Association of dopamine D1 and D2 receptors with specific cellular elements in the basal ganglia of the cat: the uneven topography of dopamine receptors in the striatum is determined by intrinsic striatal cells, not nigrostriatal axons

To ascertain the cellular associations of the D1 and D2 dopamine receptor subtypes in components of the basal ganglia, cats were prepared with unilateral, axon-sparing, ibotenic acid lesions of the striatum (n = 6) or lesions of the nigrostriatal dopamine system by intranigral infusion of 6-hydroxydopamine (n = 8). After 42 days survival, tissue sections from the brains were processed for quantitative, in vitro receptor autoradiography with [3H]SCH23390 (D1 radioligand) or [3H]spiroperidol (D2 radioligand). Lesion-induced changes in basal ganglia nuclei were assessed by comparing them to the corresponding nuclei on the intact side and in naive brains. Ibotenate lesions cause a decline in specific D1 and D2 receptor-binding in the area of the striatal lesion of 94% and 85%, respectively, and completely eliminate the uneven patterns of high- and low-density binding that are characteristic of the cat's caudate nucleus. The globus pallidus, entopeduncular nucleus and pars reticulata of the substantia nigra also show marked reductions in binding after striatal ibotenate lesions. Thus, after caudate nucleus lesions, D2 binding in the two pallidal segments declines by approximately 50%, but remains unchanged in the substantia nigra. Binding of the D1 radioligand (which is not measurable in the globus pallidus) declines by about 75% in the affected regions of the entopeduncular nucleus and pars reticulata, and by about 30% in the pars compacta. Lesions of the nigral dopamine neurons reduce D2 receptor-binding by 95% in the pars compacta and 40% in the pars reticulata, but have no effect on the concentration of D1 or D2 radioligand-binding in the striatum or pallidum. Moreover, such lesions failed to alter the uneven patterns of binding in the striatum. These data suggest that most, if not all, D1 receptors in the basal ganglia are associated with cells of the striatum and their axons in the entopeduncular nucleus and substantia nigra, and likewise, a large majority of D2 receptors are associated with striatal cells and their axons in pallidal structures. Nearly all D2 receptors in the substantia nigra are associated with dopamine neurons (autoreceptors). Finally, the heterogeneous patterns of D1 and D2 receptors in the striatum are a consequence of intrinsic neuronal distributions.     

Topographic projections from the basal ganglia to the nucleus tegmenti pedunculopontinus pars compacta of the cat with special reference to pallidal projections

Summary Projections from the basal ganglia to the nucleus tegmenti pedunculopontinus pars compacta (TPC) were studied by using anterograde and retrograde tracing techniques with horseradish peroxidase conjugated with wheat germ agglutinin (WGA-HRP) in the cat. Following WGA-HRP injections into the medial TPC area, a substantial number of retrogradely labeled cells were seen in the entopeduncular nucleus (EP) and medial half of the substantia nigra pars reticulata (SNr), whereas following WGA-HRP injections into the lateral TPC area, labeled cells were marked in the caudal half of the globus pallidus (GP) and lateral half of the SNr. To confirm the retrograde tracing study, WGA-HRP was injected into the EP or the caudal GP, and anterograde labeling was observed in the TPC areas. Terminal labeling was located in the medail TPC area in the EP injection case, while terminal labeling was observed in the lateral TPC area in the caudal GP injection case. Projections from the striatum to the pallidal complex (the EP and the caudal GP) were also studied autoradiographically by injecting amino acids into various parts of the caudate nucleus and the putamen. Terminal labeling was distributed over the whole extent of the EP and the rostral GP following injections into the rostral striatum (the head of the caudate nucleus or the rostral part of the putamen), while terminal labeling was distributed over the caudal GP following injections into the caudal striatum (the body of the caudate nucleus or the caudal part of the putamen). From these findings, we conclude that there exists a medio-lateral topography in the projection from the basal ganglia to the TPC: The EP receives afferent projections from the rostral striatum and projects to the medial TPC area, whereas the caudal GP receives projections from the caudal striatum and sends fibers to the lateral TPC area.Abbreviations BC brachium conjunctivum - CD caudate nucleus - CP cerebral peduncle - DBC decussation of the brachium conjunctivum - EP entopeduncular nucleus - GP globus pallidus - IC internal capsule - ICo inferior colliculus - LH lateral habenular nucleus - ML medial lemniscus - PN pontine nuclei - PUT putamen - SCo superior colliculus - SI substantia innominata - SN substantia nigra - SNc substantia nigra pars compacta - SNr substantia nigra pars reticulata - STN subthalamic nucleus - TH thalamus - TPC nucleus tegmenti pedunculopontinus pars compacta     

Substance P and neurokinin A regulate by different mechanisms dopamine release from dendrites and nerve terminals of the nigrostriatal dopaminergic neurons

Numerous striatal neurons innervating the substantia nigra contain substance P and/or neurokinin A. In contrast to substance P or neurokinin A, little neurokinin B is found in the substantia nigra. This led us to compare the effects of nigral application of these tachykinins on the release of dopamine from dendrites and nerve terminals of nigrostriatal dopaminergic neurons. Experiments were made in halothane-anesthetized cats implanted with one push-pull cannula in the substantia nigra and another in the ipsilateral caudate nucleus [3H]Tyrosine was delivered continuously to each push-pull cannula and the release of newly synthesized [3H]dopamine measured in the superfusate. Unlike substance P or neurokinin A, neurokinin B (10(-8) M) applied for 30 min into the pars compacta of the substantia nigra was without effect on the release of [3H]dopamine from nerve terminals or dendrites. When either substance P (10(-8) M) or neurokinin A (10(-8) M) was applied into the pars compacta, the release of [3H]dopamine from nerve terminals was enhanced. While neurokinin A also stimulated the dendritic release of [3H]dopamine, this was reduced by substance P. At a lower concentration (10(-9) M), neurokinin A induced similar effects to those observed at 10(-8) M whereas substance P (10(-9) M) stimulated moderately [3H]dopamine release from nerve terminals but did not affect the dendritic release of the [3H]amine. When superfused into the pars reticulata, substance P (10(-8) M) still stimulated [3H]dopamine release from nerve terminals but not from dendrites while neurokinin A (10(-8) M) was without effect either in the caudate nucleus or the substantia nigra. Additional experiments were made to determine whether or not substance P (10(-8) M) or neurokinin A (10(-8) M) act directly on nigral dopaminergic neurons when applied into the pars compacta. The effects of substance P on [3H]dopamine release from nerve terminals and dendrites were prevented when 2-amino-6-trifluoromethoxy benzothiazole (10(-5) M), an antagonist of glutamatergic transmission, was applied continuously into the caudate nucleus. In contrast, the stimulatory effects of neurokinin A on [3H]dopamine release from nerve terminals and dendrites were insensitive to 2-amino-6-trifluoromethoxy benzothiazole (10(-5) M). These results suggest that neurokinin A, but not substance P, acts directly on dopaminergic cells. In the light of previous observations, we propose that the effects of substance P on dopaminergic transmission are mediated by a nigro-thalamo-cortico-striatal loop.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential connections of caudate nucleus and putamen in the squirrel monkey (Saimiri sciureus)

The organization of the subcortical connections of caudate nucleus and putamen in the squirrel monkey was studied using horseradish peroxidase conjugated to wheat germ agglutinin as anterograde and retrograde neuronal tracer. The tracer was injected in similar quantities in the putamen on the left side and in the caudate nucleus on the right side in 10 monkeys, and its presence was revealed by means of the tetramethylbenzidine method. The study of anterogradely labeled fibers visualized after such injections shows that putaminofugal fibers terminate massively in the ventral two-thirds of the globus pallidus, where they display a band-like arrangement, and much less abundantly in the caudal third of the substantia nigra. In contrast, caudatofugal fibers occupy only the dorsal third of globus pallidus but arborize profusely in the rostral two-thirds of substantia nigra. In the pars reticulata of the substantia nigra the caudatonigral fibers form a highly complex network composed of fiber trabeculae while the putaminonigral fibers occur as more discrete fascicles confined to the dorsolateral region of the structure. In the pars compacta of the substantia nigra the retrogradely labeled cells occur in the form of clusters that are closely intermingled with clusters of unlabeled neurons. The labeled-cell clusters are particularly dense on the putamen-injected side and more loosely organized on the caudate-injected side. On both sides, however, the striatonigral fibers that reach the substantia nigra pars compacta can be seen to terminate almost exclusively upon clusters composed of retrogradely labeled cells, suggesting the existence of a precise reciprocal link between nigral and striatal neuronal aggregates. At thalamic levels the retrogradely labeled cells are distributed according to a strikingly asymmetric pattern. For instance, a prominent labeling of neurons in the central superior lateral nucleus is seen only on the caudate-injected side. Furthermore, in the centromedian/parafascicular complex retrograde cell labeling is seen exclusively in parafascicular nucleus on the caudate-injected side and only in the centromedian nucleus, except its lateralmost portion, on the putamen-injected side. Control experiments involving injection of the tracer in cerebral cortex overlying the striatum reveal that the neurons in the lateral segment of the centromedian, which do not project to striatum, are in fact reciprocally connected with the cerebral cortex. In addition, our data show that some of the so-called "specific" thalamic nuclei contribute significantly to the thalamostriatal projection in monkey.(ABSTRACT TRUNCATED AT 400 WORDS)     

Regional heterogeneity of dopaminergic deficits in vervet monkey striatum and substantia nigra after methamphetamine exposure

Methamphetamine (METH)-induced neurotoxicity within the striatum and substantia nigra of the vervet monkey was characterized by heterogeneous decreases in immunoreactivity (IR) for dopamine system phenotypic markers. Decreases in IR for tyrosine hydroxylase (TH), dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) were observed 1 week after METH HCI (2x2 mg/kg; 24 h apart). Regional changes throughout the rostrocaudal extent of the striatum were characterized by a gradient of neurotoxic effect (lateral greater than medial) and the preservation of patches of IR. The decreases in IR in the caudate and putamen were greater than those in the nucleus accumbens. The reduced IR in the METH-exposed striatum allowed for the visualization of dopamine phenotype cell bodies. Within the ventral midbrain, the METH-exposed substantia nigra pars compacta (SNc) also showed a heterogeneous loss of IR (lateral greater than medial). In contrast, the ventral tegmental area (VTA) showed only minor decreases in IR. The magnitude of the decreases in the SNc and VTA subregions corresponded to those observed in their respective striatal projection areas, suggesting that nigrostriatal neuron subpopulations were differentially reactive to METH. The profile of these drug-induced nigrostriatal dopamine system deficits resembles aspects of Parkinson's disease pathology and, as such, may provide a useful model with which to evaluate neuroprotective and neurorestorative strategies.     

Subdivisions of the dopamine-containing A8-A9-A10 complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal matrix

The mesostriatal projections from the dopamine-containing cells groups A8, A9 and A10 have been studied in the cat in relation to the histochemical compartments known to exist in the striatum. In order to do this, we made stereotaxic injections in the substantia nigra of either [3H]proline-[3H]leucine, [35S]methionine, wheat germ agglutinin-horseradish peroxidase, or the two last tracers combined, and compared the location of anterograde labeling in the striatum to the locations of striosomes and extrastriosomal matrix identified by their low or high content, respectively, of the enzyme acetylcholinesterase. A discrete innervation of dorsolateral striosomes by a caudal densocellular subdivision of the substantia nigra pars compacta was found. This densocellular zone of the pars compacta was readily identifiable in sections stained for tyrosine hydroxylase-like immunoreactivity and corresponded to the uniquely acetylcholinesterase-poor zone detected in the substantia nigra pars compacta in serially adjacent sections stained for this enzyme. Selective anterograde labeling of the extrastriosomal matrix occurred in cases with injection sites centered in cell group A8. Tracer deposits in cell group A10 also elicited a preferential labeling of the extrastriosomal matrix, but this innervation was sparse compared to the prominent labeling of fibers in the ventral striatum. An almost exclusive innervation of caudal and ventral striosomes of the head of the caudate nucleus occurred after a deposit of tracer in the pars lateralis of the substantia nigra. Mixed labeling of striosomes and matrix occurred with injection sites centered in the rostral, cell-sparse part of the pars compacta of the substantia nigra. Clusters of tyrosine hydroxylase-immunoreactive neurons within this zone, most likely representing finger-like extensions of the caudal densocellular zone of the pars compacta, might have accounted for part of the striosomal labeling in these cases. We conclude that different subdivisions of the A8-A9-A10 dopamine-containing cell complex of the cat's mesencephalon project preferentially to striosomes or to extrastriosomal matrix. On this basis we suggest that there may be different functional channels in the mesostriatal projection, including, from cell group A8, a channel providing dopaminergic modulation of sensorimotor processing in the striatal matrix, and, from the densocellular zone of the substantia nigra pars compacta, a channel leading to limbic-related mechanisms represented in the striosomal system.     

Dopamine innervation of the monkey mediodorsal thalamus: Location of projection neurons and ultrastructural characteristics of axon terminals

Dopamine (DA) axons and receptors have recently been identified in the primate thalamus, including the mediodorsal thalamic nucleus (MD). In order to determine whether the DA innervation of the primate MD shares the anatomical features of the mesocortical or nigrostriatal DA projections, we performed tract-tracing and immunocytochemistry studies in macaque monkeys (Macaca fascicularis) to identify the location of the DA neurons that project to MD and immuno-electron microscopy to determine the distribution of the dopamine transporter (DAT) in axons within the MD. Similar to the mesocortical projection, retrogradely-labeled, tyrosine hydroxylase-containing neurons were present in dorsal tier ventral mesencephalic nuclei, such as the ventral tegmental area and the dorsal portion of the substantia nigra pars compacta. In contrast, no dual-labeled neurons were present in the ventral tier nuclei, the primary origin of the nigrostriatal DA pathway. In addition, like the DA projection to the prefrontal cortex, DAT immunoreactivity was predominantly localized to the pre-terminal portion of axons in the MD, and was infrequently found in association with synaptic vesicles, in contrast to nigrostriatal DA axons. These findings indicate that the DA projection to the MD shares anatomical features with the mesocortical DA system, suggesting that the functional properties of DA neurotransmission in the MD might be more similar to those in the cortex than in the striatum.     

Topographic distribution of the axonal endings from the sensorimotor and associative striatum in the macaque pallidum and substantia nigra

The striatopallidonigral connection was studied by injecting anterograde tracers into either the associative or the sensorimotor striatum in ten macaques. The results were analyzed using a precise cartographic method. Injections into various parts of the associative striatum (caudate nucleus and ventromedial putamen) produced a labeling of axons in the dorsomedial and ventral pallidal regions. These associative regions occupied two-thirds of the lateral pallidum and one-third of the medial pallidum. Bands of labeled axons from the sensorimotor striatum (dorsolateral putamen) were found in the remaining, central part of the two pallidal nuclei. In the substantia nigra, the rostral associative striatum projected medially to the pars reticulata, while the caudal parts projected laterally. The whole pars reticulata and lateralis thus appeared to receive associative striatal inputs. The sensorimotor striatal territory projected to the central part of the pars reticulata/lateralis. It was concluded that the two functional territories remain separate in the two pallidal nuclei but overlap in the middle third of the substantia nigra. However, due to their great size, the pallidal neurons located at the border of the two territories may receive striatal inputs from both the associative and the sensorimotor components in the same way that nigral neurons do.     

Midbrain muscarinic receptors modulate morphine-induced accumbal and striatal dopamine efflux in the rat

Midbrain dopamine neurons are critical in mediating the rewarding effects of opiates in dependent rats, as well as modulating some manifestations of opiate withdrawal. Morphine is known to excite dopamine neurons and thereby facilitate forebrain dopamine transmission through inhibition of GABA neurons. Cholinergic neurons in the mesopontine laterodorsal and pedunculopontine tegmental nuclei provide the principal source of excitatory cholinergic input to ventral tegmental area and substantia nigra pars compacta dopamine-containing neurons, via actions on midbrain muscarinic and nicotinic acetylcholine receptors. The present study hypothesized that a reduction in tonic cholinergic input via blockade of midbrain muscarinic receptors would reduce the pharmacological effects of morphine on forebrain dopamine release. Using in vivo chronoamperometry, alterations in morphine-evoked dopamine efflux were monitored at stearate-graphite paste electrodes implanted unilaterally in the nucleus accumbens and striatum of urethane (1.5 g/kg) anesthetized rats, following the pharmacological inhibition of ventral tegmental area/substantia nigra pars compacta muscarinic receptors. The facilitatory effects of morphine (2.0 mg/kg, i.v.) on accumbens and striatal dopamine efflux were markedly reduced by prior infusion of the non-selective muscarinic receptor antagonist scopolamine (200 microg/microl) into the ventral tegmental area or substantia nigra pars compacta, respectively. These findings demonstrate that decreased activation of midbrain muscarinic receptors attenuates the excitatory effects of morphine on mesoaccumbens and nigrostriatal dopaminergic transmission.     

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.     

The subcortical afferents to caudate nucleus and putamen in primate: A fluorescence retrograde double labeling study

The cellular origin and degree of collateralization of the subcortical afferents to the caudate nucleus and the putamen in squirrel monkeys (Saimiri sciureus) were studied using the following combinations of fluorescent retrograde tracers: Evans blue and DAPI-Primuline, Fast blue and Nuclear yellow, True blue and Nuclear yellow. After the injections, cells containing the tracer delivered in caudate nucleus (caudate-labeled cells) and others labeled with the complementary tracer injected in putamen (putamen-labeled cells) occur in large number in intralaminar nuclei, substantia nigra pars compacta, midbrain raphe nuclei and central midbrain tegmentum. In addition, a small to moderate number of putamen-labeled cells is found in external pallidum, pulvinar and laterodorsal thalamic nuclei, and basolateral amygdaloid nucleus, whereas some caudate and putamen-labeled cells are scattered in ventral tegmental area and locus coeruleus. However, very few double-labeled cells are present in all these structures. In rostral intralaminar nuclei, the labeled cells are not confined to the known cytoarchitectonic boundaries of the nuclei but impinge slightly upon ventrolateral and mediodorsal nuclei. At this level, the caudate-labeled cells lie more dorsally and medially relative to putamen-labeled cells, but a high degree of intermingling exists and some double-labeled cells occur particularly in nucleus centralis lateralis. In caudal intralaminar nuclei, caudate-labeled cells are strictly confined to parafascicular nucleus and putamen-labeled cells present only in centre median, without any overlap between the two neuronal populations. In substantia nigra pars compacta, clusters of caudate-labeled cells are closely intermingled with clusters of putamen-labeled cells according to a complex mosaic-like pattern that varies along the rostrocaudal extent of the structure. Overall, however, caudate-labeled cells predominate rostrodorsally and putamen-labeled cells are more abundant caudoventrally in substantia nigra pars compacta, with only a few double-labeled cells. Some caudate and putamen-labeled cells are also scattered in contralateral substantia nigra pars compacta. In dorsal raphe nucleus, putamen-labeled cells tend to occupy a more lateral position relative to caudate-labeled cells, with again very few double-labeled neurons. The caudate and putamen-labeled cells are less numerous and more closely intermingled in nucleus centralis superior. Numerous striatal afferent cells are also found bilaterally in the peribrachial region of midbrain tegmentum, comprising the pedunculopontine nucleus area. There, the putamen-labeled cells are slightly more numerous than the caudate-labeled cells with less than 10% of these neurons being double-labeled.

Our findings suggest that the subcortical afferents to caudate and to putamen in primates arise largely from different neurons in thalamus and midbrain. These two types of striatal afferent neurons are distributed according to various patterns that are much more complex than could have been inferred from current knowledge of the topographical organization of striatal afferents.     

Experimental hemiparkinsonism in the rat following chronic unilateral infusion of MPP+ into the nigrostriatal dopamine pathway--II. Differential localization of dopamine and cholecystokinin receptors

The autoradiographical localization of dopamine D1, D2 and cholecystokinin receptors has been investigated in rat brain 6 months following unilateral infusion of 1-methyl-4-phenyl pyridinium ion (MPP+) (10 micrograms/day for 7 days) into the nigrostriatal dopamine pathway. Treatment with 1-methyl-4-phenyl pyridinium ion produced a marked depletion of dopamine cell bodies in the substantia nigra together with greater than 95% loss of tyrosine hydroxylase immunoreactivity in the striatum. Measurement of specific [3H]spiperone binding to D2 receptors indicated a 38% increase (P less than 0.01) in the maximal binding capacity of [3H]spiperone to striatal membrane homogenates and a 13% increase (P less than 0.05) in specific [3H]spiperone binding to striatal tissue sections, verifying striatal D2 receptor denervation supersensitivity. In contrast, MPP+ lesion of the nigrostriatal tract had no effect on the autoradiographical localization of striatal D1 or cholecystokinin receptors. In addition, there was a 38% loss (P less than 0.05) of D2 receptor binding sites in the substantia nigra pars compacta, whilst D1 receptors remained unchanged. Similar changes in dopamine and cholecystokinin receptor number were found following 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. These results provide further evidence that 1-methyl-4-phenyl pyridinium ion treatment in rats produces extensive destruction of the dopaminergic nigrostriatal tract and supports the differential anatomical localization of striatal and nigral D1, D2 and cholecystokinin receptors.     

Bilateral cerebral metabolic effects of pharmacological manipulation of the substantia nigra in the rat: Unilateral intranigral application of the putative excitatory neurotransmitter substance P

The metabolic activity of several anatomically distinct brain areas was investigated by means of the quantitative autoradiographic 2-deoxy-d[1-¹⁴C]glucose method in awake rats following unilateral intranigral application of the putative excitatory neurotransmitter substance P. The primary goal was to determine the metabolic effects of substance P on the substantia nigra and its targets. Intranigral injection of 1 mM substance P (1.5 μl) induced metabolic activation locally in the substantia nigra reticulata by 117% and substantia nigra compacta by 35%, as well as distally in the contralateral substantia nigra reticulata by 22% and contralateral substantia nigra compacta by 21%. All the basal ganglia components, the striatum, pallidum, entopeduncular, subthalamic nucleus and nucleus accumbens displayed bilateral metabolic activations after unilateral intranigral substance P injection. Among the principal reticulata efferent projections, the ventromedial, ventrolateral, parafascicular, mediodorsal and centrolateral thalamic nuclei, as well as the pedunculopontine nucleus displayed bilateral metabolic activations after intranigral substance P application. Moreover, unilateral intranigral substance P injection elicited metabolic activations in the thalamic and cortical components of the reticular, intralaminar, limbic and prefrontal systems, mostly bilateral.

It is suggested that substance P applied into one substantia nigra reticulata activates the compacta nigrostriatal dopaminergic and the reticulata nigrothalamic GABAergic outputs inducing distal metabolic effects, similar to those elicited by unilateral nigral electrical stimulation [Savaki et al. (1983) J. comp. Neurol.213, 46–65] and, opposite to several of those induced by intranigral injection of the inhibitory GABA_A agonist muscimol [Savaki et al. (1992) Neuroscience50, 781–794]. Furthermore, it is suggested that the ipsilateral basal ganglia effects induced by intranigral substance P application are mediated via both the compacta dopaminergic nigrostriatal projection and the reticulata GABAergic nigro-thalamo-cortico-striatal loop, whereas the contralateral basal ganglia and associated thalamocortical effects are due to the activation of the GABAergic reticulata efferents and are mediated via an interthalamic circuitry involving the motor, reticular and intralaminar thalamic nuclei.     

Compartmental origins of striatal efferent projections in the cat

Injections of the retrograde tracer, wheat germ agglutinated-horseradish peroxidase were placed in the substantia nigra, in adjoining dopamine-containing cell groups A8 and A10, and in the internal and external parts of the pallidal complex of 20 cats in order to identify the compartmental origins of striatal efferent projections to the pallidum and midbrain. Patterns of retrograde cell-labeling in the caudate nucleus were analysed with respect to its striosomal architecture as detected in sections stained for acetylcholinesterase. Where possible, a similar compartmental analysis of cell-labeling in the putamen was also carried out. In 15 cats anterograde labeling in the striatum was studied in the sections stained with wheat germ agglutinated-horseradish peroxidase or in autoradiographically treated sections from cases in which [35S]methionine was mixed with the wheat germ agglutinated-horseradish peroxidase in the injection solution. Predominant labeling of projection neurons lying in striosomes (usually with some labeling of dorsomedial matrix neurons) occurred in a subset of the cases of nigral injection, including all cases (n = 9) in which the injection sites were centered in the densocellular zone of the substantia nigra pars compacta [Jiménez-Castellanos J. and Graybiel A. M. (1987) Neuroscience 23, 223-242.] Dense labeling of neurons in the extrastriosomal matrix, with at most sparse labeling of striosomal neurons, occurred in all cases of pallidal injection (n = 8) and in two cases of nigral injection in which the injection sites were lateral and anterior to the densocellular zone. Mixed labeling of striosomal and matrical neurons occurred in a third group of cases in which the injection sites were lateral to the densocellular zone but close to it. In a single case with an injection site situated in the pars lateralis of the substantia nigra, there was preferential labeling of striosomal neurons in the caudal caudate nucleus but widespread labeling of neurons in both striosomes and matrix in the putamen. A second type of compartmental ordering of projection neurons was found in the extrastriosomal matrix of the striatum. In cases of pallidal and nigral injection, there were gaps in cell labeling that did not match striosomes precisely, and often clusters of labeled cells appeared that did not correspond to acetylcholinesterase-poor striosomes but, instead, to patches of matrix. Especially prominent were clusters beside striosomes. There was a topographic ordering of striatal projection neurons both in the striosomes and in the extrastriosomal matrix according to their dorsoventral and latitudinal positions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Projections of the paleostriatum upon the midbrain tegmentum in the pigeon

Descending projections of neurons in the avian paleostriatal complex upon cell groups of the midbrain tegmentum were investigated in the pigeon using horseradish peroxidase histochemistry and autoradiography. The purpose of this study was to determine if pathways comparable to the mammalian striato-tegmental system (descending paths from neurons in the caudate nucleus, putamen and nucleus accumbens) exist in the avian brain. Although previous reports (Karten &Dubbeldam, 1973) have described pathways in the avian brain comparable to the mammalian pallido-tegmental system, no counterpart of the mammalian striato-tegmental system has been identified in birds.Our results indicate that a striato-tegmental system does exist in the pigeon. Neurons within a small-celled field containing a rich plexus of catecholamine-positive axons and terminals were found to project upon the midbrain tegmentum. This small-celled field includes the paleostriatum augmentatum, lobus parolfactorius and nucleus accumbens. Cells in all three components of this small-celled field project upon the pars compacta and the pars dorsomedialis of the nucleus tegmenti pedunculo pontinus of the midbrain. The pars compacta of this nucleus contains many catecholamine-positive cells and has been compared to the substantia nigra pars compacta of mammals on the basis of histochemistry and anatomical connections (Brauth,Ferguson &Kitt, 1978). The pars dorsomedialis of this nucleus has been shown to contain a plexus of substance P-positive axons and terminals (Reiner,Brauth,Kitt &Karten, 1980;Reiner,Karten &Korte, 1980). It is argued that the pars dorsomedialis of the pedunculo pontine nucleus of the pigeon is comparable to the mammalian substantia nigra pars reticulata. Other projection targets of the lobus parolfactorius and nucleus accumbens in the pigeon include the area ventralis of Tsai, the lateral habenular nucleus and the nucleus subceruleus dorsalis. The locus ceruleus also receives a projection from the nucleus accumbens. The results are compared to previously reported findings in mammals and reptiles.     

A survey of substance P, somatostatin, and neurotensin levels in aging in the rat and human central nervous system

Levels of the neuropeptides substance P, somatostatin, and neurotensin were measured by radioimmunoassay in regions of the rat and human central nervous system (CNS) in aging. Somatostatin levels were significantly lower only in the corpus striatum of older rats. Substance P levels and neurotensin levels were generally stable with aging as were levels of somatostatin in regions other than the corpus striatum. In post-mortem human CNS tissues, no significant negative correlations of levels of the three peptides were observed with time to refrigeration or time to freezer for the samples. In the human CNS, there were no significant age-related alterations in substance P levels in frontal cortex, thalamus, hypothalamus, caudate nucleus, globus pallidus, or substantia nigra. There was a significant age-related decrease in substance P levels in the human putamen. This age-related decrease was not present in tissues from victims of Huntington's disease nor was there any striking difference in substance P levels as a function of duration of the disease. There were no significant age-related changes in somatostatin levels in human frontal cortex, caudate nucleus, putamen, medial globus pallidus, or substantia nigra. Among these same regions, there was a significant age-related decrease in neurotensin levels only in the pars compacta and pars reticulata of the human nigra. These results implicate neuropeptides in aging processes in certain regions of the CNS. There are differences between rats and humans with respect to neuropeptides in the aging process in the CNS. Deterioration of some neuropeptide pathways in and to human basal ganglia may be involved in the suspected functional deterioration of parts of the extrapyramidal system in aging.     

A survey of substance P, somatostatin, and neurotensin levels in aging in the rat and human central nervous system

Levels of the neuropeptides substance P, somatostatin, and neurotensin were measured by radioimmunoassay in regions of the rat and human central nervous system (CNS) in aging. Somatostatin levels were significantly lower only in the corpus striatum of older rats. Substance P levels and neurotensin levels were generally stable with aging as were levels of somatostatin in regions other than the corpus striatum. In post-mortem human CNS tissues, no significant negative correlations of levels of the three peptides were observed with time to refrigeration or time to freezer for the samples. In the human CNS, there were no significant age-related alterations in substance P levels in frontal cortex, thalamus, hypothalamus, caudate nucleus, globus pallidus, or substantia nigra. There was a significant age-related decrease in substance P levels in the human putamen. This age-related decrease was not present in tissues from victims of Huntington's disease nor was there any striking difference in substance P levels as a function of duration of the disease. There were no significant age-related changes in somatostatin levels in human frontal cortex, caudate nucleus, putamen, medial globus pallidus, or substantia nigra. Among these same regions, there was a significant age-related decrease in neurotensin levels only in the pars compacta and pars reticulata of the human nigra. These results implicate neuropeptides in aging processes in certain regions of the CNS. There are differences between rats and humans with respect to neuropeptides in the aging process in the CNS. Deterioration of some neuropeptide pathways in and to human basal ganglia may be involved in the suspected functional deterioration of parts of the extrapyramidal system in aging.     

An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphe nucleus to the substantia nigra in the rat

Evidence for a projection from the dorsal raphe nucleus to the substantia nigra was obtained by the demonstration of reactive perikarya in the dorsal raphe nucleus after injections of horseradish peroxidase into the substantia nigra of the rat. No labelled cells were observed in the median raphe nucleus. Stereotaxic injections of [³H]leucine into the dorsal raphe nucleus resulted in the appearance of autoradiographic grains over both the zona compacta and zona reticulate of the substantia nigra, although the concentration of grains was higher over the zona compacta. Electrolytic lesions of the dorsal raphe nucleus reduced nigral and striatal 5-hydroxytryptamine content by 61.5 and 70% respectively. Stimulation of the dorsal raphe nucleus was found to inhibit the unit activity of cells in both the zona compacta and zona reticulate of the substantia nigra and this inhibition could be blocked by 60–72 h pretreatment with p-chlorophenylalanine. Stimulation of the median raphe nucleus produced no consistent effects upon nigral unit activity. para-Chlorophenylalanine pretreatment did not significantly affect the rate of striatal dopamine depletion produced by injections of α-methyl-para-tyrosine, suggesting that the serotonergic raphe-nigral projection exerts a phasic rather than a tonic inhibitory influence over the dopaminergic neurons of the nigro-striatal projection.The results are discussed with reference to the possibility that the projections of the dorsal raphe nucleus to the substantia nigra and the striatum may mediate some of the interactions between central serotonergic and dopaminergic mechanisms.     

Direct projections from the central amygdaloid nucleus to the globus pallidus and substantia nigra in the cat.

Employing both anterograde and retrograde axonal tracing, we investigated direct projections from the central amygdaloid nucleus to the basal ganglia in the cat. The anterograde axonal tracing of Phaseolus vulgaris-leucoagglutinin revealed that projection fibers from the central amygdaloid nucleus to the basal ganglia ended in the globus pallidus (the feline homolog to the external segment of the globus pallidus of primates) and substantia nigra. The amygdalopallidal fibers terminated chiefly in the medial most part of the globus pallidus at its caudal level. The amygdalonigral fibers terminated densely in the substantia nigra pars lateralis, and moderately in the dorsolateral part of the substantia nigra pars reticulata; none of them were found to end in the substantia nigra pars compacta. Both of the amygdalopallidal and amygdalonigral projections were ipsilateral. These neuronal connections were confirmed by retrograde axonal tracing of cholera toxin B subunit in the second set of the experiments: The cells of origin of the amygdalopallidal and amygdalonigral projections were located predominantly in the lateral part of the central amygdaloid nucleus, and additionally in the intercalated cell islands of the amygdala. Most of them were of small bipolar or multipolar type. The cells projecting to the globus pallidus were preferentially distributed at the rostral levels of the central nucleus and intercalated cell islands of the amygdaloid complex, while those projecting to the substantia nigra were mainly located at the caudal levels of these amygdaloid subdivisions. In the third set of the experiments, sequential double-antigen immunofluorescence histochemistry for transported cholera toxin B subunit and horseradish peroxidase showed that some single neurons in the lateral part of the central amygdaloid nucleus, particularly at its middle level, issued axon collaterals to both the globus pallidus and substantia nigra pars lateralis. The results of the present study indicate that the central amygdaloid nucleus sends projection fibers to the globus pallidus and substantia nigra possibly to exert a limbic influence upon forebrain motor mechanisms.     

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)