The striatonigral projection and nigrotectal neurons in the rat. A correlated light and electron microscopic study demonstrating a monosynaptic striatal input to identified nigrotectal neurons using a combined degeneration and horseradish peroxidase procedure

In a light and electron microscopic study of the substantia nigra of the rat, the distribution and morphology of nigrotectal neurons and the pattern of termination of striatonigral fibres have been examined following the placement of horseradish peroxidase injections in the superior colliculus and kainic acid lesions in the dorsal striatum. In confirmation of previous findings, nigrotectal neurons which had been identified by the retrograde transport of horseradish peroxidase from the superior colliculus had mainly medium sized somata, varied from fusiform to stellate in shape and were found in mainly ventral regions of the rostral two-thirds of the substantia nigra pars reticulata. On electron microscopic examination, single and multiple (from two to six) degenerating striatonigral boutons were found in synaptic contact with the soma, proximal mainstem dendrites and small dendrites (but mainly on small dendrites) of labelled nigrotectal and unlabelled nigral neurons in the ventral region of the pars reticulata. In addition, a small number of degenerating striatonigral boutons formed axoaxonic synapses with degenerating or normal boutons which were presynaptic to nigral dendrites. Almost all of the identified striatonigral synapses were of the symmetrical type, although a few degenerating boutons established asymmetrical synaptic contacts on unlabelled dendrites. These findings provide evidence of a monosynaptic input from the dorsal striatum to nigrotectal projection neurons in the substantia nigra and thus demonstrate the existence of a bineuronal pathway from the striatum through the substantia nigra to the superior colliculus. The possible significance of the pattern of termination of striatonigral fibres in the substantia nigra is discussed with reference to the known dendritic arborization of nigral neurons.     

Anatomy and physiology of substantia nigra and retrorubral neurons studied by extra- and intracellular recording and by horseradish peroxidase labeling

The question of origin of the excitatory and inhibitory responses that occur in neostriatal neurons following electrical stimulation of the substantia nigra is complicated by the possible spread of stimulus currents to numerous unspecifiable systems of neuronal elements. The present work begins to address this problem through the study of conduction properties of specific nigral and perinigral neurons in the cat. Neurons of pars compacta of substantia nigra and of the retrorubral area were found to have similar latencies for antidromic activation, whether from caudate nucleus stimuli (6.8–8 ms) or medial forebrain bundle stimulation (2.4–6.4 ms).The soma-dendritic features of both pars compacta and retrorubral neurons (revealed by intracellular injection of horseradish peroxidase) resembled the sparsely-branched, medium-sized substantia nigra neurons known from Golgi studies to have long dendrites with scattered and mainly distally-located spine-like appendages. Two types of pars compacta neurons were found; one with an ascending axon lacking collateral branches, and another with a descending axon that issued collaterals which terminated in the compacta, in pars reticulata, and possibly in retrorubral areas. Despite failure to detect as ascending axonal trajectory for this latter neuron, both types of pars compacta cells responded antidromically to stimulation of the caudate nucleus or medial forebrain bundle.The conduction time for impulse propagation in axons of pars compacta or retrorubral neurons suggests that either may mediate at least some of the excitatory responses that are known to occur in neostriatal neurons following stimulation of the substantia nigra in the cat. However, these conduction times are not compatible with the production of other excitatory responses which are commonly observed in the cat striatum at latencies shorter than 6 to 7 ms following stimulation of the substantia nigra.     

Orthodromic and antidromic responses of nucleus accumbens neurons to stimulation of amygdala and substantia nigra in cats

Response of nucleus accumbens neurons to stimulation of the amygdala and the substantia nigra were investigated extracellularly in anesthetized cats. They were excited by stimulation of the basolateral amygdaloid nucleus with latencies of 9.0-20.0 ms (mean 12.8 ms). About 70% of them were activated antidromically with latencies of 5.5-33.0 ms (mean 18.8 ms) following stimulation of the substantia nigra pars reticulata. The nucleus accumbens thus relays signals from the amygdaloid complex to the substantia nigra, and may act to bridge the limbic system to the basal ganglia.     

不同剂量6-羟基多巴胺注射大鼠单侧前脑内侧束后对中脑多巴胺能神经元损伤作用的观察

将不同剂量的６－羟基多巴胺（６－ＯＨＤＡ）注入大鼠一侧黑质（ＳＮ）头端的前脑内侧束（ＭＦＢ），４７天后用酪氨酸羟化酶（ＴＨ）免疫细胞化学染色法，观察旋转鼠整个ＳＮ和腹侧被盖区（ＶＴＡ）不同切面上ＤＡ神经元的损伤程度，结果发现：损伤侧ＳＮ和ＶＴＡ的ＴＨ阳性神经元数在所有观察水平上均有明显下降，并从前囟后５．１ｍｍ开始呈现６－ＯＨＤＡ剂量依赖性。而下降率（与健侧相比）为ＳＮ致密部（ｓｎｃ）＞网状部和外侧部（ｓｎｒ＋ｓｎｌ）＞ＶＴＡ。同时还发现，ｓｎｃ的ＴＨ阳性细胞在黑质两端分布比率较高，而ＶＴＡ的相应细胞在黑质中部分布率较高。另外，在健侧前囟后４．８ｍｍ处出现非６－ＯＨＤＡ剂量依赖性的ＴＨ阳性神经元计数明显增加的现象。本文的结果提示：６－ＯＨＤＡ对中脑ＤＡ神经元的总体损伤程度取决于多种因素，如６－ＯＨＤＡ剂量、神经元对６－ＯＨＤＡ的敏感度以及敏感神经元的分布等。同时健侧中脑组织对邻侧发生的损伤并非毫无反应，一些交叉投射的纤维可能起着传递损伤信息的作用     

Dopaminergic dendrites in the pars reticulata of the rat substantia nigra and their striatal input. Combined immunocytochemical localization of tyrosine hydroxylase and anterograde degeneration

An antiserum prepared in the rabbit against bovine adrenal gland tyrosine hydroxylase has been used to identify by the immunoperoxidase method dopaminergic neurons in the rat substantia nigra. The purpose of this identification was (i) to assess the storing compartments and the release sites in the dopamine-containing processes of the pars reticulata; (ii) to determine if these processes receive a direct input from the neostriatum.Immunoreactive neurons were present in the three divisions of the substantia nigra (pars compacta, pars lateralis and pars reticulata), but they were much more numerous in pars compacta. The caudal half and the most rostral end of pars reticulata contained single and small clusters of reactive neurons, which were absent from the remaining regions. Processes emerging from the positive neurons, exhibiting also immunoperoxidase reactivity, spread throughout the whole pars reticulata. The ultrastructural study was limited to the region of the pars reticulata free of reactive perikarya, in order to analyze the processes that originate from neurons located in the pars compacta. Five hundred and eighty well-preserved immunoreactive processes were analyzed. Almost all of them (578) displayed cytological features allowing their identification as dendrites. Two of them corresponded to thin unmyelinated, non-synaptic segments of axons, probably in their way to their terminal fields outside the substantia nigra. The large majority of the reactive dendrites (82%) were postsynaptic to one or several axon terminals and did not establish direct appositions with other dendritic elements. Only 4.35% of the labeled dendrites were directly apposed to other reactive or unreactive dendrites. Two of the labeled dendrites (0.35%) contained synaptic-like vesicles. In one of them, the vesicles were clustered against a restricted area of the plasma-membrane, forming an active zone.In two animals, kainic acid was used to destroy neurons located within the central region of the main body of the neostriatum. Their projections were traced to the ipsilateral substantia nigra, in which dopaminergic neurons were visualized by the immunoperoxidase method. The axons originating from the injured neurons in the striatum established direct synaptic contacts with the immunoreactive dendrites in pars reticulata.These findings indicate that (i) there is no dopaminergic recurrent collateral axonal plexus in pars reticulata; (ii) the dopamine-storing compartment in the dendritic processes is not vesicular; the cisterns of the smooth endoplasmic reticulum might be such a compartment; (iii) The differentiation of presynaptic dendrites which establish typical junctional synaptic complexes does not occur in the dopaminergic dendrites present in pars reticulata; (iv) The proportion of presynaptic release sites observed in dopaminergic dendrites (1 active zone out of the 578 analyzed dendrites) is too low to account for the dendritic release revealed by biochemical analysis (Nieoullou, Chéramy &; Glowinski, 1977a). Therefore, the modality of transmitter release from dopaminergic dendrites must be different from that supposed in the vesicular theory; (v) combined anterograde degeneration and immunocytochemistry has allowed us to demonstrate a direct striatal input to the dopamine-containing dendrites present within the pars reticulata.     

Effect of high-frequency stimulation of the subthalamic nucleus on the neuronal activities of the substantia nigra pars reticulata and ventrolateral nucleus of the thalamus in the rat

Electrophysiological recordings were made in anaesthetized rats to investigate the mode of function of high-frequency stimulation of the subthalamic nucleus used as a therapeutic approach for Parkinson's disease. High-frequency electrical stimulation of the subthalamic nucleus (130 Hz) induced a net decrease in activity of all cells recorded around the site of stimulation in the subthalamic nucleus. It also caused an inhibition of the majority of neurons recorded in the substantia nigra pars reticulata in normal rats (94%) and in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (90%) or with ibotenic acid lesions of the globus pallidus (79.5%). The majority of cells recorded in the ventrolateral nucleus of the thalamus responded with an increase in their activity (84%).These results show that high-frequency stimulation of the subthalamic nucleus induces a reduction of the excitatory glutamatergic output from the subthalamic nucleus which results in deactivation of substantia nigra pars reticulata neurons. The reduction in tonic inhibitory drive of nigral neurons induces a disinhibition of activity in the ventrolateral motor thalamic nucleus, which should result in activation of the motor cortical system.     

Behavioral and electrophysiological changes following microinjections of colchicine into the substantia nigra.

Male Sprague-Dawley rats received bilateral microinjections of colchicine (2 or 4 μg in 1 μl) into the substantia nigra. During the first 2 days the animals were hyperactive, intense gnawing and chewing were observed, and food intake was significantly increased. During the next 3 or 4 days, activity, food and water intakes and body weight gain were markedly reduced; the behavior was similar to that previously observed following damage to the substantia nigra and nigrostriatal pathway from 6-hydroxydopamine or electrolytic lesions. This period of hypophagia and hypodipsia was followed by a rebound increase in food and water intake for several days until body weight returned to normal levels. Field potentials recorded from the caudate nucleus in response to electrical stimulation of the substantia nigra were reduced in amplitude during the first 4 days following microinjections of colchicine into the substantia nigra and recovered by Day 7.These reversible behavioral effects of microinjections of colchicine into the substantia nigra confirm the importance of the nigrostriatal pathway in motor and ingestive behaviors.     

Striato-nigral dynorphin and substance P pathways in the rat

The effect of striatal ibotenic acid lesions on dynorphin-, substance P- and enkephalin-like immunoreactivities in the substantia nigra has been studied with immunohistochemistry as well as biochemistry. A comparison was made with the effects produced by intranigral ibotenic acid lesion and by 6-hydroxy-dopamine injection into the medial forebrain bundle. In addition, the effect of the striatal lesions on nigral glutamic acid decarboxylase (GAD)-positive structures was analysed with immunohistochemistry. The effect of the lesions was analysed functionally in the Ungerstedt rotational model, in order to obtain a preliminary evaluation of the extent of the lesions. The striatal lesions produced a parallel depletion of dynorphin and substance P levels in the substantia nigra, pars reticulata, ipsilateral to the treated side, which was dependent upon the extent and location of the lesion. Ibotenic acid lesions into the tail and the corpus of the striatum produced stronger nigral-peptide depletion than lesions in the head and the corpus of the striatum. Comparison of placement of lesions and localization of depleted area in the substantia nigra revealed a topographical relationship. Furthermore, the nigral depletion patterns of dynorphin and substance P were similar. The immunohistochemical analysis revealed that also GAD-positive fibers in the pars reticulata to a large extent disappeared after striatal lesions, in parallel to the dynorphin- and substance P-positive fibers. However, the depletion was less pronounced for GAD than for the peptides, probably related to presence of local GABA neurons in the zona reticulata of the substantia nigra. These results indicate that with the types of lesion used in this study it is not possible to provide evidence for a differential localization within the striatum of dynorphin-, substance P- and GABA-positive cell bodies projecting to the substantia nigra. The radioimmunoassay showed that (Leu)- but not (Met)-enkephalin was affected to the same extent as the dynorphin peptides, supporting the view that (Leu)-enkephalin in the pars reticulata of the substantia nigra is derived from proenkephalin B and not from proenkephalin A. In the immunohistochemical analysis (Met)-enkephalin-like immunoreactivity could only be detected in the pars compacta of the substantia nigra and did not seem to be affected by any of the lesions. The striatal lesions produced a behavioural asymmetry, which could be disclosed by stimulating the rats with apomorphine, which produced ipsilateral rotation.(ABSTRACT TRUNCATED AT 400 WORDS)     

The activity of pars compacta neurons of the monkey substantia nigra is depressed by apomorphine

In the substantia nigra of anesthetized and awake monkeys, presumptive dopamine cells of the pars compacta were electrophysiologically discriminated against non-dopaminergic cells of the pars reticulata by their lower discharge rate (0.5–8 vs 20–130 imp./s), their longer impulse duration (means 2.05 vs 0.92 ms), and their exclusive depression following systemic injection of the dopamine agonist apomorphine (24 out of 30 compacta neurons at 0.05–0.1 mg/kg s.c.).     

The neurological basis of striatally induced head-turning in the rat: The effects of lesions in putative output pathways

Turning of the head towards the contralateral side was induced in the conscious unrestrained rat by electrical stimulation of the neostriatum through permanent indwelling electrodes. The possible output pathways by which this response was mediated were examined using ablative and neurotoxin lesions. Contralateral head-turning was abolished or greatly attenuated by electrolytic lesions of the globus pallidus or substantia nigra on the stimulated side. Lesions of the sensory cortex, superior colliculi, ventromedial thalamic nucleus or dopaminergic nigrostriatal pathway were ineffective.It is concluded that descending projections from the pallidum and/or substantia nigra to the brain stem may be important for the mediation of head-turning induced by striatal stimulation.     

Neural activities in the substantia nigra modulated by stimulation of the orofacial motor cortex and rhythmical jaw movements in the rat

Neurons related to jaw movements in the substantia nigra pars reticulata were explored by examining changes in their neural activities in response to electrical stimulation of the orofacial sensorimotor cortex and during rhythmical jaw movements induced by mechanical stimulation applied to the oral cavity in the rat. Out of 80 neurons tested, 59 showed changes in their firing patterns of activities in response to the electrical stimulation of the cortex. The responding neurons were mainly located in the dorsolateral part of the substantia nigra pars reticulata. The substantia nigra pars reticulata neurons showing responses were classified into the following five types according to their response patterns: (1) an inhibition preceded by an early excitation and followed by a late excitation (n = 26), (2) an inhibition preceded by an early excitation but not followed by a late excitation (n = 7), (3) an inhibition not preceded by an early excitation but followed by a late excitation (n = 2), (4) an inhibition without early or late excitations (n = 7) and (5) an excitation without an inhibition (n = 17). Out of 18 neurons responding to the cortical stimulation, 11 (61.1%) increased or decreased their neural activities during rhythmical jaw movements. Some of these neurons had a projection to the lateral part of the superior colliculus (n = 5) and/or to the parvicellular reticular formation (n = 2). These results provide first neurophysiological evidence for neurons in the dorsolateral part of the substantia nigra pars reticulata with inputs from and outputs to the areas related to jaw movements. These neurons may participate in the control of jaw movements in the rat.     

Evidence for functional interactions of morphine in substantia nigra and striatum in relation to muscular rigidity in rats

Systemic administration of morphine (15 mg/kg i.p.) induced muscular rigidity in rats, which was recorded from the gastrocnemius-soleus muscle as tonic activity in the electromyogram. Administration of morphine (5 or 10 μg) into the pars compacta of the substantia nigra antagonized the rigidity in a dose-dependent manner, whereas administration of morphine at a dose of 5 μg into the pars reticulata of the substantia nigra enhanced the tonic EMG activity. When morphine and naloxone were co-administered intranigrally, the tonic EMG activity was not affected.     

Early establishment of adult-like nigrotectal architecture in the neonatal cat: a double-labeling study using carbocyanine dyes

Virtually nothing is known about the ontogeny of substantia nigra, pars reticulata projections to the midbrain superior colliculus, even though this pathway is critical for the basal ganglia modulation of midbrain-mediated visuomotor behaviors. The present studies used the lipophilic carbocyanine dyes 1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate and 1,1'-dioctodecyl-3,3,3',3'-tetramethylindodi, 4-chlorobenzenesulfonate salt to examine the crossed and uncrossed nigrotectal projections in neonatal cats, from parturition to 14 days postnatal (the technical limits of the tracing technique). In retrograde experiments, paired placement of the dyes in each superior colliculus produced numerous retrogradely-labeled nigrotectal neurons, with the uncrossed neurons far out numbering their crossed counterparts. No double-labeled neurons were observed, indicating that crossed and uncrossed nigrotectal neurons are segregated at birth. In anterograde experiments, dye placements into each substantia nigra, pars reticulata resulted in an iterative series of labeled patches, aligned medial-to-lateral across the intermediate and deep superior colliculus, a pattern reminiscent of the adult. Uncrossed neonatal axons had simple linear morphologies with few branch points; by contrast, crossed axons displayed more extensive terminal arbors that were distributed diffusely throughout the rostrocaudal extent of the contralateral superior colliculus In the final series of experiments, one dye was placed unilaterally in the substantia nigra, pars reticulata, while the second dye was positioned in the predorsal bundle, in order to bilaterally label superior colliculus output neurons. Although both crossed and uncrossed axons appeared to have contacted superior colliculus output neurons, crossed axons preferentially targeted the soma and proximal dendrites, whereas uncrossed terminals were distributed more distally. Throughout this early postnatal period, no significant changes in cellular morphologies or gross modification of terminal projection patterns were observed; however, the presence of growth cones in even the oldest animals studied suggests that the refinement of the nigrotectal projections extends well into postnatal life. Nevertheless, the segregation of crossed and uncrossed nigrotectal neurons into a highly organized afferent mosaic that has established synaptic contacts with superior colliculus output neurons indicates that many of the salient features characterizing nigrotectal projections are established prior to the onset of visual experience.     

Distribution of γ-aminobutyrate in the rat thalamus: Specific decreases in thalamic γ-aminobutyrate following lesion or electrical stimulation of the substantia nigra

Various subnuclei of the rat's thalamus were punched out or finely microdissected from frozen coronal sections of brain and assayed for γ-aminobutyrate by microdansylation. Highest levels were recorded in the ventromedial and parafascicular regions, corresponding to the sites of termination of nigrothalamic neurones. One week after placing a unilateral electrolytic lesion in the zona reticulata of the substantia nigra there were significant decreases in γ-aminobutyrate levels in the ipsilateral ventromedial (?14%) and parafascicular (?11%) nuclei, but not in other nuclei tested. Falls in the level of γ-aminobutyrate of 19–26% were found to be confined to the ventromedial region in microdissections of brain slices containing this nucleus, two weeks after injecting 1 μg kainic acid into the substantia nigra. The concentrations of glutamate, aspartate, glutamine, glycine and alanine were not altered in the deafferented ventromedial thalamus. Pathological effects of kainate were registered as a complete loss of neuronal perikarya at the injection site coupled with intense gliosis. Mild gliosis, but no postsynaptic neuronal damage, was visible in the corresponding ventromedial and parafascicular nuclei in the thalamus, although degenerating electron-dense terminal boutons were occasionally seen in electron micrographs of this tissue.In rats in which thalamic glutamate decar?ylase activity was inhibited by systemic injection of 3-mercaptopropionic acid, trains of biphasic electrical pulses delivered to the nigra (100 Hz, 0.1 mA, width 0.6 ms for 15 min) evoked a stimulus-dependent decrease in ventromedial (?17%) and parafascicular (?10%) γ-aminobutyrate content, but not in that of other thalamic nuclei. Similar post-stimulus falls in the level of γ-aminobutyrate in the ventromedial nucleus were noted after direct stereotaxic injection of this nucleus with the enzyme inhibitor.These findings are consistent with the existence of γ-aminobutyrate-containing nigrothalamic fibres whose cell bodies lie in the medial part of the substantia nigra zona reticulata and which terminate in the ventromedial and parafascicular nuclear regions of the thalamus.     

Striatal, pallidal, and pars reticulata evoked inhibition of nigrostriatal dopaminergic neurons is mediated by GABA(A) receptors in vivo

Dopaminergic neurons express both GABA(A) and GABA(B) receptors and GABAergic inputs play a significant role in the afferent modulation of these neurons. Electrical stimulation of GABAergic pathways originating in neostriatum, globus pallidus or substantia nigra pars reticulata produces inhibition of dopaminergic neurons in vivo. Despite a number of prior studies, the identity of the GABAergic receptor subtype(s) mediating the inhibition evoked by electrical stimulation of neostriatum, globus pallidus, or the axon collaterals of the projection neurons from substantia nigra pars reticulata in vivo remain uncertain. Single-unit extracellular recordings were obtained from substantia nigra dopaminergic neurons in urethane anesthetized rats. The effects of local pressure application of the selective GABA(A) antagonists, bicuculline and picrotoxin, and the GABA(B) antagonists, saclofen and CGP-55845A, on the inhibition of dopaminergic neurons elicited by single-pulse electrical stimulation of striatum, globus pallidus, and the thalamic axon terminals of the substantia nigra pars reticulata projection neurons were recorded in vivo. Striatal, pallidal, and thalamic induced inhibition of dopaminergic neurons was always attenuated or completely abolished by local application of the GABA(A) antagonists. In contrast, the GABA(B) antagonists, saclofen or CGP-55845A, did not block or attenuate the stimulus-induced inhibition and at times even increased the magnitude and/or duration of the evoked inhibition. Train stimulation of globus pallidus and striatum also produced an inhibition of firing in dopaminergic neurons of longer duration. However this inhibition was largely insensitive to either GABA(A) or GABA(B) antagonists although the GABA(A) antagonists consistently blocked the early portion of the inhibitory period indicating the presence of a GABA(A) component. These data demonstrate that dopaminergic neurons of the substantia nigra pars compacta are inhibited by electrical stimulation of striatum, globus pallidus, and the projection neurons of substantia nigra pars reticulata in vivo. This inhibition appears to be mediated via the GABA(A) receptor subtype, and all three GABAergic afferents studied appear to possess inhibitory presynaptic GABA(B) autoreceptors that are active under physiological conditions in vivo.     

Long collateral branches of substantia nigra pars reticulata axons to thalamus,superior colliculus and reticular formation in monkey and cat. Multiple retrograde neuronal labeling with fluorescent dyes

In order to gain some impressions about the degree to which individual neurons of the pars reticulata of the substantia nigra send long collateral branches to more than one of its three major targets (thalamus, superior colliculus, reticular formation), two, or all three targets were injected with fluorescent dyes (Evan's blue, granular blue, nuclear yellow, propidium iodide) in six squirrel monkeys and four cats. The best results were obtained in the monkey brain with injections of Evan's blue in the thalamus, granular blue in the colliculus and nuclear yellow in the reticular formation. Whereas nigrothalamic and nigroreticular neurons are numerous and widely scattered throughout all parts of the pars reticulata, cells projecting only to the superior colliculus are fewer in number and restricted to a rostral-lateral zone. These results are consistent with earlier data obtained with the horseradish peroxidase method.² Although double-labeled cells with projections to both the thalamus and reticular formation occur throughout the pars reticulata, such cells are somewhat more abundant at caudal levels of the nucleus. Cells containing dyes from both the superior colliculus and reticular formation are less common and restricted to the lateral part of the pars reticulata. A small number of cells near the rostral pole of the pars reticulata contain dye from both the tectal and thalamic injection. Typically, less than two dozen cells in any case can be confidently identified as containing all three dyes and these cells are located in the rostrolateral half of the pars reticulata. Fewer than 20% of the labeled nigral cells contain more than one dye.In the cat, thalamic injection of granular blue and tectal injection of nuclear yellow indicate that most nigrotectal cells are located in the middle of the mediolateral expanse of the pars reticulata in its rostral half. Nigrothalamic cells flank the nigrotectal group medially, laterally and caudally. Where these groups border one another, several cells contain both dyes indicating that they project to both the thalamus and colliculus. In both the cats and monkeys, a less extensive cell-labeling occurs in the contralateral nigra with a pattern similar to that in the ipsilateral substantia nigra.The results indicate that several neurons of the substantia nigra's pars reticulata send long collateral branches to two or even all three of the major targets. Many reticulata cells, however, appear to project either to the thalamus, or to the superior colliculus or to the reticular formation.     

Dizocilpine maleate, MK-801, but not 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, NBQX, prevents transneuronal degeneration of nigral neurons after neurotoxic striatal-pallidal lesion

Unilateral neurotoxin lesion of rat caudate-putamen and globus pallidus resulted in delayed, transneuronal degeneration of GABAergic substantia nigra pars reticulata neurons. To explore whether the disinhibition of endogenous glutamate excitatory input played a role in the degeneration of substantia nigra pars reticulata neurons, animals with unilateral striatal-pallidal lesions received three daily intraperitoneal injections of either dizocilpine maleate (MK-801, 1 or 10 mg/kg), an N-methyl-D-aspartate glutamate receptor blocker, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, 30 mg/kg), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor blocker, that began 24 h after the striatal-pallidal neurotoxin lesion. Drug treatment affected neither the volume of the initial lesion nor the volume of striatal-pallidal glial fibrillary acidic protein immunoreactivity. Neuron number in the substantia nigra pars reticulata ipsilateral to the lesioned striatopallidum was reduced on average by 37% in untreated control rats, in low dose MK-801, and NBQX-treated rats (P<0.0001). However, in animals treated with high doses of MK-801 there was no difference in the number of neurons in the substantia nigra pars reticulata ipsilateral or contralateral to the neurotoxin lesion. These data demonstrate that dose-related treatment with N-methyl-D-aspartate glutamate receptor blockers protects substantia nigra pars reticulata neurons, and suggests that glutamatergic mechanisms play a role in delayed transneuronal degeneration.     

Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

To determine how norepinephrine affects the basic physiological properties of catecholaminergic neurons, brain slices containing the substantia nigra pars compacta and locus coeruleus were studied with cell-attached and whole-cell recordings in control and dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack norepinephrine. In the cell-attached configuration, the spontaneous firing rate and pattern of locus coeruleus neurons recorded from Dbh -/- mice were the same as the firing rate and pattern recorded from heterozygous littermates (Dbh +/-). During whole-cell recordings, synaptic stimulation produced an alpha-2 receptor-mediated outward current in the locus coeruleus of control mice that was absent in Dbh -/- mice. Normal alpha-2 mediated outward currents were restored in Dbh -/- slices after pre-incubation with norepinephrine. Locus coeruleus neurons also displayed similar changes in holding current in response to bath application of norepinephrine, UK 14304, and methionine-enkephalin. Dopamine neurons recorded in the substantia nigra pars compacta similarly showed no differences between slices harvested from Dbh -/- and control mice. These results indicate that endogenous norepinephrine is not necessary for the expression of catecholaminergic neuron firing properties or responses to direct agonists, but is necessary for auto-inhibition mediated by indirect alpha-2 receptor stimulation.     

An experimental electron microscopic study on the striatonigral projection in the cat

Summary The ultrastructure of the cat's substantia nigra was investigated from 2–21 days following large lesions of the caudate nucleus and the putamen. From 4 days on a large number of degenerating boutons and degenerating unmyelinated fibers are seen in the substantia nigra, in the pars compacta as well as the pars reticulata. Both parts, mainly the latter, receive striatal afferents. The degeneration in the substantia nigra following striatal lesions is of the dark type. Most of the degenerating boutons apparently are of the type I (see Rinvik and Grofová, 1970) and end on all parts of the nigral cell surface, including the dendritic spines. One instance of a degenerating presynaptic bouton in an axo-axonic synapse has been found. Some degenerating boutons also probably belong to the type II bouton, while degenerating boutons of type III were never seen following the striatal lesions. The electron microscopic identification of early axonal degeneration in the central nervous system, is discussed with reference to the paper of Cohen and Pappas (1969). Problems concerning the pars compacta versus the pars reticulata of the substantia nigra are taken up. The possible sources of origin of the different types of boutons in the cat's substantia nigra, is discussed.On leave of absence from the Anatomical Institute of the Medical Faculty, Charles' University in Prague, with an IBRO grant nr. E. 29.99-1.A preliminary report of some of the observations was presented at the XIIth Congress for Morphologists in Prague, October '69.We gratefully acknowledge the valuable technical assistance of Mrs. J. L. Vaaland and the skilful help by Mrs. B.E. Branil in the preparation of the microphotographs.