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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). 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