C. E. Clarke

Neural mechanisms underlying Parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The 2-deoxyglucose metabolic mapping technique has been used to investigate the neural mechanisms which underlie the symptoms of Parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinsons disease. In six cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was either (a) administered intravenously to induce generalized Parkinsonism, or (b) infused into one carotid artery to induce unilateral Parkinsonism. Post-mortem examination revealed profound cell loss from the substantia nigra, pars compacta either bilaterally or unilaterally in the two groups, respectively. In addition, there was pathological involvement of the ventral tegmental area and locus coeruleus in animals receiving intravenous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 2-Deoxyglucose autoradiography revealed widespread changes in 2-deoxyglucose uptake in the brains of parkinsonian animals when compared to controls. Most of these changes were in basal ganglia and related structures and were qualitatively similar in the two groups of experimental animals. Prominent increases in 2-deoxyglucose uptake were observed in the lateral segment of the globus pallidus (24-27%), the ventral anterior and ventral lateral nuclei of the thalamus (14-22%) and the nucleus tegmenti pedunculopontinus of the caudal midbrain (17-69%). A profound decrease (17-26%) in 2-deoxyglucose uptake was observed in the subthalamic nucleus. We propose these data to indicate that in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism there is the following pattern of abnormal neuronal activity in basal ganglia circuitry: (i) increased activity in the projection from the putamen to the lateral segment of the globus pallidus; (ii) decreased activity in the projection from the putamen to the medial segment of the globus pallidus; (iii) decreased activity in the projection from the lateral segment of the globus pallidus to the subthalamic nucleus; (iv) increased activity in the projection from the subthalamic nucleus to the globus pallidus; and (v) increased activity in neurons of the medial segment of the globus pallidus projecting to the ventral anterior/ventral lateral thalamus and the pedunculopontine nucleus. These results are compared to the 2-deoxyglucose uptake findings in previous studies from this laboratory in hemiballism and hemichorea in the monkey. The central importance of the subthalamic nucleus in all three conditions is proposed, and supportive evidence for the excitatory nature of subthalamic efferent fibres is adduced.

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis)

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from monkeys which had received unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing loss of dopamine-containing neurones of the substantia nigra pars compacta. The monkeys developed hemi-parkinsonian symptoms (tremor, bradykinesia) in limbs contralateral to the side of the toxin infusion. Administration of apomorphine (0.05-0.25 mg/kg) caused contralateral rotational behaviour, and reversal of the parkinsonian symptoms. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A reduction in these sites of 97% (mean brain value) in the caudate nucleus, and 91% in the putamen, as compared with binding values from untreated control monkeys, was accompanied by a significant increase in the binding of [3H]sulpiride (D2) in these structures. In contrast, in the same animals there was no similar increase in [3H]SCH 23390 binding to D1 receptors in the denervated areas. These results suggest that in the parkinsonian brain, where the dopaminergic innervation of the caudate nucleus and putamen has been lost, D2 receptors may be more susceptible than D1 receptors to changes, revealed here as an increase in [3H]sulpiride binding sites.

Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The right common carotid artery was surgically exposed under general anaesthesia in 6 cynomolgus monkeys and MPTP (0.5-2.2 mg/kg) directly infused. This produced a hemiparkinsonian syndrome in the contralateral limbs which responded to treatment with both levodopa and apomorphine. These drugs also precipitated dose-dependent contralateral rotation which reached a peak 2 weeks after MPTP infusion. A massive depletion of large, presumably dopaminergic cells was found from the ipsilateral substantia nigra pars compacta. Three animals receiving chronic therapy with apomorphine developed choreoathetoid movements of the limbs and the face contralateral to the infusion 2 weeks after the commencement of treatment. The severity of the dyskinesia gradually increased and after 4 weeks peak-dose hemiballistic movements were seen. Levodopa and the selective D-2 and D-1 dopamine agonists LY-171555 and SKF 38393 also reversed parkinsonian features and produced contralateral rotation and peak-dose dyskinesia. This unilateral model of parkinsonism in the primate will be of value in the elucidation of the mechanisms by which chronic levodopa or dopamine agonist therapy enhance involuntary movements in parkinsonism.

Behavioural effects of (+)-4-propyl-9-hydroxynaphthoxazine in primates rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

SummaryThree monkeys received a chronic intravenous course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) so as to produce a permanent parkinsonian syndrome. One primate was electively commenced on chronic levodopa therapy 6 weeks after the cessation of MPTP treatment. Four months following the termination of MPTP administration, the response to oral doses of the novel D-2 dopamine agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was assessed in all animals using a clinical rating scale and automatic activity counters.PHNO was found to be a highly potent anti-parkinsonian agent, completely reversing the symptoms of parkinsonism in a dose-dependent manner. Peak-dose dyskinesia was noted in 2 MPTP-treated animals during trials with PHNO, but was more severe in the animal receiving chronic levodopa therapy. Response fluctuations such as ‘end-of-dose’ deterioration and the ‘on-off’ henomenon were common to all 3 parkinsonian animals following PHNO. The anti-parkinsonian effect and frequency of treatment-induced side-effects appeared to be similar with PHNO and levodopa. These results confirm the efficacy of PHNO as an anti-parkinsonian drug and link the production of dyskinesia with the D-2 dopamine receptor.

Basal Ganglia Mechanisms Mediating Experimental Dyskinesia in the Monkey

Disordered function of the basal ganglia may lead to a wide spectrum of motor abnormalities, depending upon the nature of the precipitating factor. Thus, for example, destruction of the subthalamic nucleus produces hemiballismus, degeneration of the neostriatum induces chorea, and interruption of dopaminergic nigostriatal transmission gives rise to parkinsonism. The origin of abnormal activity in other conditions, such as athetosis and dystonia, remains speculative but almost certainly involves the basal ganglia, most likely the neostriatum.

New Parallels Between Parkinson’s Disease and MPTP-Induced Parkinsonism in the Monkey

Despite the very significant advances that have been made in the treatment of Parkinson’s disease with the introduction of levodopa therapy the management of the condition still presents major problems to the clinician. While some patients undoubtedly have a benign, relatively non-progressive type of the disorder, others develop response fluctuations, the ‘on-off’ phenomenon, peak-dose dyskinesias related to levodopa medication or become unresponsive to treatment. It has been suggested that these complications may be related to prolonged levodopa medication (Rajput et al., 1984 and Melamed, 1986) and the concept of delayed treatment and wider use of dopamine agonists has been proposed. Insight into their aetiology may come fron the introduction of PET scanning as a non-invasive method of studying cerebral metabolism and neurotransmitter receptor binding but a non-human primate model of Parkinson’s disease still remains an attractive and important development. Such a model has ironically presented itself in humans with the discovery of a parkinsonian syndrome in drug addicts who have received l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) produced during the synthesis of “designer drugs”. MPTP has been administered to monkeys and found to produce a very realistic parkinsonian syndrome but so far it has not been confirmed that the histological changes are similar in appearance and distribution to those found in Parkinson’s disease. Furthermore, it is not known whether the problems of levodopa administration are also encountered in the animal model.