CURRENT REVIEW

Developments in the Pharmacology and Therapeutics of Parkinsonism D. B. Calne, MD Advances in synaptic pharmacology have led to new approaches to understanding and attempting to alleviate the disturbances in neurotransmission that occur in parkinsonism. Techniques which were initially developed to elucidate normal synaptic phenomena are being employed to screen potential therapeutic agents for efficacy, relative potency, and neurotoxicity and to analyze the mechanism of action of antiparkinsonian drugs. In vitro methods utilizing striatal tissue include the assay of dopamine release, the determination of active dopamine reuptake, the displacement of ligands from dopamine receptors, and the stimulation of dopamine-sensitive adenylate cyclase. In vivo test systems in rats comprise alleviation of the reserpine syndrome, induction of stereotypic behavior, measurement of turning after unilateral nigrostriatal lesions, evaluation of regional changes in the concentration of dopamine and its metabolites, and recording of single-unit responses in the brain. With these tools, it is proving possible to sustain progress in the search for improved treatment, exemplified by current experimental studies with dopaminergic agonists and selective inhibitors of monoamine oxidase isoenzymes. The pursuit of practical applications has been accompanied by conceptual advances, such as the proposal that cyclic nucleotides are “second messengers” in the nigrostriatal pathway and the recognition of certain amino acids and peptides as synaptic transmitters or modulators in the basal ganglia. Calne DB: Developments in the pharmacology and therapeutics ofparkinsonism (current review).Ann Neurol 1:111-119, 1977

Over the last 2 5 years a remarkable surge has occurred in our understanding of the nervous system and the management of certain neurological diseases. The area of major achievement in neuroscience has shifted from biophysical neurophysiology to biochemical neuropharmacology. In 1951 Sherrington [ 11 vividly summarized his view of the nervous system, clearly deriving it from the biophysical concept of the nerve impulse (action potential), as an “enchanted loom where millions of flashing shuttles weave a dissolving pattern, always a meaningful pattern though never an abiding one.” Progress in defining the biochemical concept of the synaptic neurotransmitter has provided pharmacologists with a powerful new tool for analyzing the “enchanted loom” and dismissing at least some of the magic. Action potentials are relatively uniform in type, fleetingly transient, and disappear without trace throughout the nervous system. In contrast, the currently identified transmitters are sufficiently different in structure for separation among most of them to be accomplished with reasonable ease; they also have stable markers in the form of synthetic or degradative enzymes, metabolites that undergo regional accumulation, and receptors that bind to specific ligands. The advent of synaptic pharmacology may, without too much distortion of imagery, be likened to From the Ex~crirnentalTheraueutics Branch. National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, MD.

the introduction of a “color-coding” system into the infinitely complex wiring diagram of Sherrington’s electric loom. Transmitter neuropharmacology was conceived and underwent its gestation in the peripheral nervous system. The elucidation of autonomic mechanisms and neuromuscular transmission led to substantial therapeutic advances: sympathetic blockade for hypertension and a number of anticholinesterase agents for myasthenia gravis. The outstanding progress over the last 25 years has owed its origin to a number of evolving techniques for analyzing the pharmacology of the central nervous system, in particular for defining regional differences in the biochemistry of the brain at both macroscopical and microscopical levels. The study of central synapses has led to important therapeutic progress such as the rational screening of antipsychotic agents, new anticonvulsants, centrally acting hypotensive drugs, and the modulation of neuroendocrine function. However, the most cogent example of such evolution is the field of extrapyramidal pharmacology and disease. Here, close interaction between basic and clinical scientists has allowed developments generated in the laboratory to be taken quickly to the ward and applied in a clinical setting. Accepted for publication Aug 3, 1976. Address reprint requests to Dr Calne, National Institutes of Health, Building 10, Room 6D20, Bethesda, MD 20014.

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Conversely, critical observations made in a clinical context have been transferred rapidly to the laboratory for more controlled analysis. The well-known story unfolded over the decade 1957- 1967. First, evidence accumulated to indicate that dopamine is a transmitter [2, 31. Next, the normally high concentration of dopamine and its metabolites in the basalgangliawas found to be low in patients with parkinsonism [ 4 ] . Since dopamine does not readily cross the blood-brain barrier, its precursor, levodopa, was given to patients with parkinsonism in an attempt to overcome the depletion of dopamine. Low doses of levodopa led to encouraging results [ 5 , 61, but these were accompanied by prominent adverse reactions that precluded its use in routine therapy until it was found that small, gradual increments in dosage minimized unwanted effects so that substantial and often dramatic clinical improvement was achieved [71. Over the decade since 1967, prolonged treatment with levodopa has proved both beneficial and safe [8], but efficacy is still marred by conspicuous adverse reactions [9]. The advent of extracerebral decarboxylase inhibitors [ 10- 151 represented an important contribution to decreasing the unwanted effects of levodopa that are produced at the periphery (such as cardiac arrhythmias’),or in regions of the central nervous system where the blood-brain barrier is relatively penetrable (emesis probably steins from permeability of the area postrema). A number of centrally induced problems continue to limit the efficacy of levodopa therapy in an increasing proportion of patients with Parkinson’s disease. The most notable examples are dyskinesia (especially prominent in “on-off” phenomena) and psychiatric disturbances. Removal or reduction of these unwanted effects could open a new era in the treatment of parkinsonism. If it proved possible to increase the selectivity of centrally acting dopaminergic drugs, an improvement in the ratio of wanted to unwanted responses might be achieved, ie, an increase in the therapeutic index (toxic doseieffective dose). Attempts to identify separate categories of dopaminetgic receptor and different types of monoamine oxidase (MAO) might lead to development of the tools required to dissect away central adverse reactions. While these premises have yet to generate any broadly effective new treatment for parkinsonism, significant progress is being made in the development of new drugs. Before the clinical implications of these advances are discussed, it is appropriate to review some of the neuropharmacological background from which they are derived. Neuropharrnacology A simplified outline of normal synaptic components and mechanisms, summarized diagrammatically in 112

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Figure 1 [16], facilitates a review of contributions made by pharmacological studies to the improvement of antiparkinsonian therapy. Certain definitions may help. While there are receptors sensitive to the same transmitter on both the presynaptic and postsynaptic neuron, the unqualified term receptor will be employed here for those on the postsynaptic membrane. Autoreceptor.r will signify the corresponding receptors on the presynaptic neuron. T h e termagonist will be used for any agents that have a direct stimulating action on areceptor (ie,agonist here is synonymous with direct ugorziit or receptor dgonii-t). T h e term aiitagonlst will designate a substance that directly blocks the action of a transmitter at the receptor. Many compounds possess the property of an agonist at low concentration but behave as an antagonist at high concentration; they are usually referred to as incomplete or partiul agonists. liz Vitro Studies

It has now been established that a dopamine-sensitive adenplate cyclase is closely associated with the majority of dopamine receptors [17, 181. Activation of this cyclase leads to formation of cyclic adenosine monophosphate (CAMP), which appears to act as a “second messenger,” following dopamine in a series of linked reactions that culminate in altered membrane permeability with consequent depolarization or hyperpolarization. Cyclic nucleotides (CAMPand cyclic guanosine monophosphate, cGMP) seem to be widespread second messengers at central synapses, but a more direct mechanism mediates the fastest synaptic systems, such as nicotinic transmission. Dopamine-sensitive adenylate cyclase has been employed to provide a “test-tube” model for screening dopaminergic agonists and antagonists. The potential therapeutic agent is incubated with homogenates of striatal tissue, and the production of CAMP by dopamine-sensitive cyclase is measured. This procedure is simple and rapid, but it is limited to the study of substances that are reasonably water soluble at p H 7; otherwise, the enzyme systems employed in the assay of CAMP are destroyed. Compounds are available that bind specifically to receptors, and by measuring the displacement of these ligands it is possible to define the characteristics of postsynaptic drug action and to quantify a variety of different receptor properties. For example, from studies of specific dopamine binding, it has been proposed that dopaminergic receptors can exist in two interchangeable states, o n e with a high affinity for apomorphine (agonist) and another with a high affinity for haloperidol (antagonist) [ 191. Another useful in vitro test is the measurement of the action of potential therapeutic agents on dopaminergic nerve endings. Minces, slices, or purified preparations of nerve endings and synapses

PRESYNAPTIC

POSTSYNAPTIC

Postsynaptic receptor

Sites of reuptake

Presynaptrc receptor

Transmitter undergoing-. synthesis

@

Transmitter undergoing release lrorn synaptic vesicle Transmitter undergoing reuptake

Synaptic vesicle Transmitter undergoing exlracellular enzymic destruction

F i g 1 . Diagramnialii- summarj of the major features of a synapse. (From Caltze DB: Therupentics in Neimlogy. Oxford. E ngiand. Black i r e l Srierittjii- Pu blirations, 19 75 . i

(“synaptosomes” obtained by differential centrifugation of homogenates) from rat brain are incubated with radioactive-labeled dopamine and the compound under investigation [20, 211. In this way, i t is possible to establish whether the proposed medication may increase transmission by primarily releasing dopamine from nerve endings or by blocking the presynaptic active reuptake mechanism that makes a major contribution to inactivating dopamine present in the synaptic cleft. Again, these systems are appropriate only for compounds that can easily be brought into solution, since tissue minces, slices, and synaptosomes are sensitive to any distortion of the p H or ionic content of the assay medium. It would be inappropriate to leave the subject of in vitro test systems without mentioning the contributions of the following: 1. Macroscopical biochemical localization, in various regions of the brain, of the relative concentrations of transmitters or their metabolites. 2. Transmitter turnover studies, performed with radioactive-labeled precursors. 3. Specific inhibitors of enzymes, storage mechanisms, and uptake processes, which allow separation of the stages of transmitter synthesis, accumulation, release, and inactivation. 4. Histochemical identification of transmitters at the cellular level by fluorescent microscopy. 5 . Subcellular localization of enzymes involved in transmitter synthesis or degradation by ultracentrifugation, sucrose density gradient fractionation, and immunochemical techniques. 6. Ultrastructural studies of synapses, if necessary utilizing peroxidase staining to reveal transmitter, enzyme, or receptor disposition at the electron microscopical level.

All these biochemical and morphological techniques, developed for the purpose of analyzing the normal mechanisms of synaptic function, can be applied to the study of how new drugs may be designed and refined to alter synaptic transmission for a therapeutic purpose. Potential antiparkinsonian agents can be compared for their ability to increase the rate of synthesis, decrease the rate of degradation, or augment the concentration of dopamine or CAMPin striatal tissue. In Vim Studies The most sophisticated technique that can be employed for both screening therapeutic agents and elucidating the mechanism of action of a drug is microiontophoresis, in which substances are deposited directly onto neurons and their effect on the electrical activity of the cell is recorded [221. Hithrrto, this procedure has been used largely for the purpose of identifying receptive sites for putative transmitters in different areas of the brain. The accession of microiontophoresis into more widespread use in neuropharmacology laboratories will allow its application to the practical problems of predicting the therapeutic potential of new compounds. A similar technique involves recording the changes in electrical activity of single neurons when drugs are administered systemically [2 31. This method gives less direct information on the mechanism of action, but it is particularly useful when a drug is suspected to be acting indirectly via a presynaptic effect or following the formation of an active metabolite. O n e of the most satisfactory pharmacological animal models of parkinsonism derives from studies on the effect of intranigral injection of 6-hydroxydopamine in rats [24, 251. The unilateral nigrostriatal degeneration induced in this way leads to a behavioral paradigm characterized by involuntary turning and provides an ideal opportunity for quantifying the activity of potential therapeutic agents. In addition, this preparation allows some separation of

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the mechanisms of action of dopaminergic agents, in that it enables drugs that operate through presynaptic elements (and therefore act only on the intact nigrostriatal pathway) to be distinguished from compounds that drive the postsynaptic neuron directly via its receptors (and hence have their major effect on the side of the lesion, which acquires denervation supersensitivity). An older animal model of parkinsonism that has proved invaluable in the study of monoamines (dopamine, norepinephrine, and serotonin) is the reserpinized rodent. Reserpine depletes all stores of monoamines to produce an akinetic, sedated animal whose motor activity can be restored by levodopa [261. An animal model has also been proposed for dyskinesia, the most important clinical adverse reaction to antiparkinsonian drugs. In rats, the analogue seems to be a behavioral disturbance characterized by repetitive movement and compulsive gnawing and sniffing, the total syndrome being termed stereotopy [271. With single-unit recording, nigral lesions, reserpinized preparations, and stereotopy we have four approaches to evaluating the potential efficacy and toxicity of antiparkinsonian therapy in vivo. The predictive value of these systems exceeds that of any previous screening procedures available and also generates a basis for analyzing the pharmacological disturbances occurring in parkinsonism and in certain forms of overdosage with antiparkinsonian drugs.

Conceptual Developments A number of conceptual advances have arisen from the continually evolving pharmacological scene. Among the more important developments is the hypothesis that parkinsonism and chorea are two poles in a continuum of transmitter disturbances in which dopaminergic function is either decreased (parkinsonism) or increased (chorea) [281. An inhibitory pathway projecting from the striatum to the substantia nigra has been shown to employ y-aminobutyric acid (GABA) for synaptic transmission [29]. Glutamic acid decarboxylase, which controls the formation of GABA, is depleted in the brains of patients with Parkinson’s disease, but prolonged administration of levodopa corrects this deficiency [30]. This adds a new element to the already complex equation of balance and interaction between dopamine and acetylcholine. Drugs are available that increase the concentration of GABA in the brain, probably by blocking its degradation. The first such substance to be sufficiently free of toxicity to be given to man IS sodium valproate [311;it will be of interest to see whether this agent has any effect o n parkinsonism or on the actions of levodopa. T h e difficulty of predicting the cascade of consequences that might arise from modulating one of the 114 Annals of Neurology Vol 1 No 2

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many interacting transmitters in the nigrostriatal pathway is compounded by the presence of serotonin, acetylcholine, and glycine-all established transmitters-in the substantia nigra [ 321. Furthermore, nigrostriatal dopaminergic neurons have autoreceptors at their presynaptic nerve endings [33], and there are also dopamine-sensitive receptors in the substantia nigra [34-361. The role and precise cellular location of the nigral receptors have not been established with certainty, but stimulation of the striatal dopaminergic presynaptic autoreceptors leads to inhibition of the neuron’s synthesis of tyrosine hydroxylase (responsible for the rate-limiting scep in the synthesis of dopamine); these autoreceptors thus serve a negative-feedback function 1371. It is of some interest that tyrosine hydroxylase activity declines in the striatum with advancing age in nonparkinsonian subjects, and there is a corresponding loss of neurons in the dopaminergic cell bodies of the substantia nigra; both of these trends are markedly advanced in parkinsonism [37a]. Another new concept is the distinction between a transmitter and a modulator, the latter term denoting a neuronally released agent that cannot generate the usual short-latency, brief-duration excitatory or inhibitory postsynaptic potential. Instead, a modulator induces delayed-latency, long-duration changes that alter the response to a conventional transmitter. The same agent may be employed as a transmitter in one setting and a modulator in another; for example, in some mammalian sympathetic ganglia the postganglionic neuron has nicotinic receptors at which acetylcholine acts as an excitatory transmitter and muscarinic receptors where acetylcholine behaves as a modulator to produce late, slow, facilitatory depolarization [37bI. To increase the complexity still further, peptide transmitters or modulators are replacing amines and amino acids as the most rapidly growing frontier of neuropharmacological research [38]. There are high concentrations of substance P in the substantia nigra [39]; thus undecapeptide is localized to nerve fibers and synaptosomes-it seems to be a transmitter or modulator with predominantly excitatory effects [401. The enkephalins (met-enkephalin and leuenkephalin) are pentapeptides which, in rats, attain their greatest concentration in the striatum [40al. They appear to be natural transmitters or modulators which employ the same receptors that can be artificially activated with opiates; their receptors are present in high density in the striatum [4Ob]. Enkephalins induce an increase in the second messenger cGMP in the striatum [~OC], and their microiontophoretic application can induce both facilitation and inhibition of striatal neurons [ilOd]. Intraventricular or intracisternal administration of enkephalins and similar bur longer peptides leads to akinesia and rigidity similar to

the reserpine syndrome generally regarded as a rat model of parkinsonisrn [40e]. Other peptides may also be important in parkinsonism; for example, therapeutic actions have been reported following intravenous administration of melanocyte-stimulating hormone release-inhibitory factor [41]. It is not yet possible to integrate all these observations into a single, coherent framework relating peptides to extrapyramidal diseases, but the dramatic advances taking place in peptide neuropharmacology seem certain to have some relevance to the neurology of movement disorders. There have been few attempts to correlate individual clinical features of parkinsonism with regional changes in transmitters or their metabolites. In one study [ 4 2 ] it was found that the severity of akinesia was directly related to loss of homovanillic acid ( H V A b t h e major acid metabolite of doparnine-in the caudate nucleus, whereas tremor paralleled depletion of HVA in the globus pallidus. There was no statistically significant correlation between rigidity and any focal alteration in HVA. Interpretation of the decreased norepinephrine and serotonin in the brain in parkinsonisrn remains obscure. The difficulty in establishing localization of function in the basal ganglia in pharmacological or clinical terms may be a reflection of the diffuse nature of the nigrostriatal pathway. In the rat, for example, each nigral dopaminergic neuron may possess 500,000 axonal varicosities [43],which together contain 150 times the content of dopamine in the cell body, and the arborization of one axon can result in a terminal network of 77 cm (the distance from nigra to striatum being only I cm). These characteristics suggest that there is considerable dispersion of dopaminergic output in space, and recent studies indicate that there may also be considerable dispersion of dopaminergic effects in time. The relatively slow changes anticipated to arise from administering “transmitter replacement therapy” can be interpreted in conventional neurophysiological terms, since dopaminergic neurons in the substantia nigra exhibit tonically repetitive firing [44]. In addition, there are observations indicating that doparnine may elicit tonic effects on the nervous system in other ways. The mammalian superior cervical ganglion contains a dopaminergic interneuron capable of producing a slow inhibitory postsynaptic potential that may last for several seconds. Dopamine can, in addition, produce prolonged facilitation of the postsynaptic potential that is unlike any other synaptic phenomenon; this effect can persist for several hours and raises the question of whether dopamine can induce a long-lasting metabolic o r even structural change in the postsynaptic neuron [45]. Hitherto, synaptic events discovered at the periphery have usually been found to have their homologue in the central nervous system, so that

these prolonged dopaminergic influences may have their counterpart in the striatum. Some of the clinical (therapeutic or perhaps adverse) actions of dopaminergic drugs in parkinsonism might therefore stem from slow modulatory actions rather than from their mimicking the short-duration, repetitive synaptic consequences of conventional impulse traffic. The essential point is that dopamine may have more than one action on the same postsynaptic neuron: a therapeutic response (such as improvement of akinesia) may result from one effect, and an unwanted phenomenon (such as dyskinesia) may derive from another action. These possibilities create a new investigative need, namely, the quest for drugs of sufficient specificity to separate different dopaminergic effects at the same synapse. Acquisition of such agents could have therapeutic implications. Reference has already been made to the behavioral evidence for induction of dopaminergic supersensitivity in rats with unilateral nigral lesions. Biochemical observations (augmentation of dopamine-sensitive adenylate cyclase) also indicate that nigral lesions result in striatal denervation supersensitivity [46].It is not possible to predict whether supersensitivity is likely to be beneficial, by increasing the therapeutic response to a dopaminergic drug, or deleterious, by augmenting adverse reactions. The mechanism of induction of altered sensitivity is complex; although dopamine antagonists usually produce increased sensitivity analogous to that of denervation, it is also possible for a drug that increases dopaminergic transmission, such as amphetamine, to enhance sensitivity [47]. The therapeutic importance of changes in dopaminergic sensitivity is considerable. Certain actions of levodopa rapidly decline with continued administration of the drug. Such loss of sensitivity is clearly beneficial for emesis and hypotension, since it allows an increase in dosage, while the therapeutic response is less prone to decline (at least over the first few years of treatment). Altered response to a drug is often caused by pharmacokinetic changes, such as an increased rate of drug metabolism consequent o n induction of microsomal enzymes, but pharmacokinetic tolerance usually affects all drug actions equally in the same target organ. The selective decrease in dopaminergic responses suggests that certain receptors in the brain may be displaying reduced sensitivity, a phenomenon known as tachyphylaxis. Fluctuation in receptor sensitivity is poorly understood. O n e of the best-studied systems in this respect is the beta-adrenergic receptor of the rat’s pineal gland, which (like most dopaminergic receptors) mediates its action through an adenylate cyclase. It has been found that stimulation ofthis receptor leads to a rapid decrease in the number of available receptors; conversely, decreased stimulation results in the appearance of more receptors. The affinity of

Current Review: Calne: Pharmacology and Therapeutics of Parkinsonism 115

individual receptors does not change [ 4 8 ] . Such phenomena tend to impose homeostasis and do not provide any encouragement in the search for improved therapy. However, they may afford a clue to understanding the cause of some of the rapid changes in drug action shown, for example, in certain cases of on-off reaction in which the clinical response does not always correlate with plasma concentrations of drugs

[431. Apomorphine was regarded as a pure dopaminergic agonist for several years, but recently it has been found that high concentrations inhibit the formation of CAMP [50]and block the vasodilatation induced by dopamine [ 5 11, suggesting antagonism. All agonists, even the physiological transmitter, may perhaps behave as antagonists when present in high concentration. Instead of posing the qualitative question of whether or not an agonist is complete, it may be more appropriate to ask of all agonists, in quantitative terms, how incomplete each is. T h e concept of the perfect agonist may be as redundant as the ideal of a completely specific drug. It is possible that several categories of dopaminergic receptor are present in different regions of the brain, analogous to muscarinic and nicotinic receptors for acetylcholine or to alpha and beta receptors for norepinephrine. For example, autoreceptors o n presynaptic nerve endings of dopaminergic neurons are not associated with a dopamine-sensitive adenylate cyclase (in contrast to other dopaminergic receptors) [46].Recently it has been proposed that dopaminergic receptors be subdivided into two types: DA, (excitatory response to dopamine) and DAi (inhibitory response to dopamine) [ 5 2 ] .It is suggested that both types of receptors are present in the striatum, each having a distinct morphology. DA, synapses have been related to a diffuse network of nerve endings, whereas DA, synapses are associated with relative focal “islands” [ 5 3 ] . Specific agonists and antagonists have also been attributed to each category of receptor. While these ideas are somewhat speculative, they possess the most desirable attribute of any hypothesis: they can be tested and so they will undoubtedly provide a new impetus to studies o n the pharmacological activity of dopamine in the brain. Furthermore, the subdivision of dopaminergic receptors in the brain establishes a rational basis for attempting to develop antiparkinsonian drugs that separate therapeutic from adverse effects by selectively stimulating or blocking different types of receptors. Another conceptual advance of importance in relation to antiparkinsonian therapy is the recognition that there is a range of M A 0 isoenzymes [541 that have differing affinity for the various monoamines. MAOh oxidizes norepinephrine, serotonin, and, to a lesser extent, dopamine. MAOR destroys dopamine without inducing any major change in norepinephrine 116 Annals of Neurology

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or serotonin levels. Inhibitors are now being developed that can block MAOBwith relative specificity [ 5 5 ] . Such drugs should raise dopamine concentrations in the brain selectively and are therefore potential therapeutic agents for the treatment of parkinsonism. T h e r a p e u t i c Advances Several strategies could be employed in an attempt to improve the selectivity of the central action of antiparkinsonian therapy. For example, drugs might be developed that accumulate in certain areas of the brain or undergo localized breakdown to active metabolites. However, exploitation of regional differences in accessibility, storage, or metabolism of drugs remains a task for the future. Similarly, it has not proved possible to find any dopaminergic antagonist with sufficient specificity to suppress selectively adverse reactions such as dyskinesia. Nevertheless, two approaches to increasing the ratio of wanted to unwanted central effects have reached the stage of clinical study and are yielding encouraging results-the development of agonists and isoenzyme inhibitors.

D~pum in erg zc Ago 12 i.r ts If different types of dopaminergic receptors exist i n the brain, optimal therapeutic benefit should be attainable by designing a selective agonist, a compound that mimics dopamine in having a direct effect oc the receptor but ideally acts only on the category of receptor belonging to the synapses that are defective in parkinsonism. In addition to the possibility of achieving a more desirable response by possessing relative specificity for certain dopaminergic synapses, agonists have other theoretical advantages over precursors as potential therapeutic agents. These compounds do not require L-aromatic amino acid decarboxylase, the enzyme involved in the conversion of levodopa to dopamine (there is a depletion of L-aromatic amino acid decarboxylase in the brains of patierits with parkinsonism 1301), and thus agonists should induce more consistently reproducible dopaminergic effects. Agonists should also cause less disturbance of other monoamine transmitters in the nervous system; levodopa is metabolized to norepinephrine and epinephrine, and it also alters tissue concentrations of serotonin. Some of these effects may contribute to adverse reactions to levodopa. Further properties that might be sought in the quest for an ideal dopaminergic agonist include a long biological half-life and ready penetration of the blood-brain barrier. Such rational steps in the development of a new therapeutic agent are optimistic, and no perfect agonist, conforming to all these requirements, has yet been found. However, by the use of screening programs that employ the pharmacological test systems

currently available, two classes of agonists, apomorphines and ergolines, have been developed. APORPHINES. Apomorphine

was the first dopaminergic agonist reported to have therapeutic activity in parkinsonism [56].Unfortunately, the high oral doses that were required also led to azotemia, so the drug was abandoned. From the investigation of a number of congeners of apomorphine, it was found that N-propylnoraporphine was also beneficial and had the advantage of being less nephrotoxic than apomorphine [5 71. This compound is undergoing further evaluation and could prove to be a useful advance in therapy if it is possible to overcome the tolerance that commonly develops. Initial findings suggest that this problem may be alleviated b y concomitant administration of low doses of levodopa.

ERGOLINES.

A number of pharmacologically active

derivatives of ergot have been found to share a structural nucleus made up of a lysergic acid residue (ergoline). Some of these ergolines mimic dopamine in endocrinological test systems; they can suppress the release of prolactin in hyperprolactinemia [58] and decrease the concentration of circulating growth hormone in acromegaly [591. Several ergolines possess dopaminergic properties in animal models of parkinsonism [60,61].The first of such ergolines to show therapeutic activity was bromocriptine (2-bromo-aergokrpptin) [62]. This drug has a modest antiparkinsonian effect at low dosages [63-651, but with higher dose regimens, evidence suggests an action quantitatively comparable to that of levodopa [66-68]. I n patients who are experiencing certain adverse reactions such as on-off phenomena, bromocriptine appears to be preferable to levodopa (with or without a decarboxylase inhibitor) [60]. Other ergolines of current interest as potential therapeutic agents in parkinsonism include lergotrile [701 and Iisuride [7 1I. T h e structural relationships between dopamine, aporphines, and ergolines are illustrated in Figure 2.

Isoevizyyme Inhibitors Selective blockade of MAOB, the isoenzyme that specifically destroys dopamine, should increase concentrations of this transmitter in the brain without significant alteration of norepinephrine or serotonin. Recent studies suggest that relatively specific inhibition of MAOB can be achieved with a phenylethylamine, deprenil. This drug has been investigated in parkinsonism. A rapid improvement in neurological deficits was reported when deprenil was administered in combination with levodopa and an extracerebral decarboxylase inhibitor [ 5 5 ] . Other M A 0 inhibitors, such as nialamide and tranylcypromine, which block MAOA,lead to intolerable elevation of the blood pressure when combined with

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levodopa [72];the hypertensive response is reduced, but not eliminated, by concomitant administration of an extracerebral decarboxylase inhibitor [73]. It is too early to know whether any or all of these new therapeutic agents-apormorphines, ergolines, or MAOB inhibitors-will find their way into the routine management of parkinsonism. Perhaps the most important practical questions are the following: ( 1) whether long-term administration of any of these drugs will lead to sustained efficacy without serious toxicity; (2) whether optimal results will be obtained with or without concomitant levodopa therapy; and (3) whether any undesirable interactions will occur with other drugs. Theoretical problems relate to (1) whether the compounds discussed are as specific as hoped; (2) whether they form any active metabolites; and ( 3 ) whether any adverse reactions to levodopa (such as choreoathetoid movements or hallucinations, which are drug-induced paradigms of other neurological and psychiatric diseases) can be correlated with activation of different pharmacological categories of dopaminergic receptors. I wish to thank Miss Vernita Bergrneyer and Mrs Joan Kraft for typing the manuscript and collating the references. I am grateful to Drs J. Kebabian, E. Silbergeld, and J. Walters for their helpful coniine 11ts,

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References 1. Sherrington C : Man on His Nature. Cambridge, England, Cambridge University Press, 195 1 2. Bertler A, Rosenbren E: Occurrence and distribution of dopamine in brain and other tissues. Experientia 15:10, 1959 3. Carlsson A: The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol Rev 11:490-493, 1959 4. Ehringer H , Hornykiewicz 0: Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menscheii und ihr Verhalten beim Erkrankungen des extrapyramidalen Systems. Klin Wochenschr 38:1236, 1960 5 . Birkmayer W , Hornykiewicz 0:Der L-3,4-Dioxyphenylalanin (=DOPA)-Effekt bei der Parkinson-Akinese. Wien Klin 6. Barbeau A, Sourkes TL, Murphy GF: Les cattcholamines dans la maladie de Parkinson, in de Ajuriaguerra J (ed):Monamines et Systeme Nerveux Centrale. Paris, Masson et Cie, 1962, p 247 7 . Cotzias GC, Van Woert M H , Schiffer LM: Aromatic amino acids and modification of parkinsonism. N Engl J Med 2 7 6 3 7 4 , 1967 8. Yahr M D : Results oflong term administration of L-dopa, in de Ajuriaguerra J, Gauthier G (eds): Monoarnines, noyaux p i s centraux et syndrome de Parkinson. Paris, iMasson e t Cie, 1971, 17 it03 9. Barbeau A, Mars H, Gillo-Joffroy L: Adverse clinical sideeffects oilertodopa therapy, in McDowell F H , Markham C H (eds): Recent Advances in Parkinson's Disease. Philadelphia, FA Davis Company, 197 I , p p 204-237 10. Papavasiliou PS, Cotzias G C , Duby SE, e t al: Studies on metabolism and mechanism of action of methyldopa. Circulation 28:492-502, 1973 11. Chase T N , Watanabe AM: ~Methyldopahydrazine as an adjunct to L-dopa therapy in parkinsonism. Neurology (Minneap) 22:384-392, 1972 12. Calne D B , Reid JL, Vakil SD, e t al: Idiopathic parkinsonism treated with an extracerebral decarboxylase inhibitor in cornbination with levodopa. B r Mcd J 3:729-732, 1971 13. Yahr MD (ed): Treatment of parkinsonism-the role of dopa decarboxylase inhibitors. Adv Neurol 2:l-303, 1973 14. Rinne UK, Sonninen V, SiirtolaT: Treatment ofparkinsonism patients with levodopa and extracerebral decarboxylase inhibitor, Ro 4-4602. Adv Neurol 3:59-71, 1973 15. Barbeau A, Roy M: Six-year results oftreatrnent with levodopa plus benzerazide in Parkinson's disease. Neurology (Minneap) 26: 399-404, 1976 16. Calne DB: Therapeutics in Neurology. Oxford, England, Blackwell Scientific Publications, 1975, p 328 17. Kebabian JW, Greengard P: Dopamine-sensitive adenyl cyclase: possible role in synaptic transmission. Science 174: 1346-1 349, 1971 18. Kebabian JW, Petzold GL, Greengard P: Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain, and its similarity to the "dopamine recepror." Proc Natl Acad Sci USA 692145-2149, 1972 19. Creese IN, Bunt DR, Snyder SH: Dopamine receptor binding: differentiation of agonist and anmgonist states with 'JHdopamine and sHH-haloperidoLLife Sci [II] 17:993-1002, 1976 20. Seeman P, Lee T T h e dopamine releasing actions of neuroleptics and ethanol. J Pharmacol Exp Ther 190:131-140, 1974 21. H o r n AS, Coyle JT, Snyder SH: Catecholamine uptake by synaptosomes from rat brain. Mol Pharmacol7:66-80, 19'1 22. Bloom FE, Costa E, Salmoiraghi GC: Anesthesia and the responsiveness of individual neurons of the caudate nucleus of

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C u r r e n t Review: Calne: Pharmacology a n d Therapeurics of Parkinsonism

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Developments in the pharmacology and therapeutics of parkinsonism.

CURRENT REVIEW Developments in the Pharmacology and Therapeutics of Parkinsonism D. B. Calne, MD Advances in synaptic pharmacology have led to new ap...
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