEYCHENNE,
P.F., CLAVERIA,L.E.,
EASTMAN,
R. & GREENACRE,
J.K. (1974) Bromocriptine in Parkinsonism. British Medical Journal,
iv, 442-444.
CARLSSON,
A. (1959) The occurrence, distribution and
physiological role of catecholamines in the nervous
system. Pharmacological Reviews, 2,490.
COSTA,E. & GESSA,G.L. (Ed.) (1977) Non-striatal
dopaminergic neurons. In: Aduances in Biochemical
Psychopharmacology, vol. 16, pp. 1-736. Raven Press,
New York.
COSTALL,B. & NAYLOR,
R.J. (1975) Actions of dopaminergic agonists on motor function. In: Advances
in Neurology, vol. 9, pp. 285-298. Ed. Calne, D.B.,
Chase T.N. & Barbeau, A. Raven Press, New York.
CROW,T.J., JOHNSTONE, E.C., DEAKIN,J.F.W. &
LONGDEN,
A. (1 976) Dopamine and schizophrenia.
Lancet, ii, 563-566.
DA PRADA,M. & ZURCHER,G. (1976) Simultaneous
determination of plasma and tissue adrenaline.
noradrenaline and dopamine within the femtomole
range. Life Sciences, 19, 1161-1174.
306
J . L. Reid
EHRINGER,
H. & HORNYKIEWICZ,
0. (1960) Verteilung
von Noradrenaline and Dopamin im Gehirn des
Menschen and ihr Verhalten beim Erkrankungen
des extrapyramidalen Systems. Klinische Wochenschrift, 38, 1236-1239.
FUXE,
K. (1965) Evidence for the existence of monoamine neurons in the central nervous system. IV.
Distribution of monoamine terminals in the central
nervous system. Acta Physiologica Scandinavica, 64,
(S~ppl.247), 39-85.
FUXE,
K., HOKFELT,T., JONSSON,
G. & LBFSTROM,
A. (1973) Recent morphological and functional
studies on hypothalamic doparninergic and noradrenergic mechanisms. In: Frontiers in Catecholamine
Research, pp. 787-794. Ed. Usdin, E. & Snyder,
S.H. Pergamon Press, Oxford.
GOLDBERG,
L.I. (1972) Cardiovascular and renal
actions of dopamine: potential clinical applications.
Pharmacological Reviews, 24, 1-29.
GOLDSTEIN,
M., BATTISTA,
A.F., OHMOTO,
T., ANAGNOSTE, B. & FUXE,K. (1973) Tremor and involuntary
movements in monkeys. Effect of L-dopa and of a
dopamine receptor stimulating agent. Science,
179, 816-817.
GREENACRE,
J.K., TEYCHENNE,
P.P., PETRIE, A.,
CALNE,D.B., LEIGH,P.N. & REID,J.L. (1976) The
cardiovascular effects of bromocriptine in Parkinsonism. British Journal of Clinical Pharmacology, 3,
571-574.
GREENGARD,
P. & KEBABIAN,
J.W. (1974) Role of
cyclic AMP in synaptic transmission in the mammalian peripheral nervous system. Federation Proceedings, 33, 1059-1067.
HORNYKIEWICZ,
0. (1973) Dopamine in basal ganglia.
British Medical Bulletin, 29, 172-1 78.
JACOBOWITZ,
D.M. & GREENE,L.A. (1974) Histofluorescence study of chromaffin cells in dissociated
cell culture of chick embryo sympathetic ganglia.
Journal of Neurobiology, 5, 63-83.
LADER,M.H. (1970) Drug induced extrapyramidal
syndromes. Journal of the Royal CoIIege of Physicians of London, 5, 87-98.
LANCER,S.Z.. ENERO,M.A., ADLER-GRASCHINSKY.
E., DUBOCOVICH,
M.L. & CELUCHI,S.M. (1976)
Presynaptic regulatory mechanisms for noradrenaline
release by nerve stimulation. In: Central Action of
Drugs in Blood Pressure Regulation, pp. 133-151. Ed.
Davies, D.S. & Reid, J.L. Pitman, London.
MCLENNAN,
H. (1963) Synaptic Transmission. p. 23.
Saunders, Philadelphia.
MATIXYSSE,
S. (1973) Antipsychotic drug actions: a
clue to the neuropathology of schizophrenia. Federation Proceedings, 32,200-205.
PINDER,
R.M., BROGDEN,R.N.,
SAWYER,
P.R., SPEIGHT,
T.M. & AVERY,G.S. (1976) Metoclopramide: A
review of its pharmacological properties and clinical use. Drugs, 12, 81-131.
REID,J.L., CALNE,D.B., GECIRGE,C.F. & VAKIL,S.D.
(1972) The action of L-dopa on baroreflexes in
Parkinsonism. Clinical Science, 43, 851-859.
SNYDER,S.H., BANERJEE,
S.P., YAMAMURA,
H.I.&
GREENBERG,
D. (1974) Drugs, neurotransmitters
and schizophrenia. Science, 184,1243-1253.
THORNER,
M.O. (1975) Dopamine is an important
neurotransmitter in the autonomic nervous system.
Lancet, i, 662-664.
THORNER,
M.O., CHAIT, A., AITKEN, M., BLOOM,
S.R., MORTIMER,C.H., SANDERS,
P., STUARTMASON,
A. & BESSER,
G.M. (1975) Bromocriptine treatment of
acromegaly. British Medical Journal, i, 299-303.
TIIORNER,M.O., MCNEILLY. AS., HAGAN,C. &
BESSER,
G.M. (1974) Long term treatment of galactorrhoea and hypogonadisrn with bromocriptine.
British Medical Journal, ii, 419-422.
UNGERSTEDT,
U. (1971) Postsynaptic supersensitivity
after 6-hydroxydopamine induced degeneration of
nigrostriatal dopamine neurons. Acta PhysioIogica Scandinauica, Suppl. 367, 69-94.