Timing of levodopa therapy: evidence from MPTP-treated primates.
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Biomedical subjects
A R Crossman
Publications and source records attributed to A R Crossman.
Levodopa-induced dyskinesia and response fluctuations in primates rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Six non-human primates received doses of MPTP sufficient to produce a severe parkinsonian syndrome. Levodopa therapy reversed parkinsonian features in all animals, but resulted in dose-dependent choreoathetoid movements of the lower limbs of 3, together with akathisia and dystonia in 2. 'End-of-dose deterioration' was common to all animals, although 'on-off' periods were only seen in 3. Preliminary observations using a clinical rating scale and automatic activity counters demonstrate that both the motor response to levodopa and the complications of therapy are readily quantifiable. We suggest that this is a useful experimental model for testing new strategies in the management of idiopathic Parkinson's disease, particularly with regard to the prevention of drug-induced involuntary movements.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Primate models of dyskinesia: the experimental approach to the study of basal ganglia-related involuntary movement disorders.
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Animals↗
MPTP-induced parkinsonism in the monkey: neurochemical pathology, complications of treatment and pathophysiological mechanisms.
MPTP induces parkinsonism in monkeys by destruction of the substantia nigra, pars compacta. It can also damage ventral tegmental dopamine neurones and the noradrenergic locus coeruleus, both of which may be affected in Parkinson's disease. Motor symptoms in MPTP-treated monkeys respond readily to levodopa or dopamine agonist therapy. Administration of levodopa over 4-8 weeks leads to the emergence of "peak-dose" dyskinesia. Such abnormal movements are not seen following challenge doses of levodopa in animals not on long-term therapy. Radioligand studies reveal a 40-180% increase in D2 receptor binding in the striatum of parkinsonian monkeys. 2-deoxyglucose studies of regional brain metabolism indicate that MPTP-induced parkinsonism is characterised by abnormally increased activity of medial pallidal neurones which project to the thalamus and pedunculopontine nucleus and reduced activity of subthalamic nucleus neurones.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Autoradiographic analysis of [3H]kainic acid binding in primate brain.
The distribution of [3H]kainic acid binding sites was studied in the primate brain using semiquantitative autoradiography. The highest levels of binding were observed in the hippocampal area CA3 and the dentate gyrus. The deep layers of pyriform, cingulate and insular cortex, the central nucleus of the amygdala and the caudate nucleus also displayed high levels of [3H]kainic acid binding. Although these areas receive putative excitatory amino acid-containing afferents, other regions containing a similar input displayed low levels of binding. Some similarities were apparent between the distribution of binding sites and pathological changes in human neurodegenerative disorders such as temporal lobe epilepsy.
Animals↗
Neural mechanisms mediating 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced parkinsonism in the monkey: relative contributions of the striatopallidal and striatonigral pathways as suggested by 2-deoxyglucose uptake.
The neural mechanisms which mediate parkinsonian symptoms have been investigated in the monkey by application of the 2-deoxyglucose (2-DG) metabolic mapping technique to animals rendered parkinsonian by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show that 2-DG uptake was dramatically increased in the globus pallidus, but not the substantia nigra pars reticulata, in parkinsonian monkeys compared to controls. This observation has been interpreted as indicating increased synaptic activity in the putaminopallidal, but not the caudatonigral, pathway which suggests a relatively greater involvement of the putaminopallidal pathway in relation to the motor manifestations of parkinsonism.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
A semi-quantitative atlas of 5-hydroxytryptamine-1 receptors in the primate brain.
The regional distribution of 5-hydroxytryptamine-1 receptors in the primate brain was studied by semi-quantitative autoradiographic analysis of tritiated ligand binding. Areas showing the highest density of 5-hydroxytryptamine-1 receptors (greater than 200 fmol [3H]5-hydroxytryptamine bound per mg tissue), included the cerebral cortex (laminae I-II), claustrum, posterior cell group of the basal nucleus of Meynert, the infracommissural part of the globus pallidus, cortical amygdaloid nucleus, hippocampal formation (CA1-subiculum region, the anterior CA2, CA3 and CA4 regions and the molecular layer of the dentate gyrus), thalamic nuclei (parafascicular, parataenial, paraventricular and superior central lateral nuclei), substantia nigra pars reticulata, dorsal raphe nucleus and choroid plexus. The distribution of 5-hydroxytryptamine-1 receptors is compared to the distribution of both 5-hydroxytryptamine receptors and terminal fields of serotonergic projections as previously described in subprimates.
Amygdala↗
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the monkey: neurochemical pathology and regional brain metabolism.
Systemic administration of the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to macaque monkeys induced a profound parkinsonian state marked by hypokinesia/bradykinesia, rigidity and tremor. Postmortem studies revealed severe pathological changes in the substantia nigra, pars compacta and in the ventral tegmental area. The levels of dopamine and its major metabolites were reduced by about 90% in the neostriatum, including the nucleus accumbens, when compared to controls. In one animal, the locus coeruleus showed severe pathological changes in association with a reduction in forebrain noradrenaline. 2-deoxyglucose uptake studies suggested that in experimental parkinsonism there if a profound change in the activity of the striatopallidal pathway, but not necessarily in the striatonigral pathway.
Animals↗
Sites of the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the macaque monkey include the ventral tegmental area and the locus coeruleus.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a profound parkinsonian state when systemically administered in monkeys and man. Previous studies have shown MPTP to be toxic to only the dopamine (DA) cells in the substantia nigra pars compacta and not to other catecholamine (CA)-containing cells. The data presented here suggest that MPTP also has a specific neurotoxic effect on the DA-containing cells of the ventral tegmental area and the noradrenaline-containing cells of the locus coeruleus in macaque monkeys with a moderate-to-severe parkinsonian syndrome. The results suggest that MPTP-induced parkinsonism in the monkey more closely replicates the neurochemical changes seen in idiopathic Parkinson's disease than previously thought.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Common neural mechanisms in experimental chorea and hemiballismus in the monkey. Evidence from 2-deoxyglucose autoradiography.
The autoradiographic 2-deoxyglucose uptake technique was used to visualise local cerebral metabolic activity in the monkey in recently developed models of chorea and hemiballismus. Unilateral dyskinesia was induced by injection of a gamma-aminobutyric acid antagonist into the corpus striatum (in the case of chorea) or subthalamic nucleus (in the case of hemiballismus). Patterns of 2-deoxyglucose uptake suggest that during both forms of experimental dyskinesia the subthalamic nucleus and its projection to the globus pallidus are abnormally hypoactive.
Animals↗
A lesioning and 2-deoxyglucose study of the hyperactivity produced by an intra-accumbens dopamine agonist.
Lesioning and 2-deoxyglucose (2-DG) autoradiographic studies were applied to the hyperactivity induced in rats by intra-accumbens treatment with the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro-naphthalene (ADTN). Lesions made in substantia innominata and rostro-ventral globus pallidus both attenuated the hyperactivity although no consistent changes in 2-DG uptake were recorded in these areas. Compared to normal rats, hyperactive rats showed greatly increased glucose utilization in the subthalamic nucleus and lateral habenula. Lesioning the subthalamic nucleus greatly reduced the hyperactivity, whereas a lateral habenula lesion was ineffective. Hyperactivity was associated with a discrete, bilateral area of increased 2-DG uptake in the reticular formation which corresponded to the description of the deep mesencephalic nucleus (DMN). Lesions made in the DMN greatly attenuated the hyperactivity response. The DMN may be a locomotor region in the rat.
Animals↗
Regional brain uptake of 2-deoxyglucose in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey.
This preliminary report describes application of the 2-deoxyglucose (2DG) autoradiographic technique to study regional changes in brain metabolism in experimental parkinsonism, induced in the monkey by administration of the neurotoxin MPTP. In one monkey, rendered severely parkinsonian by MPTP, there was a marked increase in the uptake of 2DG in the globus pallidus (both medial and lateral segments) and in the ventral anterior and ventral lateral thalamic nuclei, in comparison to non-parkinsonian animals. Increased uptake of 2DG in the globus pallidus may reflect increased activity of striatopallidal synapses secondary to loss of nigrostriatal dopaminergic neurones. The findings are in sharp contrast to our observations on regional brain metabolism in experimental choreiform dyskinesia in the monkey.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Subcortical changes in the regional uptake of [3H]-2-deoxyglucose in the brain of the monkey during experimental choreiform dyskinesia elicited by injection of a gamma-aminobutyric acid antagonist into the subthalamic nucleus.
Hemichorea/hemiballismus was induced in monkeys by localized injections of a gamma-aminobutyric acid antagonist into the contralateral subthalamic nucleus. During active dyskinesia, [3H]-2-deoxyglucose was administered and, subsequently, regional cerebral metabolic activity was examined by autoradiographic exposure of brain sections. The results indicate that during dyskinesia there was an overall decrease in local cerebral glucose utilization in a number of structures on the side of the brain contralateral to the abnormal movements (ipsilateral to the drug injection). These structures included the injected subthalamic nucleus, both medial and lateral segments of the globus pallidus, the substantia nigra, and the ventral anterior and ventral lateral nuclei of the thalamus. On the basis of evidence that changes in the energy requirement of neurons are due mainly to changes in synaptic activity, the autoradiographic findings are interpreted as indicating that during experimental hemichorea/hemiballismus there was an overall decrease in synaptic activity of subthalamopallidal, subthalamonigral and pallidothalamic pathways on the side of the brain contralateral to the dyskinesia. This interpretation is discussed in relation to current theories of the pathophysiology of choreiform dyskinesias.
Animals↗
The organisation of the efferent projections of the zona incerta.
The hypothesis that the six cytoarchitectonically distinct subdivisions of the zona incerta send efferent projections to different parts of the brain was tested using retrograde fluorescent tracing techniques. Injections of tracer in the superior colliculus, pontomesencephalic tegmentum, thalamus or spinal cord resulted in characteristic and distinctive patterns of labelling in the zona incerta, suggesting that the different subdivisions of the zona incerta give rise to different sets of efferent projections. Thus, injections into the deep layers of the superior colliculus resulted in retrogradely labelled neurons predominantly in the zona incerta pars ventralis, whereas injections into the pontomesencephalic tegmentum, avoiding the superior colliculus, labelled neurons mostly in the zona incerta pars dorsalis. Parafascicular thalamic injections resulted in labelled neurons in the zona incerta pars rostropolaris, pars dorsalis, pars caudalis and a few in the pars ventralis. The spinal cord injections labelled predominantly the magnocellular cells of the zona incerta. The results of the double labelling experiment also give support to the conclusion that different areas of the zona incerta give rise to largely individual sets of efferent projections. Combined injections of tracers into the superior colliculus and thalamus resulted in the labelling of two essentially independent cell groups, the tectal projecting cells being found mainly in the zona incerta pars ventralis and the thalamic projecting cells being found in the zona incerta pars rostropolaris, pars dorsalis and pars caudalis. However, a small number of double labelled cells was found. These cells, which presumably send collateral projections to both the tectum and the thalamus, were found mainly in the dorsal part of the zona incerta pars ventralis, immediately next to the pars dorsalis. In the light of these findings it would appear that the zona incerta may be organised into largely distinct subdivisions, each of which has its own set of cytoarchitectonic and efferent projection characteristics.
Animals↗
Autoradiographic demonstration of 5HT1 binding sites in the primate basal nucleus of Meynert.
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Animals↗
Identification of different subpopulations of neostriatal neurones projecting to globus pallidus or substantia nigra in the monkey: a retrograde fluorescence double-labelling study.
Fluorescent tracers (Nuclear Yellow, True Blue, Fast Blue) were injected, in various combinations, into the globus pallidus and substantia nigra in three marmosets. Examination of perikarya in the ipsilateral neostriatum, well removed from pallidal injection sites, revealed that the predominant pattern was of single-labelled cells, retrogradely labelled from either the globus pallidus or substantia nigra. It is suggested, on the basis of this evidence and data previously available, that the striatum contains at least three types of efferent neurones, one projecting exclusively to the globus pallidus, one projecting exclusively to the substantia nigra, and another projecting to both structures.
Animals↗
In defence of optical density ratios in 2-deoxyglucose autoradiography.
The use of optical density ratios to describe changes in [14C]2-deoxyglucose uptake in neuroanatomical mapping experiments has recently been criticized. It has been argued that a fixed ratio of tissue isotope concentration does not yield a constant optical density ratio but is dependent on the exposure time and the absolute amounts of isotope used. Here it is demonstrated that such variations in optical density ratios are due to an artifact in calculating the optical density ratio, which can easily be corrected provided that the film is not approaching saturation and not due to the non-linearity of an exposure-density curve as has previously been suggested.
Animals↗
Experimental choreoathetosis produced by injection of a gamma-aminobutyric acid antagonist into the lentiform nucleus in the monkey.
An experiment is reported in which injections of the gamma-aminobutyric acid antagonist bicuculline into the lentiform nucleus of the monkey gave rise to a contralateral choreoathetoid dyskinesia. Evidence was obtained of functional heterogeneity between the dorsal and ventral lentiform nucleus, in that only injections into its ventral part gave rise to dyskinesia.
Animals↗