Dopaminergic and cholinergic lesions in progressive supranuclear palsy

In 9 patients with progressive supranuclear palsy and in 27 controls, dopamine and homovanillic acid concentrations, choline acetyltransferase (CAT) activity, and the number of [3H]spiperone and [3H]quinuclidinyl benzilate binding sites were measured post mortem in the striatum (caudate nucleus, putamen, and nucleus accumbens), substantia innominata, and frontal cortex. Dopamine and homovanillic acid concentrations were reduced in the caudate nucleus and putamen but not in the nucleus accumbens or frontal cortex, indicating that the nigrostriatal dopaminergic system is lesioned in patients with progressive supranuclear palsy (as in those with Parkinson's disease) but not the mesocortical and mesolimbic dopaminergic systems, which are lesioned in parkinsonian patients. CAT activity and [3H]spiperone binding decreased in parallel fashion in all the structures. In the striatum, this suggests that the cholinergic neurons, which are target cells of the nigrostriatal system, also degenerate in this disease. This might explain the decrease in the number of dopamine receptors as well as the inefficacy of levodopa or anticholinergic therapy in these patients. The decrease in CAT activity in the substantia innominata and the frontal cortex indicates that the innominatocortical cholinergic system is lesioned in patients with progressive supranuclear palsy and may play a role in the intellectual deterioration observed. This lesion is also found in demented patients with Alzheimer's and Parkinson's diseases.     

Increased dopamine turnover in the putamen after MPTP treatment in common marmosets

The differences in dopamine turnover rate between the putamen and the caudate nucleus in the striatum lesioned by a neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in the common marmoset, a small New World monkey. Systemic administration of MPTP damaged equally and dose-dependently nigrostriatal dopaminergic neurons projecting both to the caudate nucleus and the putamen. The compensatory increase of dopamine turnover, however, occurred more prominently in the putamen than in the caudate. The neural connection and function of the caudate nucleus and the putamen have been differentiated anatomically or physiologically. The compensatory increase of dopamine turnover rate is another different aspect of functions between the caudate nucleus and the putamen. Dopaminergic neurons projecting to the putamen showed more prominent cell loss than those projecting to the caudate in Parkinson's disease or related disorders. The selective augmented turnover rate of lesioned dopaminergic neurons might be, at least partly, involved with selective degeneration of nigrostriatal neurons projecting to the putamen.     

Fatty acid incorporation depicts brain activity in a rat model of Parkinson's disease

Following pulse labeling with [ ]arachidonic acid ([ ]AA), its incorporation pattern in brain reflects regional changes in neurotransmitter signal transduction using phospholipase A₂, that is, functional activity. In a rat model of Parkinson's disease, unilateral 6-hydroxydopamine lesion in the substantia nigra, [ ]AA acid incorporation from blood was increased in cerebral cortex, caudate putamen, globus pallidus, entopeduncular nucleus, subthalamic nucleus and substantia nigra pars reticulata ipsilateral to the lesion. This increased [ ]AA incorporation likely reflects disinhibition of basal ganglia and cortical circuits secondary to absent inhibitory nigrostriatal dopaminergic input.     

The nigrostriatal projection in the cat: Part 1. Silver impregnation study

The course and destination of the degenerating nigrostriatal fibers were studied by selective silver impregnation methods in 37 cats with unilateral lesions in the substantia nigra.The nigrostriatal fibers ascend along the dorsomedial border of the substantia nigra to the prerubral area; they proceed for a short distance through the lateral hypothalamus, enter the medial part of the internal capsule and run in a dorsorostral direction to reach the head of the caudate nucleus and the rostral portion of the putamen. A smaller number of degenerating fibers obliquely cross the peduncular part of the internal capsule and traverse the entopeduncular nucleus and the pallidum to terminate in the central and caudal portions of the putamen.Some features of the topical distribution of the nigrostriatal tract are described. Apparently, the more anterior part of the pars compacta sends axons primarily to the head of the caudate nucleus and to the most rostral putamen. The most medially situated nigral neurons project to the fundus striati. The posteromedial cell groups of the pars compacta innervate primarily the central putamen and the caudal part of the caudate nucleus. The projection of the lateral cell group of the posterior zona compacta to the caudal putamen is sparser than from the other nigral groups, suggesting that a part of them has another destination, possibly lower in the neuraxis. The contribution of the pars reticulata to the nigrostriatal connections seems to be modest, according to the small number of neurons; they project to the lateral caudate and putamen. Thus, the ascending nigrostriatal fibers mirror the distribution of the descending striatonigral fibers.No convincing evidence for the existence of a nigroentopeduncular and nigropallidal projection was found.     

Effects of Nigrostriatal Denervation and L-Dopa Therapy on the GABAergic Neurons of the Striatum in MPTP-treated Monkeys and Parkinson's Disease: An In Situ Hybridization Study of GAD67 mRNA

The effects of nigrostriatal denervation and L-dopa therapy on GABAergic neurons were analysed in patients with Parkinson's disease and in monkeys rendered parkinsonian by MPTP intoxication. The expression of the messenger RNA coding for the 67 kDa isoform of glutamic acid decarboxylase (GAD₆₇ mRNA), studied by quantitative in situ hybridization, was used as an index of the GABAergic activity of the striatal neurons. A significant increase in GAD₆₇ mRNA expression, generalized to all GABAergic neurons, was observed in MPTP-treated monkeys compared to control monkeys in the putamen and caudate nucleus (+44 and +67% respectively), but not in the ventral striatum. L-Dopa therapy significantly reduced GAD₆₇ mRNA expression in the putamen and caudate nucleus to levels similar to those found in control monkeys. However, the return to normal of GAD₆₇ mRNA expression was not homogeneous across all neurons since it was followed by an increase of labelling in one subpopulation of GABAergic neurons and a decrease in another. These data suggest that in MPTP-treated monkeys the degeneration of nigrostriatal dopaminergic neurons results in a generalized increase in GABAergic activity in all the GABAergic neurons of the striatum, which is partially reversed by L-dopa therapy. As the expression of GAD₆₇ mRNA is less intense in the ventral than in the dorsal striatum, this increase in striatal GABAergic activity may be related to the severity of nigrostriatal denervation. In parkinsonian patients who had been chronically treated with L-dopa, GAD₆₇ mRNA expression was significantly decreased in all GABAergic neurons, in the caudate nucleus (by 44%), putamen (by 43.5%) and ventral striatum (by 26%). The opposite variation of GAD₆₇ mRNA in patients with Parkinson's disease, compared with MPTP-treated monkeys, might be explained by the combination of chronic nigrostriatal denervation and long-term L-dopa therapy.     

Dopamine and homovanillic acid concentrations in striatal and limbic regions of human brain

In an attempt to further define the dopaminergic nature of the limbic nucleus accumbens from the morphologically similar striatal caudate and putamen, the levels of dopamine (DA), homovanillic acid (HVA), and HVA/DA ratios, an index of dopamine turnover, were measured in these three structures of human brain. The levels of dopamine in the accumbens (2.49 ng/mg), caudate (2.39 ng/mg), and putamen (3.00 ng/mg) were similar. The homovanillic acid concentration in the accumbens (7.44 ng/mg) and putamen (6.54 ng/mg) were comparable, while its concentration was considerably lower in the caudatae (3.61 ng/mg). The most striking difference between the limbic accumbens and the striatum was observed in the HVA/DA ratio. This index of turnover was significantly higher in the accumbens (3.64) when compared to the caudate (1.80), and was 59% higher than that found in the putamen (2.53). The data provide evidence for differences in dopamine activity in the mesolimbic versus the nigrostriatal pathways.     

The metabolic rate and vulnerability of dopaminergic neurons,and adenosine dynamics in the cerebral cortex,nucleus accumbens,caudate nucleus,and putamen of the common marmoset

The pathophysiology of the striatum and cerebral cortex were studied from the pharmacological aspect.

Investigation of the dopamine content in the cerebral cortex revealed that the premotor and motor area showed the highest level (61±6.2 ng/g). Intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose of 10 mg/kg reduced the dopamine content in the caudate nucleus and putamen to 2–3% of the control level in common marmosets, while it fell to 60% in the nucleus accumbens. There was no alteration of the dopamine content in the cerebral cortex. Immunohistochemical staining for tyrosine hydroxylase in the midbrains of MPTP-treated marmosets showed almost complete disappearance of dopaminergic cells from the substantia nigra and good preservation of cells in the ventrotegmental area. Dopaminergic cells projecting to the caudate/putamen, nucleus accumbens, and cerebral cortex showed marked, moderate, and no vulnerability to MPTP, respectively.

After systemic administration of MPTP, dopaminergic neurons projecting to the caudate nucleus and putamen were damaged equally. However, the compensatory increase of dopamine turnover was more prominent in the putamen than in the caudate nucleus. Thus, nigroputaminal dopaminergic neurons may have a higher level of activity than neuron in the caudate. The neural connections and functions of the caudate nucleus and putamen have already been differentiated anatomically or physiologically. This compensatory increase of the dopamine turnover rate is another aspect of functional differences between the caudate nucleus and putamen.

Investigation of the dopamine content in the heat, body, and tail of the caudate nucleus showed no differences in the concentration of dopamine. However, a study of the metabolic rate of dopamine using α-methyl-p-tyrosine, a tyrosine hydoxylase inhibitor, showed higher metabolism of dopamine in the head of the caudate nucleus in common marmosets. Thus, dopaminergic neurons projecting to the caudate nucleus may show topographical differences in their firing rates.

A microdialysis study indicated an increase in the metabolism of adenosine in the striatum of MPTP-treated animals. Cholinergic neurons are interneurons and are one of the main sources of adenosine in the striatum. Dopaminergic input from the substantia nigra acting on cholinergic neurons was decreased following MPTP treatment. The increase of adenosine metabolism suggested that cholinergic neurons in the striatum receive inhibitory inputs from nigrostriatal dopaminergic neurons.

     

An FDOPA PET study in patients with periodic limb movement disorder and restless legs syndrome

The authors investigated nine drug-naive patients with periodic limb movement disorder and restless legs syndrome (PLMD-RLS) and 27 healthy controls with PET using 6-[18F]fluoro-L-dopa (FDOPA). In the patients, the FDOPA uptake (Ki(occ)) in the caudate nucleus was 88% and in the putamen 89% of the control mean values. This equal affection of the caudate and the putamen differs, for example, from the dopaminergic dysfunction in Parkinson's disease, which affects the putamen earlier and more severely than the caudate. The current results indicate mild nigrostriatal presynaptic dopaminergic hypofunction in PLMD-RLS.     

Decreased striatal monoaminergic terminals in Huntington disease

OBJECTIVE: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). BACKGROUND: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.     

Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset

Five marmosets were unilaterally lesioned within the subthalamic nucleus (STN) by injection of 10 μg ibotenic acid. Seven marmosets served as saline injected controls. The lesioned marmosets showed an increased locomotor activity, occasional tongue protrusions, posture asymmetry, and abnormal movements of the contralateral legs and arms. The animals were sacrificed 21 days after the lbotenic acid injection and markers of γ-aminobutyric acid (GABA), dopamine (DA), and acetylcholine were studied in a variety brain regions. There was a bilateral increase in the activity of glutamic acid decarboxylase (GAD) in the caudate, putamen, globus pallidus, superior colliculus, and the ventral anterior/ventral lateral (VANL) thalamus, whereas GABA concentrations were only increased ipsilaterally in the ventral posterior medial/centromedial/parafasciculus (VPM/CM/Pf) complex of the thalamus. Tyrosine hydroxylase (TH) activity was bilaterally increased in the medial segment of globus pallidus and nucleus accumbens. However, there were also changes restricted to the side contralateral to the lesion. TH activity and DA concentrations were increased contralateral to the lesion in the putamen. Choline acetyltransferase (CAT) activity was bilaterally increased in the medial segment of globus pallidus and hypothalamus. The lbotenic acid induced STN-lesion in the marmoset, thus, seemed to cause a widespread bilateral activation of neurons within the basal ganglia.     

Organization of the ascending striatal afferents in monkeys

Horseradish peroxidase was injected in various parts of the caudate nucleus and the putamen of monkeys to ascertain the relative locations of striatal projecting cells in the mesencephalon. The nigrostriatal component, as expected, is the greatest but numerous cells of the mesencephalic raphe system also project to the striatum. The projections from the pars compacta are organized in a topographical manner in all principal planes. The rostral two thirds of the substantia nigra are related to the head of the caudate nucleus. Nigral neurons projecting to the putamen are more posteriorly located and display an anteroposterior topography. The medial two thirds of the pars compacta send efferents to the head of the caudate nucleus from ventromedial to laterodorsal regions, reflecting a mediolateral topographical relationship. An inverse relationship exists dorsoventrally between nigra and caudate so that ventral compacta cells project to dorsal caudate and the dorsally situated neurons project to ventral-ventro-medial caudate regions. The dorsal and lateral parts of the putamen are more intimately related to the lateral and posterior nigra; by contrast, the ventral and ventromedial putamen receives more afferents from medial and central regions of the substantia nigra. A large group of cells in the tegmentum dorsal and medial to the medial lemniscus shows continuity with the pars compacta, and has similar connections with the striatum. This cell group should be included with the pars compacta. Significant overlap exists between the projection fields in all planes, making the nigrostriatal topographical organization seem less than precise. This apparent lack of point-to-point reciprocity may be due to the considerable size difference between the striatum and the substantia nigra. The raphe nuclei project to the greater part of the striatum but more significantly to its ventral and medial regions. The paranigral cell group sends its efferents mainly to the ventral striatum.     

Neuronal activity in the striatum and pallidum of primates related to the execution of externally cued reaching movements

We studied changes in basal ganglia neuronal activity associated with reaching movements of the arm in two monkeys. Data were obtained from 427 single neuronal units in putamen, 199 in caudate nucleus, and 216 in globus pallidus with multiwire electrodes allowing simultaneous recordings from multiple neurons. In all structures, changes in activity related to movement occurred most often after the onset of EMG: 43% of tested neurons in the putamen, 32% in the caudate nucleus, and 38% in the globus pallidus. Less frequently, changes began before EMG activation: 20% of neurons in the putamen, 19% in caudate nucleus, and 17% in globus pallidus. In general, these changes in neuronal activity lasted longer than EMG activity associated with reaching. The proportions of neurons activated were significantly larger in the putamen than the caudate nucleus. In the pallidum, the proportions were not statistically different from either the putamen or caudate nucleus, and no significant difference was found between the internal and external pallidal segments. Significant selectivity for movements to different targets was observed in 36% of neurons in the putamen, 28% in the caudate nucleus and 9% in the globus pallidus. The lower proportion in the globus pallidus compared to the striatum was significant (P < 0.002). Clusters of activated neurons were found in the striatum, however, the timing of changes was often different for individual neurons in these clusters. A cross-correlation analysis of the activity of neurons in the clusters revealed no evidence of common inputs, suggesting that striatal neurons in close proximity with neurons showing similar changes in activity are driven by different populations of neurons. In the putamen, the anatomical locations of neurons with changes in activity related to movement execution were on average significantly more posterior and lateral than neurons with changes related to the preparation of movement described earlier [31]. These findings support the view that the putamen and the caudate nucleus contain distinct functional areas. The present studies show that most anatomical regions in both the striatum and palladum participate in the control of executing reaching movements.     

Experimental hemiplegia in the monkey: basal ganglia glucose activity during recovery

Unilateral ablation of cerebral cortical areas 4 and 6 of Brodmann in the macaque monkey results in a dense contralateral hemiplegia that recovers partially with time. During the phase of dense hemiplegia, the local cerebral metabolic rate for glucose (lCMRGlc) is decreased significantly in the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus of the hemisphere ipsilateral to the lesion. In the present study, lCMRGlc in the basal ganglia was studied during the phase of partial recovery of motor activity. lCMRGlc was partially restored, and the greatest degree of restoration occurred in structures with direct connections to the cerebral cortex (caudate nucleus, putamen, subthalamic nucleus, substantia nigra, and red nucleus). Restoration was least in structures that do not receive direct connections from the cerebral cortex (the internal and external segments of the globus pallidus). The findings support the hypothesis that corticofugal activity accounts for a substantial degree of functional recovery.     

Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter

Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit locomotor hyperactivity and profound alterations in the homeostasis of the nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice. We used quantitative in situ hybridization and found that the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybridization. Our results show that in DAT+/+ mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we found an increased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/- mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.     

Cholinergic vesicular transporters in progressive supranuclear palsy

OBJECTIVE: To determine the status of cholinergic and monoaminergic vesicular transporter binding sites in progressive supranuclear palsy (PSP). METHODS: The authors determined autoradiographically the regional expression of acetylcholine vesicular transporter (VAChT) and monoamine vesicular transporter type 2 (VMAT2) binding sites in postmortem basal ganglia samples from subjects with PSP. Comparison neurochemical measures included choline acetyltransferase (ChAT) enzyme activity and benzodiazepine (BZ) binding sites. RESULTS: VAChT expressions and ChAT activities in caudate nucleus and putamen were markedly decreased in PSP, whereas BZ binding was unaffected, consistent with selective losses of striatal cholinergic interneurons. VMAT2 density was reduced significantly in the caudate nucleus, putamen, and substantia nigra pars compacta, consistent with degeneration of dopaminergic nigrostriatal projection neurons in PSP. In the globus pallidus, BZ receptor binding sites were reduced, whereas VMAT2 and VAChT binding sites were unchanged, indicating losses of intrinsic pallidal neurons and synapses. CONCLUSIONS: These results confirm selective and marked degenerations of basal ganglia cholinergic and dopaminergic terminals in PSP. Striatal VAChT reduction may provide a unique neurochemical imaging marker for distinction of PSP from other types of basal ganglia neurodegeneration.     

Functional MRI of apomorphine activation of the basal ganglia in awake rhesus monkeys

Functional magnetic resonance imaging (fMRI) was used to analyze blood oxygen level-dependent (BOLD) responses in the nigrostriatal system (caudate nucleus, putamen and substantia nigra) of awake rhesus monkeys to systemic apomorphine administration. The study (1) measured BOLD responses as an index of neuronal activity in the three structures following injections of the mixed D1/D2 agonist, and (2) assessed the effects of isoflurane anesthesia on the fMRI responses. Compared to control saline injections, 0.1 mg/kg apomorphine significantly activated the caudate nucleus (P < or = 0.005), putamen (P < or = 0.001) and substantia nigra (P < or = 0.005). The responses were consistent with activation of GABAergic neurons in these three structures seen in other animal models. Isoflurane gas measurably blunted the response to apomorphine, so that a significant apomorphine activation was only seen in the substantia nigra of anesthetized animals. Even there, the mean MR signal change was reduced from 9.8% in awake monkeys to 2.3% in anesthetized animals. The data support the hypothesis that fMRI can be used to study the effects of drugs that alter basal ganglia activity in awake rhesus monkeys.     

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on catecholamines and metabolites in primate brain and CSF

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration is able to produce nigrostriatal damage and motor disabilities in primates similar to those seen in Parkinson's disease. Two months after MPTP treatment in African Green monkeys, significant depletions of dopamine (DA) and/or homovanillic acid (HVA) were found in the dorsal ventral tegmental area, and septum, but not in the ventral part of the ventral tegmental area or nucleus accumbens. However, DA losses were greater at all examined sites in the striatum. In putamen and caudate nucleus the decreases in DA and HVA appeared more marked dorsolaterally than ventromedially. After MPTP treatment the ratio HVA/DA was elevated in the septum and all striatal regions; in the striatum the increases in ratio were greater in the dorsolateral than in the ventromedial samples. NE concentration was not significantly altered by MPTP in the mesolimbic system. In control animals the HVA concentration and the ratio HVA/DA were higher in the putamen than in the caudate nucleus. A longitudinal study showed that CSF HVA and 3-methoxy-4-hydroxyphenylglycol were reduced by MPTP and remained below baseline level for 12 months after MPTP treatment. This biochemical study indicates that in the monkey MPTP is able to induce selective damage within both the nigrostriatal and mesolimbic DA systems.     

The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease

A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer, 6-L-(18F)-fluorodopa, was used as an analog of levodopa to assess its regional brain uptake, conversion into, and retention as dopamine and further metabolites. The second tracer, (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease, striatal uptake of both tracers was decreased, putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen, but not caudate, correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values, suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful, a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.     

Neurochemical changes in the substantiae nigrae and caudate nuclei following acute unilateral intranigral infusions of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Acute unilateral intranigral infusions of MPTP at doses (200 micrograms) which produce robust contralateral rotation in the rat induced significant neurochemical changes in the ipsilateral as well as contralateral nigrostriatal systems. There were pronounced increases in the levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the ipsilateral substantia nigra and a significant decrease in the levels of DA in the ipsilateral caudate nucleus while opposite changes occurred in the contralateral substantia nigra and caudate nucleus. The DOPAC:DA and HVA:DA ratios were significantly higher in the ipsilateral caudate nucleus indicating increased activity of the ipsilateral nigrostriatal DA neurones. The levels of noradrenaline and 4-hydroxy-3-methoxyphenylethyline glycol (MHPG) increased and decreased significantly in the ipsilateral and contralateral substantia nigra, respectively, but there were no significant changes in the caudate nuclei. The levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased significantly in the ipsilateral substantia nigra and caudate nucleus as well as in the contralateral caudate nucleus but did not increase significantly in the contralateral substantia nigra. The 5-HIAA:5-HT ratio was significantly decreased in the contralateral caudate nucleus indicating a reduced activity of the contralateral nigrostriatal 5-HT neurones. The data thus indicate that MPTP applied to one substantia nigra is capable of producing profound neurochemical changes not only locally but also in the ipsilateral striatum as well as in the contralateral nigrostriatal system. Previous neuropharmacological studies have suggested that the rotation induced by intranigral MPTP may be mediated via dopamine released from dendrites in the pars reticulata in response to MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)     

苍白球在电针镇痛及兴奋尾壳核镇痛中的作用

用行为学和电生理学的方法 ,探讨苍白球在电针镇痛及兴奋尾壳核镇痛中的作用。结果表明 :电针可以延长辐射热引起的缩腿潜伏期 ,电针或兴奋尾壳核可抑制丘脑束旁核神经元的伤害性反应 ;苍白球微量注射红藻氨酸 7d后 ,电针对辐射热引起的大鼠缩腿潜伏期无明显影响 ,电针或兴奋尾壳核对丘脑束旁核神经元的伤害性反应亦无明显影响 ,与毁损前相比有显著性差异 (P <0 .0 5 ) ,与苍白球微量注射生理盐水 7d后 ,电针可延长大鼠缩腿潜伏期 ,及电针或兴奋尾壳核对束旁核神经元伤害性反应的抑制作用相比有显著性差异 (P <0 .0 5 )。结果提示 :苍白球在电针及兴奋尾壳核镇痛中发挥重要作用