Acta neurol. scandinav. 60, 1-11, 1979 Laboratory of Neurophysiology, National Institute of Mental Health and Experimental Therapeutics Branch, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A. REVIEW
Developments in understanding the physiology and pharmacology of parkinsonism HEIKKITERXVAINEN AND DONALDB.
CALNE
While the era of major advances in understanding and treating parkinsonism seems to be over, steady progress is being made in elucidating physiological and pharmacological aspects of extrapyramidal function. The dramatic impact of levodopa therapy has been followed by the recognition of serious limitations to its long-term use, which provides a continuing stimulus for efforts to analyze the physiological and pharmacological properties of the basal ganglia and substantia nigra. There are reasonable grounds for the hope that this research will lead to significant developments in therapy. Key words: Parkinsonism - physiology - pharmacology - basal ganglia substantia nigra - neurotransmitters - neuromodulators - dopaminergic receptors
Over the last 20 years the study of Parkinson’s disease has burgeoned from one of the lowest priority topics in neuroscience to become an area of intense coordinated research in both the laboratory and the clinic. Advances in physiology, biochemistry, pharmacology and treatment have arisen from new interest, innovative concepts and a multidisciplinary approach which has exploited a wide range of technical developments. PATHOPHYSIOLOGY
Hitherto there has been considerable confusion and disagreement over the role of the basal ganglia and substantia nigra in motor function. Recently, accumulating evidence has allowed a relatively coherent though imprecise concept to be discerned. The extrapyramidal nuclei appear to be responsible for the assembly of a plan for movement, which is executed via the motor cortex and monitored for errors by the cerebellum. Although broad generalizations of this kind must bear the criticism of oversimplification, they are useful in setting the stage for a more detailed presentation of particular aspects of motor physiology. Nigrostriatal interconnections are of central importance in any consideration of extrapyramidal function. Neurons in the zona compacta of the sub0001-6314/79/070001-11 $0.2.50/0 @ 1979 Munksgaard, Copenhagen
2 stantia nigra (SN) synapse with striatal nuclei via a slowly conducting pathway comprising fine axons with extensive arborization and multiple variosities which contain dopamine. These dopaminergic cells display a pattern of firing lquite exceptional for the motor system; impulse frequency appears to be sustained at approximately similar levels in unconscious immobile animals, conscious animals at rest, and conscious animals during movement. Such observations have led to the suggestion that the zona compacta neurons may “function as a tonic system with a more general role7’ (DeLong & Georgopoulos 1978). In current terminology, dopamine may be exerting a diffusemodulatory influence in the striatum rather than localized inhibition or excitation of neuronal activity related to voluntary or involuntary movements. From the striatum there is a feedback GABAergic pathway; recent evidence indicates that this projection may synapse in the zona reticdata of the SN, where interneurons transmit inhibition to the dopaminergic cells in the zona compacta (Waszczak & Walters 1979). The major pathway from the striatum is via the pallidum through the thalamus to the motor cortex, linking extrapyramidal to corticospinal (pyra-
1
MOTOR COMMANDS VIA DESCENDING PATHS
I
FEEDBACK INFO\YLTION ASCENDING PATHS
RELAY CENTERS
LOWER MOTOR
9-y
AFFERENT INPUT
I
I
+
MOTONEURON
REFLEX ARC
i
OUTPUT
Figure 1. Simplified circuit diagram of the main components involved in voluntary and involuntary movements in parkinsonism. Both the corticospinal tract and indirect extrapyramidal pathways through brain stem to spinal cord are shown as “motor commands via descending paths.” Damage to the pathway from substantia nigra (SN)to striatum (SR) results in excessive excitation o f the ventrolateral nucleus (VL) o f the thalamus by impulses through globus pallidus (GP). Thalamo-cortical connections to motor cortex ( M C ) finally link the diseased extrapyramidal function to pyramidal output (Evarts et al. 1979).
3 midal) function (Fig. 1). The projections from the motor cortex are complex, as illustrated by the work of Lawrence & Kuypers (1968), who sectioned pyramidal tracts in monkey, leaving the extrapyramidal pathways intact. The monkeys moved slowly, tired easily and lost manipulative skills, but could still walk and climb in a way closely similar to that before the operation. Thus, the motor cortex can drive the spinal motoneurons via brainstem-spinal pathways; these projections are poorly understood in both health and disease. Physiological analysis of parkinsonism has elucidated certain aspects of the cardinal features - rigidity, tremor, and the less obvious but most incapacitating deficits, akinesia and bradykinesia. Rigidity Rigidity derives from increased activity of the alpha motoneurons innervating the extrafusal muscle fibers, and it is markedly enhanced by reflex reinforcement, achieved through the Jendrassik maneuver or by voluntary movement in the contralateral extremity. Evidense has been sought to elucidate whether the increase of the alpha activity is due to (1) direct excitation of the alpha motoneurons (alpha rigidity) or (2) indirect drive by a selective increase in fusimotor activity resulting in increased afferent (Ia) input to the alpha motoneurons (gamma rigidity), or (3) both of these mechanisms. Studies involving direct recordings of Ia afferents during passive movements (Wallin et al. 1973) indicate that in both controls and parkinsonian subjects, Ia responses to rapid passive stretch are similar, whereas maintained stretch leads to enhanced Ia activity in rigid patients. This work supports the earlier and much debated reports of increased tonic reflex responses in parkinsonism (Dietrichson 1971). So while there appears to be normal coactivation of alpha and gamma motoneurons during fast muscle stretch in parkinsonian patients, increased fusimotor discharge may occur during sustained muscle stretch.
Akinesia and Bradykinesia The reaction time is minimally elevated in parkinsonism, values ranging from about 310-430 ms, compared to 210-310 ms in normal subjects (Evarts et al. 1979). There is a more definite and substantial reduction of the speed of movement in parkinsonian patients, associated with difficulty in augmenting the velocity as the amplitude increases (Flowers 1976). Other deficits to have been identified include difficulty in correcting errors (Angel et al. 1970), in carrying out two movements simultaneously (Horne 1973), in performing a sequence of movements (Perret et al. 1970) and in the normal activation of muscles in more complex motor tasks such as walking (Buchthal & Fernandez-Ballesteros 1965). 1.
4 The neurophysiological basis of these problems has not been established with certainty. Lee & Tatton (1978) and Mortimer & Webster (1978) have reported normal short latency (segmental) reflexes but increased long latency (50-120 ms) responses to rapid muscle stretch in rigid parkinsonian patients; these workers inferred the existence of an abnormal suprasegmental modulation of the peripheral inputs. Augmented long latency responses are also found in some normal elderly subjects who have enhanced background EMG activity at rest (Evarts et al. 1979). Flowers (1978) has studied motor control by means of a tracking task with oscilloscope display under joystick control; his results indicate that the patients “seem to lack a dynamic internal model of their movements.” The patients were unable to follow repetitive movement patterns without visual control, an abnormality resembling that produced by cooling the globus pallidus in monkeys (Hore et al. 1977). Tremor Low frequency (3-7 Hz) tremor in resting limbs is usually the most striking physical sign of parkinsonism. The frequency varies in different extremities, and can alter over the course of time. In addition to the resting tremor, patients often exhibit an action tremor. The abnormal activity culminating as tremor can be suppressed by cutting the physiological connections between the basal ganglia and the thalamus, or between thalamus and the cerebral cortex, or between the cerebral cortex and the spinal segments. These observations, together with the known location of the pathology within the brain, indicate that central mechanisms are of major importance in the genesis of tremor. On the other hand, several peripheral manipulations of the limb can modify parkinsonian tremor, including ischemia, tonic vibration, partial nerve block (Rondot & Bathien 1976), and electrical stimulation of the muscles (Hufschmidt 1963) or nerves (Liberson 1962). Displacements of the limb can both trigger tremor and abruptly change the phase of action and resting tremor (Lee & Stein 1978, Teravainen et al. 1978). While it can be modulated by peripheral input, tremor can also persist after the elimination of afferent influence by section of the dorsal roots in both parkinsonian patients (Pollock & Davis 1930) and experimental animals with parkinsonlike tremor (Ohye et al. 1970). The contributions of both central and peripheral factors to the genesis of parkinsonian tremor are not mutually exclusive. A recent hypothesis (Evarts et al. 1979) proposes that the tremor is due to oscillations within a supraspinal feedback loop involving the VL-nucleus of the thalamus and the motor cortex (Fig. 1). Ascending afferent input can trigger and modify oscillations within the loop as can voluntary initiation of movement. The role of VL-nucleus of the thalamus in producing parkinsonian tremor may be
5
considered as analogous to that of the spinal segments in pyramidal disease associated with clonus, where interruption of the upper motoneuron leads to a hyperexcitable spinal segment, and oscillation (clonus) can be triggered in a structurally normal but physiologically altered peripheral feedback loop. Similarly, in parkinsonism diseased nigrostriatal output results in increased excitability of the VL-nucleus; perturbation (passive displacement or voluntary movement) activates a structurally normal but physiologically altered central feedback loop, leading to oscillation. When there is an appropriate “central excitatory state” oscillation can develop without a change in afferent signals, so that spontaneous tremor can develop in parkinsonism, just as spontaneous clonus can occur in pyramidal disease. BIOCHEMISTRY AND PHARMACOLOGY
One of the most notable biochemical advances in relation to nigral and basal ganglia function has been the plethora of neuroregulatory agents found in these regions of the brain. In addition to dopamine, there exists acetylcholine, gamma aminobutyric acid and serotonin, norepinephrine, glycine, taurine and a number of small peptides (Dray & Straughan 1976). There is a particularly high concentration of substance P in the substantia nigra (Powell et al. 1973), and a similarly privileged tissue level of methionineenkephalin and leucine enkephalin in the basal ganglia (Smith et al. 1976). However, no significant effect on parkinsonism has been detected following administration of the few drugs that are available to modify the influence of neurohumeral agents other than dopamine and acetylcholine. Biochemically the substantia nigra and basal ganglia offer an embarrassment of riches, the physiological, pharmacological and pathological significance of which are unclear. In this review attention will be focused on dopamine since the role of other neurohumeral agents remains obscure. Recent studies have led, in particular, to developments in receptor pharmacology, to extended concepts of neurohumeral transmission, and to new approaches to treatment. Receptors An important pharmacological development over the last few years is the recognition that there are multiple categories of dopamine receptors in basal ganglia and substantia nigra. While classification of these receptors can be based on various criteria, separation into D-1 and D-2 receptors has recently been suggested on the basis of whether the receptors are linked to an adenylate cyclase (Kebabian & Calne 1979). Those receptors which are associated with an adenylate cyclase have been termed D-1 type, and those which are independent of the enzyme have been designated D-2 type. Subclassification within these primary divisions may prove possible in the
6
Figure 2. A schematic representation o f the neurons in the nigrustriatal axis which contain dopamine receptors. The dopaminergic neurons contain autoreceptors which regulate either electrical firing of these cells in the substantia nigra (site 1 ) or tyrosine hydroxylase activity (site 2) in the terminals. Cortical neurons which project to the striatum possess binding sites for radiolabelled haloperidol which have been indentified as dopamine receptors (site 3). Neurons intrinsic to the caudate contain dopamine-sensitive adenylate cyclase activity (site 4). Finally, terminals o f striatal neurons which project t o the nigra also contain a dopamine-sensitive adenylate cyclase (site 5). The dopamine receptors at sites 1-3 have not been associated with adenylate cyclase activity (type 0 - 2 ) ; only the receptors at sites 4 and 5 regulate this enzyme activity (type D-1) (Kebabian & Calne 1979).
future. Drugs which improve parkinsonism appear to have a predominantly agonist effect on D-2 receptors, whereas agents which induce or exacerbate parkinsonism are antagonists of D-2 receptors. The complexity of the organization of D-1 and D-2 receptors in the pathways between the substantia nigra and striatum are illustrated in Fig. 2. This shows the disposition of presynaptic and postsynaptic receptors which can, on present evidence, be classified into D-1 and D-2 types. There may be other sites in this area of the brain where dopamine receptors play a role, but already we have more than we can use to develop any unified coherent hypothesis of dopaminergic function in motor control - another embarrassment of riches! Although the evidence is very limited, in vitro studies with certain dopaminergic ergots suggest that there may be a reciprocal relationships between some of the effects of stimulating D-1 and D-2 receptors (Kebabian et al. 1977). Another aspect of receptor pharmacology which has an important bearing on parkinsonism is sensitivity. Alterations in the postsynaptic response to a given concentration of humeral agent in the synaptic cleft can, in theory, arise from (1) modulation of the affinity of receptors, (2) changes in the number of receptors. Current observations indicate that the usual mechanism for normal alteration of sensitivity is a change in the number of available receptors (Kebabian et al. 1975). In pathological situations, changes in receptor sensitivity have a signifi-
7
cant bearing on the results of pharmacotherapy. An increase in dopamine receptor sensitivity may, for example, be necessary to enable dopaminergic agents to improve the motor deficits of parkinsonism; supersensitivity may also underlie some of the centrally induced adverse reactions to treatment. Conversely, subsensitivity could be the basis of the declining therapeutic efficacy of dopaminergic treatment for parkinsonism, which commonly emerges after 3-6 years of levodopa. Fluctuations in receptor sensitivity are one possible explanation of the “on-off ” reactions which so frequently disrupt levodopa therapy after a prolonged period of satisfactory response. While there are only scanty observations on the clinical relevance of changes in dopamine receptor sensitivity, there is irrefutable evidence that denervation of the striatum induces supersensitivity in animals (Ungerstedt 1971). Furthermore, postmortem studies have shown that in the brains of parkinsonian patients with degeneration of the nigrostriatal pathway, there are increased binding sites for radioactive haloperidol (an index of dopamine receptor sensitivity). It is of particular interest that after chronic treatment with levodopa this evidence of enhanced dopamine receptor sensitivity is lacking (Lee et al. 1978). The simplicity of this scheme is marred by the report that administration of dopaminergic agents can, in experimental animals, lead to increased sensitivity (Klawans et al. 1975). Neuromodulators An important new concept to emerge is the recognition that chemical agents are employed to communicate between neurons in ways rather different from those traditionally associated with neurotransmitters. The term neuromodulation has been coined to describe the action of substances which do not, themselves, induce depolarization or hyperpolarization but instead modify the effect of conventional neurotransmitters on neuronal membrane potential. Compared to neurotransmission, neuromodulation usually involves communication of slower onset, more diffuse distribution and more gradual termination. The same substances, such as catecholamines and oligopeptides, may function as neurotransmitters at one location and neuromodulators at another. It may even be possible that along the course of the same axon, varicosities containing the same active substance may utilize this agent as a neurotransmitter at one site and as a neuromodulator at another. For example, while some norepinephrine varicosities in the cerebral cortex make typical morphological synaptic contact with adjacent neurons, other varicosities are quite devoid of histological hallmarks of a synapse (Beaudet d Descarries 1978). By extending the concept of neuromodulation further, the term neurohormone has been introduced for substances which are carried by body fluids to transfer information from one part of the brain to another.
8
The best characterized neurohormones are the hypothalamic factors that are carried by the hypophysial portal circulation to the anterior pituitary (Guillernin 1978). While many of these neurohormones are oligopeptides, catecholamines also participate; for example, dopamine released in the median eminence appears to be the prolactin inhibitory factor that controls the secretion of this hormone by mammotroph cells in the anterior pituitary. From these developments an analogy is clearly discernible between the nervous and the endocrine systems. They share the use of humeral agents to communicate between cells, and just as the same substances may be employed as neurotransmitters in one setting and hormones in another, there is also a sharing of receptor mechanisms. Linkage to an enzyme forming a nucleotide (cyclic AMP or cyclic GMP) is employed in such diverse settings as receptors for acetylcholine, dopamine, norepinephrine, histamine, thyrotrophin, corticotrophin, glucagon, vasopressin and secretin (Robison et al. 1971). The notion of the brain as an endocrine gland has led to the formulation of questions which might have seemed absurd a decade ago. For many years it has been known that a hormonal deficiency may be corrected by transplantation of endocrine tissue. Recently, it has been shown that in rats with unilateral lesions leading to depletion of striatal dopamine, fetal substantia nigra cells can be injected into the lateral ventricle where they survive and grow to produce dopamine in the striatum (Perlow et al. 1979). Such observations must be confirmed and extended, but they naturally elicit the speculation that certain neurological disorders might at some future time be treatable by transplantation of regionally localized selected preparations of neural tissue. Therapy The search for improved treatment for parkinsonism has continued. One approach has been an attempt to find drugs which are dopaminergic agonists with a relatively selective action on those dopamine receptors which, when stimulated, elicit a therapeutic response. This is predicated upon pharmacological separation between the receptors that are predominantly involved in achieving efficacy, from others thought to be concerned with the induction of central adverse reactions such as dyskinesia and psychosis. While there is no firm basis for the optimism inherent in this premise, the profile of response certainly varies between different dopaminergic agents - for example, bromocriptine causes less dyskinesia but more psychosis than levodopa (Calm et al. 1978). These findings justify a continued effort to develop dopaminergic agents with a more favorable therapeutic index than levodopa. A complimentary approach is the quest for relatively selective dopamine antagonists, which might preferentially block the receptors involved in pro-
9
ducing central adverse reactions, without inhibiting those receptors essential for efficacy. Such agents might be used in combination with dopaminergic drugs; some encouraging experience has been reported with the dopamine receptor antagonists oxiperomide and tiapride (Be‘dard et al. 1978, Price et al. 1978). Finally, continued attempts are being made to improve the pharmacokinetic properties of levodopa; in particular, extending the half-life to alleviate “wearing off’’ reactions and “end of dose” akinesia. Some benefit has been claimed with deprenyl, a selective inhibitor of monoamine oxidase B (Lees et al. 1977). Since monoamine oxidase B contributes to the intracellular degradation of dopamine but not of norepinephrine, it can be blocked without the risk of catastrophic hypertension when levodopa is administered. Another pharmacokinetic maneuver currently under investigation is inhibition of catechol-0-methyltransferase. This enzyme plays a major part in destroying extracellular catecholamines. Recent animal studies suggest that catechol-0-methyltransferase can be blocked by U0521, so this drug might also have a role in the treatment of parkinsonism (Fahn et al. 1978).
ACKNOWLEDGMENTS We wish to thank Ms. P. Barnicoat and Ms. L. Wease for typing the manuscript and collating the references. REFERENCES Angel, R. W., W. Alston & H. Garland (1971): L-dopa and error correction time in Parkinson’s disease. Neurol. (Minneap.) 21, 1255-1260. Beaudet, A. & L. Descarries (1978): The monoamine innervation of rat cerebral cortex: synaptic and nmsynaptic axon terminals. Neurmcience 3, 851-860. BCdard, P., I. D. Parkes & C. D. Marsden (1978): Effect of new dopamineblocking agent (Oxiperomide) on drug-induced dyskinesias in Parkinson’s disease and spontaneous dyskinesias. Br. Med. J. 1, 954-956. Buchthal, F. & M. L. Fernandez-Ballesteros (1965): Electromyographic study of the muscles of the upper arm and shoulder during walking in patients with Parkinson’s disease. Brain 88, 875-896. Calne, D. B., A. C . Williams, A. Neophytides, C. Plotkin, J. G. Nutt & P. F. Teychenne (1978): Long-term treatment of parkinsonism with bromocriptine. Lancet i, 735738. DeLong, M. R. & A. P. Georgopoulos (1978): Functional organization of the substantia nigra, globus pallidus and subthalamic nucleus in the monkey. Book of Abstracts, p. 28. VIth International Symposium on Parkinson’s Disease, Sept. 24-27, Quebec, Canada. Dietrichson, P. (1971): Tonic ankle reflex in parkinsonian rigidity and in spasticity. Acta Neurol. Scaad. 47, 163-182. Dray, A. & D. W. Straughan (1976): Synaptic mechanisms in the substantia nigra. J. Pharm. Pharmac. 28, 400-405.
10 Evarts, E. V., H. T. Teravainen, D. E. Beuchert & D. B. Calne (1979): Pathophysiology of motor performance in Parkinson’s disease. Dopaminergic Ergot Derivatives and Motor Functions, ed. K. Fwe & D. B. Calne. Pergamon Press Ltd., England. (In press). Fahn, S., R. Comi & S. R. Snider (1978): Effect of COMT inhibitor U-0521, with levodopa administration. 4th International Catecholamine Symposium, Sept. 17-22, Pacific Grove, California. Flowers, K. A. (1976): Visual “closed-loop” and “open-loop” characteristics of voluntary movement in patients with parkinsonism and intention tremor. Brain 99, 269-310. Flowers, K. A. (1978): Lack of prediction in the motor behaviour of parkinsonism. Brain 101, 35-52. Guillemin,R. (1978): Peptides in the brain: The new endocrinology of the neuron. Science 202, 390-402. Hore, J., J. Meyer-Lohman & V. B. Brooks (1977): Basal ganglia coding disables learned arm movements of monkeys in the absence of visual guidance. Science 195, 584586. Horne, D. J. DeL. (1973): Sensorimotor control in parkinsonism. J. Neurol. Neurosurg. Psychiat. 36, 742-746. Hufschmidt, H. J. (1963): Proprioceptive origin of parkinsonian tremor. Nature 200, 367-368. Kebabian, J. W. & D. B. Calne (1979): Multiple receptors for dopamine. Nature 277, 93-96. Kebabian, J. W., D. B. Calne & P. R. Kebabian (1977): Lergotrile mesylate: an in vivo dopamine agonist which blocks dopamine receptors in vitro. C m m u n . Psychopharmacol. 1 , 311-318. Kebabian, J. W., M. Zatz, J. A. Romero & J. Axelrod (1975): Rapid changes in rat pineal P-adrenergic receptor: Alterations in Z-(3H)alprenolol binding and adenylate cyclase. Proc. Nat. Acad. Sci. USA 72, 3735-3739. Klawans, H. L., P. Crossett & N. Dana (1975): Effect of chronic amphetamine exposure on stereotyped behavior. Adv. Neurol. 9, 105-112. Lawrence, D. G . & H. G. J. M. Kuypers (1968): The functional organization of the motor system in the monkey. The effects of bilateral pyramidal lesions. Brain 91, 1-14. Lee, T., P. Seeman, A. Rajput et al. (1978): Receptor basis for dopaminergic supersensitivity in Parkinson’s disease. Nature 273, 59-61. Lee, R. G. & R. B. Stein (1978): Reflex mechanisms in parkinsonian tremor and essential tremor. Book of Abstracts, p. 56. VIth International Symposium on Farkinson’s Disease, Sept. 24-27, Quebec, Canada. Lee,R. G. & W. G.Tatton (1978): Long loop reflexes in man; clinical applications. Cerebral Motor Control in Man: Long Loop Mechanisms. Prog. Clin. Neurophysiol., Vol. 4, ed. J. E. Desmedt, pp. 320-333, Karger, Basel. Lees, A. J., K. M. Shaw, L. J. Kohout et al. (1977): Deprenil in Parkinson’s disease. Lancet ii, 791-794. Liberson, W. T. (1962): Monosynaptic reflexes and their clinical significance. Electroenceph. Clin. Neurophys., Suppl. 22, 79-89. Mortimer, J. A. & D. D. Webster (1978): Relationships between quantitative measures of rigidity and tremor and the electromyographic responses to load perturbations in unselected normal subjects and Parkinson patients. Cerebral Motor Control in Man: Long Loop Mechanisms. Progr. Clin. Neurophysiol., Vol. 4, ed. J. E. Des-
11 medt, pp. 342-360, Karger, Basel. Ohye, C., R. Bouchard, L. Larochelle, P. BBdard, R. Boucher, B. Raphy & L. J. Poirier (1970): Effect of dorsal rhizotmny on postural tremor in the monkey. Exp. Brain Res. 10, 140-150. Perlow, M. J., W. J. Freed, B. J. Hoffer, A. Seiger, L. Olson & R. J. Wyatt (1979): Brain grafts decrease motor abnormalities produced by destruction of the nigro-striatal dopamine system: behavioral and histochemical evidence. Science. (In press). Perret, E., E. Eggenberger & J. Siegfried (1970): Simple and complex finger movement performance of patients with Parkinsonism before and after a unilateral sterotaxic thalamotomy. J. Neural. Neurmurg. Psychiat. 33, 16-21. Pollock, L. J. & L. Davis (1930): Muscle tone in parkinsonian states. Arch. Neurol. Psychiat. (Chic.) 23, 303-319. Powell, D., S. Leeman & G. W. Tregear et al. (1973): Radioimmunoassay for substance P. Nature (New Biol.) 241, 252-254. Price, P., J. D. Parkes & C. D. Marsden (1978): Tiapride in Parkinsods disease. Lancet ii, 1106. Robism, G. A., R. W. Butcher & E. W. Sutherland (1971): Cyclic AMP, pp. 531. Academic Press, New York. Rondot, P. & N. Bathien (1976): Peripheral factors modulating parkinsonian tremor. Advances in Parkinsonism, ed. W. Birkmayer & 0. Hornykiewicz, p. 269. Hoffmann-La Roche & Co. Ltd., Basle. Smith, T. W., J. Hughes & H. W. Kosterlitz et al. (1976): Enkephalins: isolation, distribution and function. Opiates and Endogenous Opioid Peptides, ed. H. W. Kosterlitz, pp. 57-62. Elsevier Publishing Company, Amsterdam. Teravainen, H., D. B. Calne & E. V. Evarts (1978): Triggering and resetting of parkinsonian tremor by arm displacement. Book of Abstracts, p. 108. VIth International Symposium on Parkinson’s Disease, Sept. 24-27, Quebec, Canada. Ungerstedt, U. (1971): Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system in the rat brain. Acta Physiol. Scand. 82 (Suppl. 367), 69-93. Wallin, B. G., A. Hongell & K.-E. Hagbarth (1973): Recordings from muscle afferents in parkinsonian rigidity. New Developments in electromyography and Clinical Neurophysiology, Vol. 3, ed. J. E. Desmedt, pp. 263-272. Karger, Basel. Waszczak, B. L. & J. R. Walters (1979): Effects of GABA-mimetics upon substantia nigra neurons. Advances in Neurology, ed. A. Barbeau, T. N. Chase & N. Wexler, Raven Press, Neur York. (In press).
D. B. Calne, D.M., F.R.C.P. Clinical Director National Institute of Neurological and Communicative Disorders & Stroke National Institutes of Health Building 10, Rm. 6D-20 Bethesda, Maryland 20205 U.S.A.
Developments in understanding the physiology and pharmacology of parkinsonism HEIKKITERXVAINEN AND DONALDB.
CALNE
While the era of major advances in understanding and treating parkinsonism seems to be over, steady progress is being made in elucidating physiological and pharmacological aspects of extrapyramidal function. The dramatic impact of levodopa therapy has been followed by the recognition of serious limitations to its long-term use, which provides a continuing stimulus for efforts to analyze the physiological and pharmacological properties of the basal ganglia and substantia nigra. There are reasonable grounds for the hope that this research will lead to significant developments in therapy. Key words: Parkinsonism - physiology - pharmacology - basal ganglia substantia nigra - neurotransmitters - neuromodulators - dopaminergic receptors
Over the last 20 years the study of Parkinson’s disease has burgeoned from one of the lowest priority topics in neuroscience to become an area of intense coordinated research in both the laboratory and the clinic. Advances in physiology, biochemistry, pharmacology and treatment have arisen from new interest, innovative concepts and a multidisciplinary approach which has exploited a wide range of technical developments. PATHOPHYSIOLOGY
Hitherto there has been considerable confusion and disagreement over the role of the basal ganglia and substantia nigra in motor function. Recently, accumulating evidence has allowed a relatively coherent though imprecise concept to be discerned. The extrapyramidal nuclei appear to be responsible for the assembly of a plan for movement, which is executed via the motor cortex and monitored for errors by the cerebellum. Although broad generalizations of this kind must bear the criticism of oversimplification, they are useful in setting the stage for a more detailed presentation of particular aspects of motor physiology. Nigrostriatal interconnections are of central importance in any consideration of extrapyramidal function. Neurons in the zona compacta of the sub0001-6314/79/070001-11 $0.2.50/0 @ 1979 Munksgaard, Copenhagen
2 stantia nigra (SN) synapse with striatal nuclei via a slowly conducting pathway comprising fine axons with extensive arborization and multiple variosities which contain dopamine. These dopaminergic cells display a pattern of firing lquite exceptional for the motor system; impulse frequency appears to be sustained at approximately similar levels in unconscious immobile animals, conscious animals at rest, and conscious animals during movement. Such observations have led to the suggestion that the zona compacta neurons may “function as a tonic system with a more general role7’ (DeLong & Georgopoulos 1978). In current terminology, dopamine may be exerting a diffusemodulatory influence in the striatum rather than localized inhibition or excitation of neuronal activity related to voluntary or involuntary movements. From the striatum there is a feedback GABAergic pathway; recent evidence indicates that this projection may synapse in the zona reticdata of the SN, where interneurons transmit inhibition to the dopaminergic cells in the zona compacta (Waszczak & Walters 1979). The major pathway from the striatum is via the pallidum through the thalamus to the motor cortex, linking extrapyramidal to corticospinal (pyra-
1
MOTOR COMMANDS VIA DESCENDING PATHS
I
FEEDBACK INFO\YLTION ASCENDING PATHS
RELAY CENTERS
LOWER MOTOR
9-y
AFFERENT INPUT
I
I
+
MOTONEURON
REFLEX ARC
i
OUTPUT
Figure 1. Simplified circuit diagram of the main components involved in voluntary and involuntary movements in parkinsonism. Both the corticospinal tract and indirect extrapyramidal pathways through brain stem to spinal cord are shown as “motor commands via descending paths.” Damage to the pathway from substantia nigra (SN)to striatum (SR) results in excessive excitation o f the ventrolateral nucleus (VL) o f the thalamus by impulses through globus pallidus (GP). Thalamo-cortical connections to motor cortex ( M C ) finally link the diseased extrapyramidal function to pyramidal output (Evarts et al. 1979).
3 midal) function (Fig. 1). The projections from the motor cortex are complex, as illustrated by the work of Lawrence & Kuypers (1968), who sectioned pyramidal tracts in monkey, leaving the extrapyramidal pathways intact. The monkeys moved slowly, tired easily and lost manipulative skills, but could still walk and climb in a way closely similar to that before the operation. Thus, the motor cortex can drive the spinal motoneurons via brainstem-spinal pathways; these projections are poorly understood in both health and disease. Physiological analysis of parkinsonism has elucidated certain aspects of the cardinal features - rigidity, tremor, and the less obvious but most incapacitating deficits, akinesia and bradykinesia. Rigidity Rigidity derives from increased activity of the alpha motoneurons innervating the extrafusal muscle fibers, and it is markedly enhanced by reflex reinforcement, achieved through the Jendrassik maneuver or by voluntary movement in the contralateral extremity. Evidense has been sought to elucidate whether the increase of the alpha activity is due to (1) direct excitation of the alpha motoneurons (alpha rigidity) or (2) indirect drive by a selective increase in fusimotor activity resulting in increased afferent (Ia) input to the alpha motoneurons (gamma rigidity), or (3) both of these mechanisms. Studies involving direct recordings of Ia afferents during passive movements (Wallin et al. 1973) indicate that in both controls and parkinsonian subjects, Ia responses to rapid passive stretch are similar, whereas maintained stretch leads to enhanced Ia activity in rigid patients. This work supports the earlier and much debated reports of increased tonic reflex responses in parkinsonism (Dietrichson 1971). So while there appears to be normal coactivation of alpha and gamma motoneurons during fast muscle stretch in parkinsonian patients, increased fusimotor discharge may occur during sustained muscle stretch.
Akinesia and Bradykinesia The reaction time is minimally elevated in parkinsonism, values ranging from about 310-430 ms, compared to 210-310 ms in normal subjects (Evarts et al. 1979). There is a more definite and substantial reduction of the speed of movement in parkinsonian patients, associated with difficulty in augmenting the velocity as the amplitude increases (Flowers 1976). Other deficits to have been identified include difficulty in correcting errors (Angel et al. 1970), in carrying out two movements simultaneously (Horne 1973), in performing a sequence of movements (Perret et al. 1970) and in the normal activation of muscles in more complex motor tasks such as walking (Buchthal & Fernandez-Ballesteros 1965). 1.
4 The neurophysiological basis of these problems has not been established with certainty. Lee & Tatton (1978) and Mortimer & Webster (1978) have reported normal short latency (segmental) reflexes but increased long latency (50-120 ms) responses to rapid muscle stretch in rigid parkinsonian patients; these workers inferred the existence of an abnormal suprasegmental modulation of the peripheral inputs. Augmented long latency responses are also found in some normal elderly subjects who have enhanced background EMG activity at rest (Evarts et al. 1979). Flowers (1978) has studied motor control by means of a tracking task with oscilloscope display under joystick control; his results indicate that the patients “seem to lack a dynamic internal model of their movements.” The patients were unable to follow repetitive movement patterns without visual control, an abnormality resembling that produced by cooling the globus pallidus in monkeys (Hore et al. 1977). Tremor Low frequency (3-7 Hz) tremor in resting limbs is usually the most striking physical sign of parkinsonism. The frequency varies in different extremities, and can alter over the course of time. In addition to the resting tremor, patients often exhibit an action tremor. The abnormal activity culminating as tremor can be suppressed by cutting the physiological connections between the basal ganglia and the thalamus, or between thalamus and the cerebral cortex, or between the cerebral cortex and the spinal segments. These observations, together with the known location of the pathology within the brain, indicate that central mechanisms are of major importance in the genesis of tremor. On the other hand, several peripheral manipulations of the limb can modify parkinsonian tremor, including ischemia, tonic vibration, partial nerve block (Rondot & Bathien 1976), and electrical stimulation of the muscles (Hufschmidt 1963) or nerves (Liberson 1962). Displacements of the limb can both trigger tremor and abruptly change the phase of action and resting tremor (Lee & Stein 1978, Teravainen et al. 1978). While it can be modulated by peripheral input, tremor can also persist after the elimination of afferent influence by section of the dorsal roots in both parkinsonian patients (Pollock & Davis 1930) and experimental animals with parkinsonlike tremor (Ohye et al. 1970). The contributions of both central and peripheral factors to the genesis of parkinsonian tremor are not mutually exclusive. A recent hypothesis (Evarts et al. 1979) proposes that the tremor is due to oscillations within a supraspinal feedback loop involving the VL-nucleus of the thalamus and the motor cortex (Fig. 1). Ascending afferent input can trigger and modify oscillations within the loop as can voluntary initiation of movement. The role of VL-nucleus of the thalamus in producing parkinsonian tremor may be
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considered as analogous to that of the spinal segments in pyramidal disease associated with clonus, where interruption of the upper motoneuron leads to a hyperexcitable spinal segment, and oscillation (clonus) can be triggered in a structurally normal but physiologically altered peripheral feedback loop. Similarly, in parkinsonism diseased nigrostriatal output results in increased excitability of the VL-nucleus; perturbation (passive displacement or voluntary movement) activates a structurally normal but physiologically altered central feedback loop, leading to oscillation. When there is an appropriate “central excitatory state” oscillation can develop without a change in afferent signals, so that spontaneous tremor can develop in parkinsonism, just as spontaneous clonus can occur in pyramidal disease. BIOCHEMISTRY AND PHARMACOLOGY
One of the most notable biochemical advances in relation to nigral and basal ganglia function has been the plethora of neuroregulatory agents found in these regions of the brain. In addition to dopamine, there exists acetylcholine, gamma aminobutyric acid and serotonin, norepinephrine, glycine, taurine and a number of small peptides (Dray & Straughan 1976). There is a particularly high concentration of substance P in the substantia nigra (Powell et al. 1973), and a similarly privileged tissue level of methionineenkephalin and leucine enkephalin in the basal ganglia (Smith et al. 1976). However, no significant effect on parkinsonism has been detected following administration of the few drugs that are available to modify the influence of neurohumeral agents other than dopamine and acetylcholine. Biochemically the substantia nigra and basal ganglia offer an embarrassment of riches, the physiological, pharmacological and pathological significance of which are unclear. In this review attention will be focused on dopamine since the role of other neurohumeral agents remains obscure. Recent studies have led, in particular, to developments in receptor pharmacology, to extended concepts of neurohumeral transmission, and to new approaches to treatment. Receptors An important pharmacological development over the last few years is the recognition that there are multiple categories of dopamine receptors in basal ganglia and substantia nigra. While classification of these receptors can be based on various criteria, separation into D-1 and D-2 receptors has recently been suggested on the basis of whether the receptors are linked to an adenylate cyclase (Kebabian & Calne 1979). Those receptors which are associated with an adenylate cyclase have been termed D-1 type, and those which are independent of the enzyme have been designated D-2 type. Subclassification within these primary divisions may prove possible in the
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Figure 2. A schematic representation o f the neurons in the nigrustriatal axis which contain dopamine receptors. The dopaminergic neurons contain autoreceptors which regulate either electrical firing of these cells in the substantia nigra (site 1 ) or tyrosine hydroxylase activity (site 2) in the terminals. Cortical neurons which project to the striatum possess binding sites for radiolabelled haloperidol which have been indentified as dopamine receptors (site 3). Neurons intrinsic to the caudate contain dopamine-sensitive adenylate cyclase activity (site 4). Finally, terminals o f striatal neurons which project t o the nigra also contain a dopamine-sensitive adenylate cyclase (site 5). The dopamine receptors at sites 1-3 have not been associated with adenylate cyclase activity (type 0 - 2 ) ; only the receptors at sites 4 and 5 regulate this enzyme activity (type D-1) (Kebabian & Calne 1979).
future. Drugs which improve parkinsonism appear to have a predominantly agonist effect on D-2 receptors, whereas agents which induce or exacerbate parkinsonism are antagonists of D-2 receptors. The complexity of the organization of D-1 and D-2 receptors in the pathways between the substantia nigra and striatum are illustrated in Fig. 2. This shows the disposition of presynaptic and postsynaptic receptors which can, on present evidence, be classified into D-1 and D-2 types. There may be other sites in this area of the brain where dopamine receptors play a role, but already we have more than we can use to develop any unified coherent hypothesis of dopaminergic function in motor control - another embarrassment of riches! Although the evidence is very limited, in vitro studies with certain dopaminergic ergots suggest that there may be a reciprocal relationships between some of the effects of stimulating D-1 and D-2 receptors (Kebabian et al. 1977). Another aspect of receptor pharmacology which has an important bearing on parkinsonism is sensitivity. Alterations in the postsynaptic response to a given concentration of humeral agent in the synaptic cleft can, in theory, arise from (1) modulation of the affinity of receptors, (2) changes in the number of receptors. Current observations indicate that the usual mechanism for normal alteration of sensitivity is a change in the number of available receptors (Kebabian et al. 1975). In pathological situations, changes in receptor sensitivity have a signifi-
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cant bearing on the results of pharmacotherapy. An increase in dopamine receptor sensitivity may, for example, be necessary to enable dopaminergic agents to improve the motor deficits of parkinsonism; supersensitivity may also underlie some of the centrally induced adverse reactions to treatment. Conversely, subsensitivity could be the basis of the declining therapeutic efficacy of dopaminergic treatment for parkinsonism, which commonly emerges after 3-6 years of levodopa. Fluctuations in receptor sensitivity are one possible explanation of the “on-off ” reactions which so frequently disrupt levodopa therapy after a prolonged period of satisfactory response. While there are only scanty observations on the clinical relevance of changes in dopamine receptor sensitivity, there is irrefutable evidence that denervation of the striatum induces supersensitivity in animals (Ungerstedt 1971). Furthermore, postmortem studies have shown that in the brains of parkinsonian patients with degeneration of the nigrostriatal pathway, there are increased binding sites for radioactive haloperidol (an index of dopamine receptor sensitivity). It is of particular interest that after chronic treatment with levodopa this evidence of enhanced dopamine receptor sensitivity is lacking (Lee et al. 1978). The simplicity of this scheme is marred by the report that administration of dopaminergic agents can, in experimental animals, lead to increased sensitivity (Klawans et al. 1975). Neuromodulators An important new concept to emerge is the recognition that chemical agents are employed to communicate between neurons in ways rather different from those traditionally associated with neurotransmitters. The term neuromodulation has been coined to describe the action of substances which do not, themselves, induce depolarization or hyperpolarization but instead modify the effect of conventional neurotransmitters on neuronal membrane potential. Compared to neurotransmission, neuromodulation usually involves communication of slower onset, more diffuse distribution and more gradual termination. The same substances, such as catecholamines and oligopeptides, may function as neurotransmitters at one location and neuromodulators at another. It may even be possible that along the course of the same axon, varicosities containing the same active substance may utilize this agent as a neurotransmitter at one site and as a neuromodulator at another. For example, while some norepinephrine varicosities in the cerebral cortex make typical morphological synaptic contact with adjacent neurons, other varicosities are quite devoid of histological hallmarks of a synapse (Beaudet d Descarries 1978). By extending the concept of neuromodulation further, the term neurohormone has been introduced for substances which are carried by body fluids to transfer information from one part of the brain to another.
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The best characterized neurohormones are the hypothalamic factors that are carried by the hypophysial portal circulation to the anterior pituitary (Guillernin 1978). While many of these neurohormones are oligopeptides, catecholamines also participate; for example, dopamine released in the median eminence appears to be the prolactin inhibitory factor that controls the secretion of this hormone by mammotroph cells in the anterior pituitary. From these developments an analogy is clearly discernible between the nervous and the endocrine systems. They share the use of humeral agents to communicate between cells, and just as the same substances may be employed as neurotransmitters in one setting and hormones in another, there is also a sharing of receptor mechanisms. Linkage to an enzyme forming a nucleotide (cyclic AMP or cyclic GMP) is employed in such diverse settings as receptors for acetylcholine, dopamine, norepinephrine, histamine, thyrotrophin, corticotrophin, glucagon, vasopressin and secretin (Robison et al. 1971). The notion of the brain as an endocrine gland has led to the formulation of questions which might have seemed absurd a decade ago. For many years it has been known that a hormonal deficiency may be corrected by transplantation of endocrine tissue. Recently, it has been shown that in rats with unilateral lesions leading to depletion of striatal dopamine, fetal substantia nigra cells can be injected into the lateral ventricle where they survive and grow to produce dopamine in the striatum (Perlow et al. 1979). Such observations must be confirmed and extended, but they naturally elicit the speculation that certain neurological disorders might at some future time be treatable by transplantation of regionally localized selected preparations of neural tissue. Therapy The search for improved treatment for parkinsonism has continued. One approach has been an attempt to find drugs which are dopaminergic agonists with a relatively selective action on those dopamine receptors which, when stimulated, elicit a therapeutic response. This is predicated upon pharmacological separation between the receptors that are predominantly involved in achieving efficacy, from others thought to be concerned with the induction of central adverse reactions such as dyskinesia and psychosis. While there is no firm basis for the optimism inherent in this premise, the profile of response certainly varies between different dopaminergic agents - for example, bromocriptine causes less dyskinesia but more psychosis than levodopa (Calm et al. 1978). These findings justify a continued effort to develop dopaminergic agents with a more favorable therapeutic index than levodopa. A complimentary approach is the quest for relatively selective dopamine antagonists, which might preferentially block the receptors involved in pro-
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ducing central adverse reactions, without inhibiting those receptors essential for efficacy. Such agents might be used in combination with dopaminergic drugs; some encouraging experience has been reported with the dopamine receptor antagonists oxiperomide and tiapride (Be‘dard et al. 1978, Price et al. 1978). Finally, continued attempts are being made to improve the pharmacokinetic properties of levodopa; in particular, extending the half-life to alleviate “wearing off’’ reactions and “end of dose” akinesia. Some benefit has been claimed with deprenyl, a selective inhibitor of monoamine oxidase B (Lees et al. 1977). Since monoamine oxidase B contributes to the intracellular degradation of dopamine but not of norepinephrine, it can be blocked without the risk of catastrophic hypertension when levodopa is administered. Another pharmacokinetic maneuver currently under investigation is inhibition of catechol-0-methyltransferase. This enzyme plays a major part in destroying extracellular catecholamines. Recent animal studies suggest that catechol-0-methyltransferase can be blocked by U0521, so this drug might also have a role in the treatment of parkinsonism (Fahn et al. 1978).
ACKNOWLEDGMENTS We wish to thank Ms. P. Barnicoat and Ms. L. Wease for typing the manuscript and collating the references. REFERENCES Angel, R. W., W. Alston & H. Garland (1971): L-dopa and error correction time in Parkinson’s disease. Neurol. (Minneap.) 21, 1255-1260. Beaudet, A. & L. Descarries (1978): The monoamine innervation of rat cerebral cortex: synaptic and nmsynaptic axon terminals. Neurmcience 3, 851-860. BCdard, P., I. D. Parkes & C. D. Marsden (1978): Effect of new dopamineblocking agent (Oxiperomide) on drug-induced dyskinesias in Parkinson’s disease and spontaneous dyskinesias. Br. Med. J. 1, 954-956. Buchthal, F. & M. L. Fernandez-Ballesteros (1965): Electromyographic study of the muscles of the upper arm and shoulder during walking in patients with Parkinson’s disease. Brain 88, 875-896. Calne, D. B., A. C . Williams, A. Neophytides, C. Plotkin, J. G. Nutt & P. F. Teychenne (1978): Long-term treatment of parkinsonism with bromocriptine. Lancet i, 735738. DeLong, M. R. & A. P. Georgopoulos (1978): Functional organization of the substantia nigra, globus pallidus and subthalamic nucleus in the monkey. Book of Abstracts, p. 28. VIth International Symposium on Parkinson’s Disease, Sept. 24-27, Quebec, Canada. Dietrichson, P. (1971): Tonic ankle reflex in parkinsonian rigidity and in spasticity. Acta Neurol. Scaad. 47, 163-182. Dray, A. & D. W. Straughan (1976): Synaptic mechanisms in the substantia nigra. J. Pharm. Pharmac. 28, 400-405.
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D. B. Calne, D.M., F.R.C.P. Clinical Director National Institute of Neurological and Communicative Disorders & Stroke National Institutes of Health Building 10, Rm. 6D-20 Bethesda, Maryland 20205 U.S.A.
