Secondary degeneration of substantia nigra following massive basal ganglia infarction

Two autopsied cases of massive unilateral cerebral infarction due to occlusion of the middle cerebral artery (MCA) were reported with special reference to presence of the secondary degeneration of the substantia nigra. Case 1 was a 70-year-old male who suddenly suffered from left hemiplegia 3 years and 2 months prior to death. CT scan showed massive infarction involving basal ganglia and fronto-parietal white matter on the right side. Some parkinsonian features such as oily face and rigidity of limbs were noted during the course. At autopsy, the proximal portion of rt MCA was found occluded and the right substantia nigra was found depigmented. Case 2 was a 71 year-old male who suddenly became hemiplegic 4 years prior to death. CT scan revealed a low density area in the corona radiata of the right cerebral hemisphere. On carotid antiography, complete obstruction of the horizontal portion of right MCA at its distal end was observed, which was confirmed at autopsy. Histologically, the right substant a nigra in case 1 showed marked neuronal loss with gliosis as well as presence of many extracellular melanin pigments. These changes were more prominent in its medial portion where chromatolytic neurons were occasionally seen. The adjacent fronto-pontine tract and pyramidal tract showed secondary degeneration. The left substantia nigra appeared normal. In case 2, the substantia nigra on both sides appeared normal. The whole right cerebral peduncle, on the other hand, showed diffuse myelin pallor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible interactions between dynorphin and dopaminergic systems in rat basal ganglia and substantia nigra

Chronic haloperidol treatment markedly increases dynorphin-related peptide contents in caudate-putamen, globus pallidus and substantia nigra. Leu-enkephalin levels follow dynorphin-related peptide concentrations in these areas while Met-enkephalin-related peptide contents are unchanged in the substantia nigra following a similar treatment. An acute haloperidol injection had no effect on any opioid peptide levels in the basal ganglia. This suggests that Leu-enkephalin is likely to be derived from prodynorphin in the rat striatonigral pathway. Moreover, the Leu-enkephalin/dynorphin projection appears to be under striatal dopaminergic control.     

Reduction in basal ganglia and substantia nigra substance P levels in Huntington''s disease

Substance P (SP) levels were determined by radioimmunoassay (RIA) in several regions of post-mortem brain of controls and Huntington's disease (HD) patients. In controls, highest SP levels were found in basal ganglia, substantia nigra and hypothalamus. Nigral pars reticulata contained 3--4-fold higher levels than pars compacta. In HD, SP levels were reduced in all basal ganglia and substantia nigra. The reductions ranged from 48% in caudate nucleus to over 90% in nigral pars reticulata. There were no changes in SP levels in HD frontal cortex, thalamus or hypothalamus.     

The deep mesencephalic nucleus as an output center of basal ganglia: morphological and electrophysiological similarities with the substantia nigra

The deep mesencephalic nucleus (DMN) is a large midbrain reticular region between the superior colliculus, the substantia nigra compacta, the periaqueductal gray, and the medial geniculate body. Although some data suggest that it is involved in nociception and visceral control, its functions remain unclear. In the present study, by using morphological (combination of anterograde and retrograde tracers with immunocytochemistry and in situ hibrydization) and electrophysiological (firing activity and transynaptic response to striatal stimulation) methods, we show that a subpopulation of DMN cells shares many morphological and electrophysiological characteristics with those of the substantia nigra reticulata (SNR). These similarities include the following: 1) firing rate, firing pattern, and conduction velocity; 2) expression of GAD65, GAD67, and PV; 3) excitatory and inhibitory inputs from the striatum; and 4) projections to the ventral thalamus, superior colliculus, and pedunculopontine tegmental nucleus. Some differences were also found. In comparison with SN, DMN cells and striatal afferents are more sparsely distributed and they show conspicuous contralateral projections to the thalamus and superior colliculus. This suggests that, similarly to the SNR, the DMN acts as an output center of basal ganglia and probably facilitates the inter-hemispheric regulation of these centers.     

Substantia nigra opiate receptors on basal ganglia efferents

Many behavioral effects of opiate narcotics and peptides have been linked to effects on dopamine neurons originating in the substantia nigra pars compacta and ventral tegmental area. Selective brain lesions were combined with quantitative autoradiography to determine whether opiate receptors are on dopaminergic somata and/or processes in the substantia nigra pars compacta and ventral tegmental area. 6-Hydroxydopamine lesions that eliminated dopamine neurons produced little change in the pattern or density of [³H]-naloxone binding in the substantia nigra pars compacta or ventral tegmental area. Radiofrequency lesions of the internal capsule or globus pallidus and kainic acid lesions of the striatum markedly decreased [³H]-naloxone binding in the pars compacta and pars reticulata. These results are consistent with a dense distribution of opiate receptors on pallido-nigral and/or striato-nigral fibers and strengthen the likelihood that local effects of opiates on dopamine function in the nigrostriatal pathway are mediated indirectly by actions on nondopaminergic processes.     

Immunocytochemical studies of substance P and Met-enkephalin in the basal ganglia and substantia nigra in Huntington's, Parkinson's and Alzheimer's diseases

Immunocytochemical studies of the distribution and intensity of Substance P and Met-enkephalin staining in the basal ganglia and substantia nigra were carried out in five cases each of brains from patients with Huntington's disease, Parkinson's disease, Alzheimer's disease, and normal controls. The usefulness of the peroxidase-antiperoxidase method for human autopsy material was confirmed. Substance P and Met-enkephalin fibers were distributed in essentially the same pattern as described in experimental animals and in human brains. In Huntington's disease brains decreased Substance P staining was found in the internal globus pallidus and the substantia nigra, in agreement with radioimmunoassay studies by others. Met-enkephalin staining in the external globus pallidus was of normal intensity, although present within a shrunken area. In Parkinson's and Alzheimer's diseases there was intense immunoreactivity for Substance P in the globus pallidus and substantia nigra, and for Met-enkephalin in the globus pallidus, at variance with reported decreases in Parkinson's disease by radioimmunoassay, but in essential agreement with other immunocytochemical studies. Immunocytochemical methods complement radioimmunoassays of human brain and may help in mapping neuropeptidergic pathways and in pinpointing abnormalities in these pathways in basal ganglia disorders.     

Decrease of substance P-like immunoreactivity in the substantia nigra and pallidum of parkinsonian brains

Substance P-like immunoreactivity was measured in the basal ganglia of controls and parkinsonian patients. A significant decrease in substance P-like immunoreactivity was observed within the substantia nigra and the external segment of the globus pallidus from parkinsonian brains. This suggests an alteration of the striatonigral substance P-containing neurons in Parkinson's disease.     

Mechanisms of action selection and timing in substantia nigra neurons

The timing of actions is critical for adaptive behavior. In this study we measured neural activity in the substantia nigra as mice learned to change their action duration to earn food rewards. We observed dramatic changes in single unit activity during learning: both dopaminergic and GABAergic neurons changed their activity in relation to behavior to reflect the learned instrumental contingency and the action duration. We found the emergence of "action-on" neurons that increased firing for the duration of the lever press and mirror-image "action-off" neurons that paused at the same time. This pattern is especially common among GABAergic neurons. The activity of many neurons also reflected confidence about the just completed action and the prospect of reward. Being correlated with the relative duration of the completed action, their activity could predict the likelihood of reward collection. Compared with the GABAergic neurons, the activity of dopaminergic neurons was more commonly modulated by the discriminative stimulus signaling the start of each trial, suggesting that their phasic activity reflected sensory salience rather than any reward prediction error found in previous work. In short, these results suggest that (1) nigral activity is highly plastic and modified by the learning of the instrumental contingency; (2) GABAergic output from the substantia nigra can simultaneously inhibit and disinhibit downstream structures, while the dopaminergic output also provide bidirectional modulation of the corticostriatal circuits; (3) dopaminergic and GABAergic neurons show similar task-related activity, although DA neurons are more responsive to the trial start signal.     

Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate

The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway. Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway. Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation. This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro‐cuneiform nucleus pathway could control axial posture whereas the pallido‐pedunculopontine nucleus pathway could modulate locomotion. © 2011 Movement Disorder Society     

Changes of amino acid and monoamine levels after neonatal 6-hydroxydopamine denervation in rat basal ganglia,substantia nigra,and raphe nuclei

The effects of a neonatal dopaminergic deafferentation with the neurotoxin 6-hydroxydopamine (6-OHDA) on endogenous tissue levels of catecholamines, indoleamines, and amino acids were investigated in discrete rat brain regions. After producing the lesion at postnatal day 3 by intraventricular injections of 6-OHDA, with a desipramine pretreatment to protect noradrenaline neurons, the animals were kept for 3 months. Their brains were dissected to obtain samples of neostriatum, Globus pallidus, Substantia nigra, and Raphe nuclei, which were then analyzed by high-performance liquid chromatography, coupled either to electrochemical detection for aromatic monoamines, or to post-column ninhydrin derivatization with spectrophotometry for amino acids. The neonatal 6-OHDA treatment depleted dopamine (DA) levels in neostriatum, Globus pallidus, and Substantia nigra, but in Raphe nuclei DA was increased. The main metabolites of DA were also decreased in neostriatum, Globus pallidus, and Substantia nigra but remained unchanged in Raphe nuclei. Serotonin (5-HT) and its metabolite 5-hydroxyindole-3-acetic acid increased in neostriatum and Raphe nuclei; in Substantia nigra there was a slight increase in 5-HT only. The 6-OHDA lesion caused heterogeneous alterations in amino acid contents, which varied according to the region. In the neostriatum there were increases of γ-aminobutyric acid (GABA), aspartic acid, and glycine. In the Globus pallidus taurine, GABA, glutamic acid, glutamine, aspartic acid, serine, and alanine were elevated. In the Substantia nigra only increases in taurine, GABA, glutamic acid, and glutamine could be documented. This study shows important changes in amino acid levels and in some of their ratios, occurring in different anatomical subdivisions of the basal ganglia and related brainstem nuclei following a neonatal treatment with 6-OHDA. The results thus demonstrate major biochemical modifications in amino acids in the aftermath of a DA denervation and/or a 5-HT hyperinnervation during an early developmental period. © 1993 Wiley-Liss, Inc.     

Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions

The relative roles of D1 and D2 dopamine receptor stimulation in mediating the antiparkinsonian effects of dopaminergic drugs remain unclear. To determine the functional metabolic consequences of selective dopamine receptor stimulation, we used 2-deoxyglucose (2-DG) autoradiography to examine the effects of the D1 agonist SKF-38393 and the D2 agonist LY-171555 on regional cerebral glucose utilization (RCGU) in rats with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions. SKF-38393 (0.5-25.0 mg/kg) and LY-171555 (0.01-5.0 mg/kg) produced indistinguishable behavioral responses, including vigorous contralateral rotation. Treatment with each drug similarly increased glucose utilization, dose-dependently, in the parafascicular thalamus, subthalamic nucleus, deep layers of the superior colliculus, and lateral midbrain reticular formation ipsilateral to the nigral lesion; glucose utilization was decreased in the ipsilateral lateral habenula. By contrast, the D1 and D2 agonists differentially altered glucose utilization in the entopeduncular nucleus (EP) and the substantia nigra pars reticulata (SNr). SKF-38393, 5.0 and 25.0 mg/kg, increased glucose utilization 127 and 275%, respectively, in the pars reticulata ipsilateral to the lesion. LY-171555, 1.0 and 5.0 mg/kg, caused maximal contralateral turning, yet did not alter glucose utilization in the ipsilateral SNr. The glucose utilization response of the ipsilateral EP paralleled that of the SNr demonstrating large increases following administration of SKF-38393 and minimal change following the use of LY-171555. The results demonstrate that the selective D1 agonist reproduces the marked glucose utilization increases (2-3-fold above control values) in the EP and SNr that were previously observed using L-DOPA and apomorphine in this model, whereas the selective D2 agonist does not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperpolarizing action of baclofen on neurons in the rat substantia nigra slice

Rabbit carotid bodies were excised and the membrane potentials (MPs) of the glomus cells were recorded in vitro. Upstream injections of dopamine (DA; 25-250 micrograms) elicited a slow, long lasting depolarization in 76% of the cells studied. The remaining 24% were hyperpolarized by DA. Regardless of polarity, the DA-induced potential was associated with a significant increase in input resistance (Ro). On the other hand, changes in MP which were produced artificially by passing direct current through the recording electrode had little effect on Ro. It is concluded that DA alters the MP and Ro of glomus cells and that this may serve to modulate synaptic excitability within the carotid body.     

Increased 2-deoxyglucose uptake in hippocampus, globus pallidus and substantia nigra after cerebral ischemia

Ten minutes of complete cerebral ischemia in the rat results in a short period of increased ¹⁴C-2-deoxyglucose uptake in hippocampus, globus pallidus and substantia nigra, regions which selectively develop ischemic nerve cell changes, possibly as a result of damage to a transmitter system.     

Changes in dynorphin, enkephalin and cholecystokinin content of hippocampus and substantia nigra after amygdala kindling

Amygdaloid kindling of rats produced an increase in hippocampal Met5-enkephalin-Arg6-Gly7-Leu8 and cholecystokinin immunoreactivities and simultaneously a decrease in dynorphin A1-8 content. In substantia nigra Met5-enkephalin-Arg6-Gly7-Leu8 was increased and no change was observed in dynorphin A1-8 content. These data suggest that specific alterations of neuropeptides in limbic and extrapyramidal circuits are prominent manifestations of the kindling process or kindled seizures.