Pharmacology & Toxicology 1990, 67, 95-100.
Animal Models of Parkinsonism Seppo Kaakkola and HeUrki Teraviiinen* Department of Neurology, University of Helsinki, Haartmaninkatu 4, SF-00290 Helsinki, Finland (Received January 2,1990; Accepted April 2,1990) Abstract: The discovery of profound dopamine depletion of basal ganglia in patients with Parkinson’s disease and the development of antiparkinsonian drug therapy were largely based on animal models. The behavioural changes caused by cholinergic drugs, reserpine and related agents, and unselective neuronal lesions were the first widely used animal models for Parkinson’s disease. The crucial breakthrough was the observation of the circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model still is one of the basic animal models of Parkinson’s disease. It is suitable for the screeningof new potential antiparkinsonian agents with the classic spectrum.The parkinsonism induced by the neurotoxin l-methyl4phenyl-l,2,3,6-tetrahydr0pyridine(MPTP) in the mouse and the monkey is the latest and the best animal model for Parkinson’s disease. Especially when given to the monkey, MPTP causes biochemical, behavioural and neuropathological changes which largely mimick those of Parkinson’s disease in man. The MPTPinduced parkinsonism in the monkey can be used for the study of the neurobiology and new forms of drugs therapy of Parkinson’s disease. However, because the MPTP monkey model is expensive and laborious, it is not particularly convenient for the screening of new drugs. Recently, a new approach in the treatment of Parkinson’s disease is to develop drugs which might prevent or retard the disease progression. The prevention of behavioural changes of aged rodents is used as an animal model and promising results with selegiline have been obtained.
Carlsson et al. (1957) first described the depletion of catecholamine (and 5-hydroxytryptamine) stores by reserpine, with concomitant hypokinesia in the mouse. As the changes were antagonized by levodopa, the first actual animal model for Parkinson’s disease was developed. All these observations contributed to a rapid advance in the understanding of the biochemical changes of Parkinson’s disease in which the destruction of dopaminergic nerve cells and dopamine stores of basal ganglia was the main finding. The development both in animal and human studies laid the foundation for the levodopa replacement therapy in Parkinson’s disease. Parkinson’s disease is one of the few neurological diseases for which a variety of animal models has been developed. These models have been and still are of great importance for the understanding of the pathophysiology of Parkinson’s disease and for the development of novel antiparkinsonian drugs. With a proper animal model one should be able 1) to screen reliably for new potential agents; 2) to eludicate the mechanism of action of these agents; and 3) to clarify the pathophysiology of the corresponding human disease. However, even a proper animal model will probably never be equivalent to a human disease. In the following, the most important “in vivo” models of a Parkinson’s disease are reviewed in brief. Cholinergic models. Tremor, one of the characteristic features of Parkinson’s disease, can be induced in rodents by various cholinergic agents, such as arecoline, oxotremorine, physostigmine and nicotine (Brimblecombe & Pinder 1972) and quantitated
with special devices (c.f. Clement & Dyck 1989). Tremorine and its metabolite, oxotremorine, are the two most used agents (Everett 1964). Their tremorigenic action seems to be mediated mainly by central muscarinic receptors. The antagonism of oxotremorine-induced tremor can be used to investigate the central antimuscarink effect of a drug (Brimblecombe& Pinder 1972). A relationship was observed between antimuscarinic potency and antitremorine activity of a number of antiparkinsonian drugs in mice (Ahmed & Marshall 1962). However, the tremor induced by cholinergic agonists resembled more a condition of cholinergic intoxication than parkinsonian tremor (Duvoisin 1976). Large doses of cholinergic drugs to rodents also induced catalepsy, including akinesia, an ability to maintain an abnormal posture, and often rigidity. The intensity of catalepsy can be quantified, and its inhibition by muscarinic drugs (e.g. atropine) can be used as an indication of their central activity (Zetler 1968). Unselective neuronal lesions. A lesion of ventromedial tegmentum in monkeys produced by electrocoagulation caused resting tremor and hypokinesia (Poirier et ul. 1966; Pkchadre et al. 1976). The method is unselective; it destroys dopaminergic cells but also other nerve cells and tracts locating in the lesioned area. This method has been formerly used to tet potential dopaminergic drugs (Goldstein et al. 1977). It is to be noted that a lesion limited to the substantia nigra does not cause tremor in the monkey, though it does often cause hypokinesia. Both the nucleus ruber and the substantia nigra must be lesioned in order to induce rigidity in the monkey (Pkchadre et al. 1976).
* To whom correspondence should be directed.
A unilateral destruction of rat striatum by electrocoagula-
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tion or by suction induced a slight turning behaviour; the rat showed a tendency to turn towards the site of lesion (ipsilateral turning). After administration of drugs facilitating dopaminergic transmission (e.g. levodopa), the postural asymmetry was increased and a marked circling behaviour was induced (Andbn et ul. 1966; Ungerstedt et ul. 1973). This method allows evaluation of drug effect on the intact contralateral nigrostriatal dopaminergic system. However, the method is non-selective and it does not reproduce the specific neuronal changes of Parkinson’s disease. Chemical methods. Reserpine. This drug interferes with the storage of dopamine (and also of noradrenaline and 5-hydroxytryptamine)in the intracellular granules, leading to the depletion of dopamine in nerve terminals. Its central action produces sedation, hypokinesia, rigidity (catalepsy) and often tremor (Hornykiewicz 1966). A very similar condition can be induced by tetrabenazine and also by a-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. Hypokinesia and its prevention by e.g. levodopa can be reliably measured with automatic motor activity apparatus, often coupled with computer systems (Ljungberg & Ungerstedt 1978; Cooper et al. 1987; LindCn et al. 1988). The effect of both reserpine and a-methyl-ptyrosine is reversible, since these agents do not cause any permanent neuronal lesions. They have also peripheral effects in addition to the central ones. Thus, the condition induced by these agents does not resemble human Parkinson’s disease in all respects. Most neuroleptics are antagonists of dopamine receptors. The ability of neuroleptics to produce catalepsy in rodents varies but seems to be correlated with their ability to induce parkinsonism in man (Biirki 1979). The neuroleptic-induced catalepsy is acute, transient, and it is not connected with the lesion of dopaminergic neurones. Thus catalepsy induced by neuroleptics is an appropriate model for drug-induced parkinsonism in man but not for idiopathic Parkinson’s disease. 6-Hydroxydopamine. This is the first agent which quite selectively destroyed catecholaminergic nerve systems. Its selectivity is based on its utilization of the same amine uptake system as the endogenous catecholamines (dopamine, noradrenaline) (Sachs & Jonsson 1975). Since 6-hydroxydopamine does not penetrate the blood-brain barrier, it must be given intraventricularly or intracerebrally in order to produce a degeneration of brain dopaminergic or noradrenergic neurones. A quite selective and permanent destruction of dopaminergic nerve cells is produced by injection of 6hydroxydopamine locally to the substantia nigra or slightly anterior to it. When given bilaterally to both substantia nigra of rodents, the animals became not only hypokinetic but also aphagic and adipsic which required artificial tube feeding to keep the animals alive (Ungerstedt 1971a). Due to this problem, the method was developed further by Ungerstedt (1971b). He injected 6-hydroxydopamine in small amounts (6-8 pg) unilaterally to one substantia nigra of
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rats in order to avoid aphagia and adipsia. When apomorphine, a potent dopamine agonist, was given a few days later to these animals they began to circle in the direction opposite to the lesion (Ungerstedt 1971b) (fig. 1). This apomorphine-induced contralateral circling behaviour is related to the development of supersensitivity of dopaminergic receptors in the lesioned side. The circling behaviour is easily measured either by observing and calculating, or by special devices, called rotometers. The use of rotometers makes it possible to follow several animals simultaneously and to use computerized systems for rapid graphic output and statistical analysis (Etemadzadeh et al. 1989). Bromocriptine and other directly acting dopamine agonists and also levodopa produced contralateral circling behaviour similar to that caused by apomorphine. However, there were quantitative variations between these compounds in duration of action, potency and efficacy (Fuxe & Ungerstedt 1976). On the other hand, (+)-amphetamine caused ipsilateral circling which is due to its indirect presynaptic effect. It releases dopamine only from the intact nerve endings on the unlesioned side (Ungerstedt 1971c) (fig. 1). Thus, an imbalance in the activity between dopaminergic systems of left and right side results in circling: the animal circles away from the side of higher dopaminergic activity. The Ungerstedt model is an appropriate method for the evaluation of a potential dopaminergic feature of a new agent. The method can be used to differentiate whether the dopaminergic action of a agent is pre- or postsynaptic. The behavioural consequences of direct (postsynaptic) and indirect (presynaptic) dopaminergic stimulation are, in fact, opposite: a compound acting directly causes contralateral circling behaviour whereas a compound acting indirectly L-dopa
Fig. 1. Diagram of circling behaviour in rodents as originally described by Ungerstedt (1971b). The left dopaminergic nigrostriatal tract is destroyed by injection of 6-hydroxydopamine to the substantia nigra. The postsynaptic receptors in the left striatum become supersensitive. As a result, apomorphine, levodopa and other dopamine receptor stimulating agents cause circling away from the lesion (contralateral circling), whereas dopamine releasing agents (e.g. amphetamine) cause circling towards the lesion (ipsilateral circling).
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causes ipsilateral one. Moreover, the potentiation or the inhibition of the effect of levodopa by other drugs can be evaluated with this model. The “circling” model has been used for years for the screening of new dopaminergic drugs. It seems to be a valid method for predicting antiparkinsonian activity of new compounds, although it mainly reveals drugs with the classic dopaminergic or cholinergic spectrum (Ungerstedt et al. 1973). The level of striatal dopamine must be decreased by over 90% for the model to work (Heikkila et al. 1981). This reduction correlates with that seen in Parkinson’s disease where clinical symptoms appear only after a dopamine reduction of about 80% (Bernheimer et al. 1973).The dopaminergic lesion after the intranigral injection of 6-hydroxydopamine is quite stable, although some increased sensitivity has been observed, e.g. to apomorphine when given repeatedly (Ungerstedt 1971b). The specificity of the neuronal destruction induced by intracerebrally administered 6-hydroxydopamine was questioned (Pokier et al. 1972; Butcher et al. 1974). For instance, Butcher et al. (1974) found no clear differences in neuronal damages between 6-hydroxydopamine and copper sulphate. However, others demonstrated specific dopaminergic degeneration after intranigral injection of 6-hydroxydopamine, although a minor unspecific lesion was also observed (Agid et al. 1973; Hokfelt & Ungerstedt 1973). The specificity was dependent on the dose and the volume of 6-hydroxydopamine injected, and on the injection technique (Agid et al. 1973; Hokfelt & Ungerstedt 1973). In the original Ungerstedt model, besides the nigrostriatal dopaminergic tracts, also the other ascending dopaminergic tracts are partially destroyed. Recently, an improved modification of the original model of Ungerstedt was introduced, where only the nigrostriatal dopaminergic neurons are destroyed by 6-hydroxydopamine using an accurate stereotactic technique (Perese et al. 1989). I-Methyl-4-phenyl-I ,2,3$-tetrahydropyridine ( M P T P ). This synthetic agent structurally resembles pethidine. Its toxic effect was observed in several young individuals who used it by accident as a by-product of pethidine-like analgesic agent (Langston e t a / . 1983). MPTP caused symptoms virtually identical to those of the idiopathic Parkinson’s disease (Langston et al. 1983; Burns et al. 1985). These patients responded to levodopa and dopamine agonists. Even in the symptom-free persons who were exposed to MPTP, the dopaminergic neurones seemed to be partially destroyed as judged from positron emission tomography (PET) scanning studies with ‘8F-6-fluorolevodopa (Calne et al. 1985). Thus, the individuals who used MPTP served in a sense as “human models” of Parkinson’s disease. There are considerable differences between species in the sensitivity to the toxic effect of MPTP: the monkey is clearly the most sensitive; the mouse, the cat, the guinea-pig and the dog are quite sensitive, whereas the rat is relatively resistant to MPTP (Langston & Irwin 1989). MPTP is a protoxin which is converted to toxic 1-methyl-4-phenylpyridinium ion (MPP+) by glial monoamine oxidase type B
(Chiba et al. 1984; Markey et al. 1984; Ransom et al. 1987). MPP+ is then taken up by dopaminergic neurones which it destroys, probably by interfering with the mitochondria1 respiration (Chiba et al. 1985; Javitch & Snyder 1985; Nicklas et al. 1987; Trevor et al. 1987). The toxic effect of MPTP in animals was prevented by administration of monoamine oxidase type B inhibitor, such as selegiline (Heikkila et al. 1984; Cohen et al. 1985). The dopamine uptake inhibitors were also effective in preventing the toxic effect of MPTP in mice, but no or partial protection was noticed in monkeys (Langston & Irwin 1989; Schultz et al. 1989). Of the mouse strains, the C57 black mouse is the most sensitive to MPTP, and the sensitivity increases with age (Heikkila & Sonsalla 1987). Extensive striatal dopamine deficiency induced by MPTP caused behavioural changes (e.g. hypokinesia) in mice which responded to levopoda (Heikkila & Sonsalla 1987). However, these behavioural changes were not permanent. The biochemical, pathological and behavioural deficits in monkeys after the administration of MPTP resembled to a considerable degree those of Parkinson’s disease (table 1) (Burns et al. 1983; Chiueh et al. 1984; Crossman et al. 1987; Langston & Irwin 1989). There were some differences in the sensitivity to MPTP and in the stability of MPTP-induced behavioural deficits which seemed to be dependent on the age, the dosing schedule and the strain (Burns et al. 1986; Eidelberg et al. 1986; Crossman et al. 1987; Tetrud & Langston 1989a; Ueki et al. 1989). MPTP induced a clear-cut resting tremor only in the African green monkey (Langston & Irwin 1989), whereas mainly postural tremor was observed in other strains (Burns et a/. 1986; Crossman et 01. 1987). Levodopa and dopamine agonists reserved the behavioural deficits induced by MPTP (Crossman et al. 1987). Regular use of levodopa can cause dyskinesias in monkeys and also in patients with MPTP-induced parkinsonism (Langston & Ballard 1984; Crossman et al. 1987).
Table 1.
A comparison of changes induced by MPTP in the mouse, the monkey andman (based on data from Chiueh et al. 1984; Markey et al. 1986; Heikkila & Sonsalla 1987; Langston & Irwin 1989).
Variable Hypokinesia Rigidity Resting tremor Stooping posture Dysphagia Permanency of features Depletion of striatal dopamine Loss of cells in substantia nigra Protection by MAO-B inhibitors Response to levodopa Cumulative dose (mg/kg)
+ , constant feature f , transient or variable feature
-, lacking feature ?, uncertain or unknown feature MAO-B, monoamine oxidase type B.
Mouse Monkey
+ k + +
+ + k + + + + + + +
80
2
+
-
f
-
-
Man
+ + + + + + + +? ?
+ ?
98
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Recently, a hemiparkinsonian model was produced by injecting MPTP directly into one of the carotid arteries of the monkey (Bankiewicz et al. 1986; Clarke et al. 1989). This model resembles the Ungerstedt model in rat. The MPTPinduced parkinsonian and hemiparkinsonian monkey models are suitable also for PET scanning studies with ISF6-fluorolevodopa (Chiueh et al. 1986; Guttlan et al. 1988). They also are well suited to studies of brain o r adrenal medulla grafting (Lindvall 1989). The MPTP-induced parkinsonism in the monkey has been shown to be the best available model of Parkinson’s disease. Since investigations in monkeys are expensive and laborious, they are best suited to pathophysiological, neurochemical and specific long-term drug investigations, and less suited for screening studies of new and potentially useful drugs in the treatment of Parkinson’s disease. Aging model. The latest strategy in the antiparkinsonian therapy has been to develop drugs which would prevent or retard the progression of the disease in contrast to symptomatic therapy with levodopa and dopamine agonists (Quinn 199). It was suggested that the natural aging process of the nigrostriatal dopaminergic neurones is due to specific neorotoxins originating from dopamine metabolism, and Parkinson’s disease might be a form of premature rapid aging due to unknown toxic origin (Knoll 1987). Both endogenous toxins, such as free radicals and quinones, and exogenous toxins, analogously to MPTP, may contribute to the pathogenesis of Parkinson’s disease (Shoulson 1989). Selegiline, a monoamine oxidase type B inhibitor, prevented the breakdown of dopamine, facilitated the activity of nigrostiatal neurones and protected from the neurotoxic effect of 6-hydroxydopamine in animals (Knoll 1987). It also protected from the toxic effect of MPTP (see above). However, in these studies it was administered before or concomitantly with MPTP. The first clinical studies with selegiline were promising with regard to preventing the progression of Parkinson’s disease (The Parkinson Study Group 1989; Tetrud & Langston 1989b). The inhibition of age-related changes in rat was used as an animal model for the drugs which would be active also in Parkinson’s disease. The life span and sexual performance were employed as behavioural criteria (Knoll 1988). The administration of selegiline significantly increased the life expectancy and the sexual activity of male rats (Knoll 1988; Knoll et al. 1989). The obstacle of this model is that longterm daily administration of a drug is necessary and the follow-up time may be even 3.5 years (Knoll 1988). Another problem is that aging process alone does not explain the degeneration of nigrostriatal dopaminergic neurones in Parkinson’s disease (Scherman et al. 1989). Concurrent data concern only selegiline and much further work with other drugs is necessary before a validity of aging model for Parkinson’s disease can be concluded. Marshall & Bernos (1979) described an impairment in swimming ability of aged rats, which was reversed by levodopa and apomorphine.
This test might be another indicator of age-related dopaminergic alterations and suitable also for the drug protection studies. References Agid, Y., F. Javoy, J. Glowinski, D. Bouvet & C. Sotelo: Injection of 6-hydroxydopamine into the substantia nigra of the rat. 11. Diffusion and specificity. Brain Rex 1973, 58, 291-301. Ahmed, A. & P. B. Marshall: Relationship between anti-acetylcholine and anti-tremorine activity in anti-parkinsonian and related drugs. Brit. J. Pharmacol. 1962, 18, 247-254. Andtn, N.-E., A. Dahlstrom, K. Fuxe & K. Larsson: Functional role of the nigroneostriatal dopamine neurons. Acta pharmacol. et toxicol. 1966, 24, 263-274. Bankiewicz, K. S., E. H. Oldfield, C. C. Chiueh, J. L. Doppman, D. M. Jacobowitz & I. J. Kopin: Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine(MPTP). Life Sci. 1986, 39, 7-16. Bernheimer, H., W. Birkmayer, 0. Hornykiewicz, K. Jellinger & F. Seitelberger: Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J. Neurol. Sci. 1973, 20, 15455. Brimblecombe, R. W. & R. M. Pinder: Tremors and tremorogenic agents. Scientechnica, Bristol, 1972. Burns, R. S., C. C. Chiueh, S. P. Markey, M. E. Ebert, D. M. Jacobowitz & I. J. Kopin: A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacts of the substantia nigra by N-rnethyl-4-phenyl-l,2,3,6-tetrahydropyridine. Proc. Natl. Acad. Sci. USA 1983,80, 454M550. Bums, R. S., P. A. LeWitt, M. H. Ebert, H. Pakkenberg & I. J. Kopin: The clinical syndrome of striatal dopamine deficiency: parkinsonism induced by 1-methyl-Cphenyl-1,2,3,6-tetrahydropyridine (MPTP). New Engl. J . Med. 1985, 312, 1418-1421. Burns, R. S., J. M. Phillips, C. C. Chiueh, J. E. Parisi: The MPTPtreated monkey model of Parkinson’s disease. In: MPTP: a neurotoxin producing a parkinsonian syndrome. Eds.: S . P.Markey, N. Castagnoli, Jr., A. J. Trevor & I. J. Kopin. Academic Press, New York, 1986, pp. 2342. Butcher, L. L., S . M. Eastgate & G. K. Hodge: Evidence that punctate intracerebral administration of 6-hydroxydopamine fails to produce selective neuronal degeneration. Comparison with copper sulfate and factors governing the department of fluids injected into brain. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1974, 285, 31-70. Biirki, H. R.: Extrapyramidal side-effects. Pharmacol. Therap. 1979, 5, 525-534. Calne, D. B., J. W. Langston, W. R. Martin, A. J. Stoessl, T. J. Ruth, M. J. Adam, D. B. Pate & M. Schulzer: Positron emission tomography after MPTP: observations relating to the cause of Parkinson’s disease. Nature 1985, 317, 246248. Carlsson, A., M. Lindqvist & T. Magnusson: 3,4-Dihydroxyphenylanine and 5-hydroxytryptophan as reserpine antagonists. Nature 1957,180, 1200. Chiba, K., A. Trevor & N. Castagnoli, Jr.: Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun. 1984, 120, 574-578. Chiba, K., A. J. Trevor & N. Castagnoli, Jr.: Active uptake of MPP+, a metabolite of MPTP, by brain synaptosornes. Biochem. Biophys. Res. Commun. 1985, 128, 1228-1232. Chiueh, C. C., R. S. Bums, I. J. Kopin, K. L. Kirk, G. Firnau, C. Nahmias, R. Chirakal & E. S. Garnett: 6-’*F-dopa/positron emission tomography visualized degree of damage to brain dopamine in basal gangha of monkeys with MPTP-inducd parkinsonism: In: MPTP: a neurotoxin producing a parkinsonian syndrome. Eds.: S. P. Markey, N. Castagnoli, Jr., A. J. Trevor & I. J. Kopin. Academic Press, New York, 1986, pp. 327-338.
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Schultz, W., E. Scarnati, E. Sundstrom & R. Romo: Protection I-methyl-4-phenyl-l,2,3,6-tetrahdyropyridine-induced against parkinsonism by the catecholamine uptake inhibitor nomifensine: behavioral analysis in monkeys with partial striatal dopamine depletions. Neuroscience 1989, 31, 219-230. Scherman, D., C. Demos, F. Darchen, P. Pollak, F. Javoy-Agid & Y. Agid: Striatal dopamine deficiency in Parkinson’s disease: role of aging. Ann. Neurol. 1989, 26, 551-557. Shoulson, I.: Experimental therapeutics directed at the pathogenesis of Parkinson’s disease: In: Drugs for the treatment of Parkinson’s disease. Handbook of Experimental Pharmacology, Vol. 88. Ed.: D. B. Calne. Springer-Verlag, Berlin, Heidelberg, 1989, pp. 289-305. Tetrud, J. W. & J. W. Langston: MPTP-induced parkinsonism as a model for Parkinson’s disease. Acta neurol. scand. 1989a, 80 (Suppl. 126), 35-40. Tetrud, J. W. & J. W. Langston: The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 1989b, 245, 5 19-522. The Parkinson Study Group: Effect of deprenyl on the progression of disability in early Parkinson’s disease. New Engl. J. Med. 1989, 321, 1364-1371. Trevor, A. J., N. Castagnoli, Jr., P. Caldera, R. R. Ramsay & T. P.
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Singer: Bioactivation of MPTP: reactive metabolites and possible biochemical sequelae. Life Sci 1987, 40, 713-719. Ueki, A., P. N. Chong, A. Albanese, S. Rose, J. K. Chivers, P. Jenner & C. D. Marsden: Further treatment with MPTP does not produce parkinsonism in marmosets showing behavioural recovery from motor deficits induced by an earlier exposure to the toxin. Neuropharmacology 1989, 28, 1089-1097. Ungerstedt, U.: Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta physiol. scand .1971a, 82 (Suppl. 367), 95-122. Ungerstedt, U.: Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta physiol. scand. 1971b, 82 (Suppl. 367), 69-93. Ungerstedt, U.: Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour. Acta physio[. scand. 1971c, 82 (Suppl. 367), 49-68. Ungerstedt, U., A. Avemo, E. Avemo, T. Ljungberg & C. Ranje: Animal models of parkinsonism. Adv. Neurol. 1973, 3, 257-271. Zetler, G.: Cataleptic state and hypothermia in mice, caused by central cholinergic stimulation and antagonized by anticholinergic and antidepressant drugs. Int. J . Neuropharmacol. 1968, I, 325-335.
Animal Models of Parkinsonism Seppo Kaakkola and HeUrki Teraviiinen* Department of Neurology, University of Helsinki, Haartmaninkatu 4, SF-00290 Helsinki, Finland (Received January 2,1990; Accepted April 2,1990) Abstract: The discovery of profound dopamine depletion of basal ganglia in patients with Parkinson’s disease and the development of antiparkinsonian drug therapy were largely based on animal models. The behavioural changes caused by cholinergic drugs, reserpine and related agents, and unselective neuronal lesions were the first widely used animal models for Parkinson’s disease. The crucial breakthrough was the observation of the circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model still is one of the basic animal models of Parkinson’s disease. It is suitable for the screeningof new potential antiparkinsonian agents with the classic spectrum.The parkinsonism induced by the neurotoxin l-methyl4phenyl-l,2,3,6-tetrahydr0pyridine(MPTP) in the mouse and the monkey is the latest and the best animal model for Parkinson’s disease. Especially when given to the monkey, MPTP causes biochemical, behavioural and neuropathological changes which largely mimick those of Parkinson’s disease in man. The MPTPinduced parkinsonism in the monkey can be used for the study of the neurobiology and new forms of drugs therapy of Parkinson’s disease. However, because the MPTP monkey model is expensive and laborious, it is not particularly convenient for the screening of new drugs. Recently, a new approach in the treatment of Parkinson’s disease is to develop drugs which might prevent or retard the disease progression. The prevention of behavioural changes of aged rodents is used as an animal model and promising results with selegiline have been obtained.
Carlsson et al. (1957) first described the depletion of catecholamine (and 5-hydroxytryptamine) stores by reserpine, with concomitant hypokinesia in the mouse. As the changes were antagonized by levodopa, the first actual animal model for Parkinson’s disease was developed. All these observations contributed to a rapid advance in the understanding of the biochemical changes of Parkinson’s disease in which the destruction of dopaminergic nerve cells and dopamine stores of basal ganglia was the main finding. The development both in animal and human studies laid the foundation for the levodopa replacement therapy in Parkinson’s disease. Parkinson’s disease is one of the few neurological diseases for which a variety of animal models has been developed. These models have been and still are of great importance for the understanding of the pathophysiology of Parkinson’s disease and for the development of novel antiparkinsonian drugs. With a proper animal model one should be able 1) to screen reliably for new potential agents; 2) to eludicate the mechanism of action of these agents; and 3) to clarify the pathophysiology of the corresponding human disease. However, even a proper animal model will probably never be equivalent to a human disease. In the following, the most important “in vivo” models of a Parkinson’s disease are reviewed in brief. Cholinergic models. Tremor, one of the characteristic features of Parkinson’s disease, can be induced in rodents by various cholinergic agents, such as arecoline, oxotremorine, physostigmine and nicotine (Brimblecombe & Pinder 1972) and quantitated
with special devices (c.f. Clement & Dyck 1989). Tremorine and its metabolite, oxotremorine, are the two most used agents (Everett 1964). Their tremorigenic action seems to be mediated mainly by central muscarinic receptors. The antagonism of oxotremorine-induced tremor can be used to investigate the central antimuscarink effect of a drug (Brimblecombe& Pinder 1972). A relationship was observed between antimuscarinic potency and antitremorine activity of a number of antiparkinsonian drugs in mice (Ahmed & Marshall 1962). However, the tremor induced by cholinergic agonists resembled more a condition of cholinergic intoxication than parkinsonian tremor (Duvoisin 1976). Large doses of cholinergic drugs to rodents also induced catalepsy, including akinesia, an ability to maintain an abnormal posture, and often rigidity. The intensity of catalepsy can be quantified, and its inhibition by muscarinic drugs (e.g. atropine) can be used as an indication of their central activity (Zetler 1968). Unselective neuronal lesions. A lesion of ventromedial tegmentum in monkeys produced by electrocoagulation caused resting tremor and hypokinesia (Poirier et ul. 1966; Pkchadre et al. 1976). The method is unselective; it destroys dopaminergic cells but also other nerve cells and tracts locating in the lesioned area. This method has been formerly used to tet potential dopaminergic drugs (Goldstein et al. 1977). It is to be noted that a lesion limited to the substantia nigra does not cause tremor in the monkey, though it does often cause hypokinesia. Both the nucleus ruber and the substantia nigra must be lesioned in order to induce rigidity in the monkey (Pkchadre et al. 1976).
* To whom correspondence should be directed.
A unilateral destruction of rat striatum by electrocoagula-
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tion or by suction induced a slight turning behaviour; the rat showed a tendency to turn towards the site of lesion (ipsilateral turning). After administration of drugs facilitating dopaminergic transmission (e.g. levodopa), the postural asymmetry was increased and a marked circling behaviour was induced (Andbn et ul. 1966; Ungerstedt et ul. 1973). This method allows evaluation of drug effect on the intact contralateral nigrostriatal dopaminergic system. However, the method is non-selective and it does not reproduce the specific neuronal changes of Parkinson’s disease. Chemical methods. Reserpine. This drug interferes with the storage of dopamine (and also of noradrenaline and 5-hydroxytryptamine)in the intracellular granules, leading to the depletion of dopamine in nerve terminals. Its central action produces sedation, hypokinesia, rigidity (catalepsy) and often tremor (Hornykiewicz 1966). A very similar condition can be induced by tetrabenazine and also by a-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. Hypokinesia and its prevention by e.g. levodopa can be reliably measured with automatic motor activity apparatus, often coupled with computer systems (Ljungberg & Ungerstedt 1978; Cooper et al. 1987; LindCn et al. 1988). The effect of both reserpine and a-methyl-ptyrosine is reversible, since these agents do not cause any permanent neuronal lesions. They have also peripheral effects in addition to the central ones. Thus, the condition induced by these agents does not resemble human Parkinson’s disease in all respects. Most neuroleptics are antagonists of dopamine receptors. The ability of neuroleptics to produce catalepsy in rodents varies but seems to be correlated with their ability to induce parkinsonism in man (Biirki 1979). The neuroleptic-induced catalepsy is acute, transient, and it is not connected with the lesion of dopaminergic neurones. Thus catalepsy induced by neuroleptics is an appropriate model for drug-induced parkinsonism in man but not for idiopathic Parkinson’s disease. 6-Hydroxydopamine. This is the first agent which quite selectively destroyed catecholaminergic nerve systems. Its selectivity is based on its utilization of the same amine uptake system as the endogenous catecholamines (dopamine, noradrenaline) (Sachs & Jonsson 1975). Since 6-hydroxydopamine does not penetrate the blood-brain barrier, it must be given intraventricularly or intracerebrally in order to produce a degeneration of brain dopaminergic or noradrenergic neurones. A quite selective and permanent destruction of dopaminergic nerve cells is produced by injection of 6hydroxydopamine locally to the substantia nigra or slightly anterior to it. When given bilaterally to both substantia nigra of rodents, the animals became not only hypokinetic but also aphagic and adipsic which required artificial tube feeding to keep the animals alive (Ungerstedt 1971a). Due to this problem, the method was developed further by Ungerstedt (1971b). He injected 6-hydroxydopamine in small amounts (6-8 pg) unilaterally to one substantia nigra of
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rats in order to avoid aphagia and adipsia. When apomorphine, a potent dopamine agonist, was given a few days later to these animals they began to circle in the direction opposite to the lesion (Ungerstedt 1971b) (fig. 1). This apomorphine-induced contralateral circling behaviour is related to the development of supersensitivity of dopaminergic receptors in the lesioned side. The circling behaviour is easily measured either by observing and calculating, or by special devices, called rotometers. The use of rotometers makes it possible to follow several animals simultaneously and to use computerized systems for rapid graphic output and statistical analysis (Etemadzadeh et al. 1989). Bromocriptine and other directly acting dopamine agonists and also levodopa produced contralateral circling behaviour similar to that caused by apomorphine. However, there were quantitative variations between these compounds in duration of action, potency and efficacy (Fuxe & Ungerstedt 1976). On the other hand, (+)-amphetamine caused ipsilateral circling which is due to its indirect presynaptic effect. It releases dopamine only from the intact nerve endings on the unlesioned side (Ungerstedt 1971c) (fig. 1). Thus, an imbalance in the activity between dopaminergic systems of left and right side results in circling: the animal circles away from the side of higher dopaminergic activity. The Ungerstedt model is an appropriate method for the evaluation of a potential dopaminergic feature of a new agent. The method can be used to differentiate whether the dopaminergic action of a agent is pre- or postsynaptic. The behavioural consequences of direct (postsynaptic) and indirect (presynaptic) dopaminergic stimulation are, in fact, opposite: a compound acting directly causes contralateral circling behaviour whereas a compound acting indirectly L-dopa
Fig. 1. Diagram of circling behaviour in rodents as originally described by Ungerstedt (1971b). The left dopaminergic nigrostriatal tract is destroyed by injection of 6-hydroxydopamine to the substantia nigra. The postsynaptic receptors in the left striatum become supersensitive. As a result, apomorphine, levodopa and other dopamine receptor stimulating agents cause circling away from the lesion (contralateral circling), whereas dopamine releasing agents (e.g. amphetamine) cause circling towards the lesion (ipsilateral circling).
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causes ipsilateral one. Moreover, the potentiation or the inhibition of the effect of levodopa by other drugs can be evaluated with this model. The “circling” model has been used for years for the screening of new dopaminergic drugs. It seems to be a valid method for predicting antiparkinsonian activity of new compounds, although it mainly reveals drugs with the classic dopaminergic or cholinergic spectrum (Ungerstedt et al. 1973). The level of striatal dopamine must be decreased by over 90% for the model to work (Heikkila et al. 1981). This reduction correlates with that seen in Parkinson’s disease where clinical symptoms appear only after a dopamine reduction of about 80% (Bernheimer et al. 1973).The dopaminergic lesion after the intranigral injection of 6-hydroxydopamine is quite stable, although some increased sensitivity has been observed, e.g. to apomorphine when given repeatedly (Ungerstedt 1971b). The specificity of the neuronal destruction induced by intracerebrally administered 6-hydroxydopamine was questioned (Pokier et al. 1972; Butcher et al. 1974). For instance, Butcher et al. (1974) found no clear differences in neuronal damages between 6-hydroxydopamine and copper sulphate. However, others demonstrated specific dopaminergic degeneration after intranigral injection of 6-hydroxydopamine, although a minor unspecific lesion was also observed (Agid et al. 1973; Hokfelt & Ungerstedt 1973). The specificity was dependent on the dose and the volume of 6-hydroxydopamine injected, and on the injection technique (Agid et al. 1973; Hokfelt & Ungerstedt 1973). In the original Ungerstedt model, besides the nigrostriatal dopaminergic tracts, also the other ascending dopaminergic tracts are partially destroyed. Recently, an improved modification of the original model of Ungerstedt was introduced, where only the nigrostriatal dopaminergic neurons are destroyed by 6-hydroxydopamine using an accurate stereotactic technique (Perese et al. 1989). I-Methyl-4-phenyl-I ,2,3$-tetrahydropyridine ( M P T P ). This synthetic agent structurally resembles pethidine. Its toxic effect was observed in several young individuals who used it by accident as a by-product of pethidine-like analgesic agent (Langston e t a / . 1983). MPTP caused symptoms virtually identical to those of the idiopathic Parkinson’s disease (Langston et al. 1983; Burns et al. 1985). These patients responded to levodopa and dopamine agonists. Even in the symptom-free persons who were exposed to MPTP, the dopaminergic neurones seemed to be partially destroyed as judged from positron emission tomography (PET) scanning studies with ‘8F-6-fluorolevodopa (Calne et al. 1985). Thus, the individuals who used MPTP served in a sense as “human models” of Parkinson’s disease. There are considerable differences between species in the sensitivity to the toxic effect of MPTP: the monkey is clearly the most sensitive; the mouse, the cat, the guinea-pig and the dog are quite sensitive, whereas the rat is relatively resistant to MPTP (Langston & Irwin 1989). MPTP is a protoxin which is converted to toxic 1-methyl-4-phenylpyridinium ion (MPP+) by glial monoamine oxidase type B
(Chiba et al. 1984; Markey et al. 1984; Ransom et al. 1987). MPP+ is then taken up by dopaminergic neurones which it destroys, probably by interfering with the mitochondria1 respiration (Chiba et al. 1985; Javitch & Snyder 1985; Nicklas et al. 1987; Trevor et al. 1987). The toxic effect of MPTP in animals was prevented by administration of monoamine oxidase type B inhibitor, such as selegiline (Heikkila et al. 1984; Cohen et al. 1985). The dopamine uptake inhibitors were also effective in preventing the toxic effect of MPTP in mice, but no or partial protection was noticed in monkeys (Langston & Irwin 1989; Schultz et al. 1989). Of the mouse strains, the C57 black mouse is the most sensitive to MPTP, and the sensitivity increases with age (Heikkila & Sonsalla 1987). Extensive striatal dopamine deficiency induced by MPTP caused behavioural changes (e.g. hypokinesia) in mice which responded to levopoda (Heikkila & Sonsalla 1987). However, these behavioural changes were not permanent. The biochemical, pathological and behavioural deficits in monkeys after the administration of MPTP resembled to a considerable degree those of Parkinson’s disease (table 1) (Burns et al. 1983; Chiueh et al. 1984; Crossman et al. 1987; Langston & Irwin 1989). There were some differences in the sensitivity to MPTP and in the stability of MPTP-induced behavioural deficits which seemed to be dependent on the age, the dosing schedule and the strain (Burns et al. 1986; Eidelberg et al. 1986; Crossman et al. 1987; Tetrud & Langston 1989a; Ueki et al. 1989). MPTP induced a clear-cut resting tremor only in the African green monkey (Langston & Irwin 1989), whereas mainly postural tremor was observed in other strains (Burns et a/. 1986; Crossman et 01. 1987). Levodopa and dopamine agonists reserved the behavioural deficits induced by MPTP (Crossman et al. 1987). Regular use of levodopa can cause dyskinesias in monkeys and also in patients with MPTP-induced parkinsonism (Langston & Ballard 1984; Crossman et al. 1987).
Table 1.
A comparison of changes induced by MPTP in the mouse, the monkey andman (based on data from Chiueh et al. 1984; Markey et al. 1986; Heikkila & Sonsalla 1987; Langston & Irwin 1989).
Variable Hypokinesia Rigidity Resting tremor Stooping posture Dysphagia Permanency of features Depletion of striatal dopamine Loss of cells in substantia nigra Protection by MAO-B inhibitors Response to levodopa Cumulative dose (mg/kg)
+ , constant feature f , transient or variable feature
-, lacking feature ?, uncertain or unknown feature MAO-B, monoamine oxidase type B.
Mouse Monkey
+ k + +
+ + k + + + + + + +
80
2
+
-
f
-
-
Man
+ + + + + + + +? ?
+ ?
98
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Recently, a hemiparkinsonian model was produced by injecting MPTP directly into one of the carotid arteries of the monkey (Bankiewicz et al. 1986; Clarke et al. 1989). This model resembles the Ungerstedt model in rat. The MPTPinduced parkinsonian and hemiparkinsonian monkey models are suitable also for PET scanning studies with ISF6-fluorolevodopa (Chiueh et al. 1986; Guttlan et al. 1988). They also are well suited to studies of brain o r adrenal medulla grafting (Lindvall 1989). The MPTP-induced parkinsonism in the monkey has been shown to be the best available model of Parkinson’s disease. Since investigations in monkeys are expensive and laborious, they are best suited to pathophysiological, neurochemical and specific long-term drug investigations, and less suited for screening studies of new and potentially useful drugs in the treatment of Parkinson’s disease. Aging model. The latest strategy in the antiparkinsonian therapy has been to develop drugs which would prevent or retard the progression of the disease in contrast to symptomatic therapy with levodopa and dopamine agonists (Quinn 199). It was suggested that the natural aging process of the nigrostriatal dopaminergic neurones is due to specific neorotoxins originating from dopamine metabolism, and Parkinson’s disease might be a form of premature rapid aging due to unknown toxic origin (Knoll 1987). Both endogenous toxins, such as free radicals and quinones, and exogenous toxins, analogously to MPTP, may contribute to the pathogenesis of Parkinson’s disease (Shoulson 1989). Selegiline, a monoamine oxidase type B inhibitor, prevented the breakdown of dopamine, facilitated the activity of nigrostiatal neurones and protected from the neurotoxic effect of 6-hydroxydopamine in animals (Knoll 1987). It also protected from the toxic effect of MPTP (see above). However, in these studies it was administered before or concomitantly with MPTP. The first clinical studies with selegiline were promising with regard to preventing the progression of Parkinson’s disease (The Parkinson Study Group 1989; Tetrud & Langston 1989b). The inhibition of age-related changes in rat was used as an animal model for the drugs which would be active also in Parkinson’s disease. The life span and sexual performance were employed as behavioural criteria (Knoll 1988). The administration of selegiline significantly increased the life expectancy and the sexual activity of male rats (Knoll 1988; Knoll et al. 1989). The obstacle of this model is that longterm daily administration of a drug is necessary and the follow-up time may be even 3.5 years (Knoll 1988). Another problem is that aging process alone does not explain the degeneration of nigrostriatal dopaminergic neurones in Parkinson’s disease (Scherman et al. 1989). Concurrent data concern only selegiline and much further work with other drugs is necessary before a validity of aging model for Parkinson’s disease can be concluded. Marshall & Bernos (1979) described an impairment in swimming ability of aged rats, which was reversed by levodopa and apomorphine.
This test might be another indicator of age-related dopaminergic alterations and suitable also for the drug protection studies. References Agid, Y., F. Javoy, J. Glowinski, D. Bouvet & C. Sotelo: Injection of 6-hydroxydopamine into the substantia nigra of the rat. 11. Diffusion and specificity. Brain Rex 1973, 58, 291-301. Ahmed, A. & P. B. Marshall: Relationship between anti-acetylcholine and anti-tremorine activity in anti-parkinsonian and related drugs. Brit. J. Pharmacol. 1962, 18, 247-254. Andtn, N.-E., A. Dahlstrom, K. Fuxe & K. Larsson: Functional role of the nigroneostriatal dopamine neurons. Acta pharmacol. et toxicol. 1966, 24, 263-274. Bankiewicz, K. S., E. H. Oldfield, C. C. Chiueh, J. L. Doppman, D. M. Jacobowitz & I. J. Kopin: Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine(MPTP). Life Sci. 1986, 39, 7-16. Bernheimer, H., W. Birkmayer, 0. Hornykiewicz, K. Jellinger & F. Seitelberger: Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J. Neurol. Sci. 1973, 20, 15455. Brimblecombe, R. W. & R. M. Pinder: Tremors and tremorogenic agents. Scientechnica, Bristol, 1972. Burns, R. S., C. C. Chiueh, S. P. Markey, M. E. Ebert, D. M. Jacobowitz & I. J. Kopin: A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacts of the substantia nigra by N-rnethyl-4-phenyl-l,2,3,6-tetrahydropyridine. Proc. Natl. Acad. Sci. USA 1983,80, 454M550. Bums, R. S., P. A. LeWitt, M. H. Ebert, H. Pakkenberg & I. J. Kopin: The clinical syndrome of striatal dopamine deficiency: parkinsonism induced by 1-methyl-Cphenyl-1,2,3,6-tetrahydropyridine (MPTP). New Engl. J . Med. 1985, 312, 1418-1421. Burns, R. S., J. M. Phillips, C. C. Chiueh, J. E. Parisi: The MPTPtreated monkey model of Parkinson’s disease. In: MPTP: a neurotoxin producing a parkinsonian syndrome. Eds.: S . P.Markey, N. Castagnoli, Jr., A. J. Trevor & I. J. Kopin. Academic Press, New York, 1986, pp. 2342. Butcher, L. L., S . M. Eastgate & G. K. Hodge: Evidence that punctate intracerebral administration of 6-hydroxydopamine fails to produce selective neuronal degeneration. Comparison with copper sulfate and factors governing the department of fluids injected into brain. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1974, 285, 31-70. Biirki, H. R.: Extrapyramidal side-effects. Pharmacol. Therap. 1979, 5, 525-534. Calne, D. B., J. W. Langston, W. R. Martin, A. J. Stoessl, T. J. Ruth, M. J. Adam, D. B. Pate & M. Schulzer: Positron emission tomography after MPTP: observations relating to the cause of Parkinson’s disease. Nature 1985, 317, 246248. Carlsson, A., M. Lindqvist & T. Magnusson: 3,4-Dihydroxyphenylanine and 5-hydroxytryptophan as reserpine antagonists. Nature 1957,180, 1200. Chiba, K., A. Trevor & N. Castagnoli, Jr.: Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun. 1984, 120, 574-578. Chiba, K., A. J. Trevor & N. Castagnoli, Jr.: Active uptake of MPP+, a metabolite of MPTP, by brain synaptosornes. Biochem. Biophys. Res. Commun. 1985, 128, 1228-1232. Chiueh, C. C., R. S. Bums, I. J. Kopin, K. L. Kirk, G. Firnau, C. Nahmias, R. Chirakal & E. S. Garnett: 6-’*F-dopa/positron emission tomography visualized degree of damage to brain dopamine in basal gangha of monkeys with MPTP-inducd parkinsonism: In: MPTP: a neurotoxin producing a parkinsonian syndrome. Eds.: S. P. Markey, N. Castagnoli, Jr., A. J. Trevor & I. J. Kopin. Academic Press, New York, 1986, pp. 327-338.
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