Subpopulations of neurons in rat substantia nigra display GABA(B)R2 receptor immunoreactivity.

A functional gamma-aminobutyric acid (GABA) B receptor is the first metabotropic receptor known to be composed of two heteromeric subunits, GABA_BR1 and GABA_BR2. Our previous report [Neuroscience 99 (2000) 65] has demonstrated that subpopulations of neurons in the rat substantia nigra display distinct patterns of distribution of GABA_BR1 receptor immunoreactivity. A robust level of GABA_BR1 receptor is only found in the dopaminergic neurons of the substantia nigra pars compacta (SNc). The objective of the present study was to determine the precise cellular localization of GABA_BR2 subunit in the rat substantia nigra using double immunofluorescence. Neuropilar elements in the SNc and the substantia nigra pars reticulata (SNr) were found to display GABA_BR2 immunoreactivity. In addition, the tyrosine hydroxylase-immunoreactive dopaminergic neurons and the parvalbumin-immunoreactive GABAergic neurons in the SNr were also found to display GABA_BR2 immunoreactivity. The present results thus demonstrate that a functional GABA_B receptor may be expressed by the dopaminergic neurons in the SNc. It is less clear whether neurons in the SNr express a functional GABA_B receptor. The present findings have important functional implications in GABA neurotransmission in the substantia nigra.     

Subpopulations of neurons in rat substantia nigra display GABABR2 receptor immunoreactivity

A functional gamma-aminobutyric acid (GABA) B receptor is the first metabotropic receptor known to be composed of two heteromeric subunits, GABA_BR1 and GABA_BR2. Our previous report [Neuroscience 99 (2000) 65] has demonstrated that subpopulations of neurons in the rat substantia nigra display distinct patterns of distribution of GABA_BR1 receptor immunoreactivity. A robust level of GABA_BR1 receptor is only found in the dopaminergic neurons of the substantia nigra pars compacta (SNc). The objective of the present study was to determine the precise cellular localization of GABA_BR2 subunit in the rat substantia nigra using double immunofluorescence. Neuropilar elements in the SNc and the substantia nigra pars reticulata (SNr) were found to display GABA_BR2 immunoreactivity. In addition, the tyrosine hydroxylase-immunoreactive dopaminergic neurons and the parvalbumin-immunoreactive GABAergic neurons in the SNr were also found to display GABA_BR2 immunoreactivity. The present results thus demonstrate that a functional GABA_B receptor may be expressed by the dopaminergic neurons in the SNc. It is less clear whether neurons in the SNr express a functional GABA_B receptor. The present findings have important functional implications in GABA neurotransmission in the substantia nigra.     

Differential Localization of AMPA Glutamate Receptor Subunits in the Two Segments of the Globus Pallidus and the Substantia Nigra Pars Reticulata in the Squirrel Monkey

The subthalamic nucleus has long been known as the main source of glutamatergic afferents to the pallidum and the substantia nigra in primates. Recent findings showed that the excitatory effects induced by the subthalamic nucleus in pallidal cells are mediated through the activation of non-NMDA receptors in the rat. The objective of the present study was to analyse the distribution of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptor subunits in the external pallidum (GPe), the internal pallidum (GPi) and the substantia nigra pars reticulata (SNr) in squirrel monkeys ( Saimiri sciureus ). This was achieved by means of immunohistochemistry using antibodies raised against the GluR1 and the GluR2/3 subunits of the AMPA receptor. Our results show that all neuronal perikarya in GPe and GPi display immunoreactivity for GluR2/3 subunits whereas GluR1 is confined exclusively to cells in the GPe. The proportion of GluR1-immunoreactive neurons is not uniform throughout the rostrocaudal extent of GPe; in the rostral third all GPe cells display GluR1 immunoreactivity, whereas in the caudal third the proportion of GluR1-positive cells decreases to 50%. The intensity of GluR1 immunostaining associated with GPe cells is lower than that associated with neighbouring large-sized neurons in the nucleus basalis of Meynert. In contrast to GPi cells, the neurons in the SNr display immunoreactivity for both GluR1 and GluR2/3 subunits. In conclusion, our results provide the first evidence for a different distribution of the GluR1 subunit of the AMPA receptors in the two segments of the globus pallidus in monkeys. These findings imply that the control of the basal activity of GPe and GPi cells by the subthalamic nucleus is exerted via the activation of AMPA receptors composed of different subunits. These data reinforce the view that the two segments of the globus pallidus are different entities that possess their own functional characteristics in primates.     

Differential co-localization of neurokinin-3 receptor and NMDA/AMPA receptor subunits in neurons of the substantia nigra of C57/BL mice

By using a double immunofluorescence method we examined co-localization of neurokinin-3 receptor (NK-3R) and N-methyl-D-aspartate (NMDA)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits in neurons of the substantia nigra of adult mice. Overlapping distribution of NMDA receptor subunit 1 (NR1)/AMPA receptor subunits 1-4 (GluR1-4) and NK-3R-immunoreactive neurons were found in the substantia nigra pars compacta. It revealed that all (100%) of NK-3R-positive neurons displayed NR1, GluR2 or GluR3 immunoreactivity, 80% of them showed GluR1 immunoreactivity. In contrast, these neurons exhibiting both NK-3R and GluR4 immunoreactivity were hardly detected although GluR4-positive neurons were still distributed in the substantia nigra. The co-expression of NK-3R and NMDA/AMPA receptor subunits in the nigral neurons has provided a structural basis for functional modulation of neuronal glutamate receptors by neurokinin-3, suggesting that neurokinin peptides may be involved in modulation of neuronal properties and excitotoxicity in the substantia nigra of basal ganglia.     

Substantia nigra pars reticulata lesion induces preconvulsive behavior and changes in glutamate receptor gene expression in the rat brain

The substantia nigra pars reticulata (SNpr) has been proposed to play an important role in the control of the propagation and/or the generation of epileptic seizures. Earlier studies have shown differential effects of the lesion of the SNpr on seizure genesis that demonstrated a regional difference in the anterior and posterior parts of the SNpr in preconvulsive behavior induced by unilateral reticulata injection of dopamine (DA). This study was aimed to investigate some of the underlying mechanisms of the preconvulsive behavior elicited by unilateral SNpr DA injection by the study of changes in the gene expression of glutamate receptor subunits (GluR1, GluR2 and NMDAR1) and of changes in animal behavior following coinfusion of DA and a DA D1 antagonist SCH 23390 into the SNpr. Unilateral injection of exogenous DA into the anterior region of the SNpr induced rapid and short lasting preconvulsive behavior up to wet dog shakes stage and a significant reduction of gene expression for GluR1, GluR2 and NMDAR1 subunits in rat hippocampal subfields including CA1 through CA4 and dentate gyrus (DG) at 1 day after nigral DA injection. The effect was long lasting and persisted for at least 3 weeks. Both preconvulsive behavior and downregulation of glutamate receptor subunit genes were completely blocked by simultaneous coinfusion of DA and SCH 23390. The results suggest, for the first time, that DA D1 receptor in the SNpr may mediate the nigral-involved seizure development. Glutamate desensitization, and/or selective early neuronal damage might be responsible for the downregulation of glutamate receptor subunits by transient preconvulsive activity.     

Differential expression of kainate receptors in the basal ganglia of the developing and adult rat brain

Glutamate is the principal excitatory transmitter of the mammalian brain and plays a particularly important role in the physiology of the basal ganglia structures responsible for movement regulation. Using in situ hybridization with oligonucleotide probes, we examined the expression patterns of the five known kainate type glutamate receptor subunit genes, KA1, KA2 and GluR5–7, in the basal ganglia of adult and developing rat brain. In the adult rat, a highly organized and selective pattern of expression of the kainate subunits was observed in the basal ganglia and associated structures as well as in other regions of the brain. KA2 mRNA was abundant in the striatum, nucleus accumbens, subthalamic nucleus and substantia nigra pars compacta, and was present at lower levels in the globus pallidus and substantia nigra pars reticulata. Neither KA1 nor GluR5 expression was observed in the basal ganglia of adult rats, although these messages were present in other regions. GluR6 was highly expressed in the striatum and subthalamic nucleus and to a lesser extent in the substantia nigra pars reticulata, while no hybridization signal was detectable in the large, presumably dopaminergic neurons of the substantia nigra pars compacta. In contrast, GluR7 was strongly expressed in the substantia nigra pars compacta, was present at lower levels in the striatum, globus pallidus and substantia nigra pars reticulata, and was not detectable in the subthalamic nucleus. During postnatal development, expression of the kainate receptor subunits was characteristically highest on postnatal day 1 and declined to adult levels by day 20; however, in the globus pallidus we did observe the transient expression of KA1 and GluR5 between day 1 and day 10. These results demonstrate that the neuronal structures comprising the basal ganglia express a distinct combination of kainate receptor subunit genes, suggesting that the pharmacological properties of the resultant glutamate receptors are likely to be regionally specific. The organization of expression of these genes is established early in life, which is consistent with the important role they may play in establishing the functions of the motor system.     

Comparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits

The GABA(B) receptor is a G-protein linked metabotropic receptor that is comprised of two major subunits, GABA(B)R1 and GABA(B)R2. In this study, the cellular distribution of the GABA(B)R1 and GABA(B)R2 subunits was investigated in the normal human basal ganglia using single and double immunohistochemical labeling techniques on fixed human brain tissue. The results showed that the GABA(B) receptor subunits GABA(B)R1 and GABA(B)R2 were both found on the same neurons and followed the same distribution patterns. In the striatum, these subunits were found on the five major types of interneurons based on morphology and neurochemical labeling (types 1, 2, 3, 5, 6) and showed weak labeling on the projection neurons (type 4). In the globus pallidus, intense GABA(B)R1 and GABA(B)R2 subunit labeling was found in large pallidal neurons, and in the substantia nigra, both pars compacta and pars reticulata neurons were labeled for both receptor subunits. Studies investigating the colocalization of the GABA(A) alpha(1) subunit and GABA(B) receptor subunits showed that the GABA(A) receptor alpha(1) subunit and the GABA(B)R1 subunit were found together on GABAergic striatal interneurons (type 1 parvalbumin, type 2 calretinin, and type 3 GAD neurons) and on neurons in the globus pallidus and substantia nigra pars reticulata. GABA(B)R1 and GABA(B)R2 were found on substantia nigra pars compacta neurons but the GABA(A) receptor alpha(1) subunit was absent from these neurons. The results of this study provide the morphological basis for GABAergic transmission within the human basal ganglia and provides evidence that GABA acts through both GABA(A) and GABA(B) receptors. That is, GABA acts through GABA(B) receptors, which are located on most of the cell types of the striatum, globus pallidus, and substantia nigra. GABA also acts through GABA(A) receptors containing the alpha(1) subunit on specific striatal GABAergic interneurons and on output neurons of the globus pallidus and substantia nigra pars reticulata.     

Cellular localization of GluR1, GluR2/3 and GluR4 glutamate receptor subunits in neurons of the rat neostriatum

Glutamate excitocytotoxicity is implied in the cause of neuronal degeneration in the neostriatum, in which the toxicity may be mediated by different families of glutamate receptors. The precise cellular localization of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)-type glutamate receptor subunits (GluR1–4), one of the major family that involves in the mechanisms of glutamate excitocytotoxicity, in different populations of striatal neurons is therefore of special interest. Immunoreactivity for GluR2/3 subunits was detected in the medium-sized spiny neurons. By double labelling experiments, immunoreactivity for GluR1 and GluR4 was detected only in aspiny striatal neurons that display parvalbumin immunoreactivity, but not in the other neuron populations that display choline acetyltransferase or muscarinic m2 receptor immunoreactivity, nor neurons that display nitric oxide synthase immunoreactivity or nicotinamide adenine dinucleotide phosphate-diaphorase activity. These results indicate that GluR1 and GluR4 immunoreactivity is displayed only in the GABAergic interneurons in the neostriatum. In addition, almost all of the GluR1-immunoreactive neurons were found to display GluR4 immunoreactivity. This finding indicates for the first time that the striatal GABAergic interneurons co-express GluR1 and GluR4 subunits. The results of the present study indicate that there is a differential localization of AMPA-type glutamate receptor subunits in different populations of striatal neurons and they may have a different susceptibility to glutamate excitocytotoxicity.     

Co-localization of tyrosine hydroxylase and glutamate decarboxylase in a subpopulation of single nigrotectal projection neurons.

The neurotransmitter phenotype(s) of nigral neurons innervating the superior colliculus (SC) in the rat was examined using a combination of immunohistochemical techniques and fluorescent retrograde tracing. After double-immunofluorescent histochemistry for tyrosine hydroxylase (TH) and glutamate decarboxylase (GAD), single cells in the rostral ventrolateral portion of the substantia nigra pars reticulata (SNr) and to a lesser extent the substantia nigra pars lateralis (SN1) displayed immunoreactivity to both antigens. Furthermore, following True blue (TB) injections into the SC and incubation for both TH and GAD immunoreactivity, a considerable number of cells in the SNr retrogradely labeled with TB (approximately 10%) were also immunopositive for both synthetic enzymes. The present study provides evidence for the coexistence of TH and GAD and thus, the coexistence of dopamine and GABA in a subpopulation of single nigrotectal projection cells.     

The subcellular localization of GABA(B) receptor subunits in the rat substantia nigra

The inhibitory effects of GABA within the substantia nigra (SN) are mediated in part by metabotropic GABA(B) receptors. To better understand the mechanisms underlying these effects, we have examined the subcellular localization of the GABA(B) receptor subunits, GABA(B1) and GABA(B2), in SN neurons and afferents using pre-embedding immunocytochemistry combined with anterograde or retrograde labelling. In both the SN pars compacta (SNc) and pars reticulata (SNr), GABA(B1) and GABA(B2) showed overlapping, but distinct, patterns of immunolabelling. GABA(B1) was more strongly expressed by putative dopaminergic neurons in the SNc than by SNr projection neurons, whereas GABA(B2) was mainly expressed in the neuropil of both regions. Immunogold labelling for GABA(B1) and GABA(B2) was localized in presynaptic and postsynaptic elements throughout the SN. The majority of labelling was intracellular or was associated with extrasynaptic sites on the plasma membrane. In addition, labelling for both subunits was found on the presynaptic and postsynaptic membranes at symmetric, putative GABAergic synapses, including those formed by anterogradely labelled striatonigral and pallidonigral terminals. Labelling was also observed on the presynaptic membrane and at the edge of the postsynaptic density at asymmetric, putative excitatory synapses. Double immunolabelling, using the vesicular glutamate transporter 2, revealed the glutamatergic nature of many of the immunogold-labelled asymmetric synapses. The widespread distribution of GABA(B) subunits in the SNc and SNr suggests that GABA(B)-mediated effects in these regions are likely to be more complex than previously described, involving presynaptic autoreceptors and heteroreceptors, and postsynaptic receptors on different populations of SN neurons.     

Co-localization of AMPA-type glutamate receptor immunoreactivity in neurons of the rat subthalamic nucleus

In order to determine the precise cellular localization of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)-type glutamate receptor subunit immunoreactivity in the rat subthalamic nucleus, single and double immunofluorescence was performed. Intense level of GluR1, GluR2, GluR2/3 and GluR4 immunoreactivity was found in almost all neurons of the subthalamic nucleus. By double immunofluorescence, the subthalamic neurons in the same sections that displayed a strong immunoreactivity for GluR1 were found to display a robust GluR2 immunoreactivity and the subthalamic neurons that displayed GluR2 immunoreactivity were also found to express GluR4 immunoreactivity. The present results thus demonstrate that individual neurons of the subthalamic nucleus are likely to co-express GluR1 and GluR2, and GluR2 and GluR4 immunoreactivity. The native AMPA channels in the subthalamic neurons may, therefore, be composed of heteromeric subunits. The present results provide information of the neuroanatomical localization of AMPA receptor subunits in neurons of the subthalamic nucleus. The localization of AMPA receptor subunits may be related to functional characteristics of AMPA channels in the subthalamic neurons.     

Neurons of the substantia nigra reticulata receive a dense GABA-containing input from the globus pallidus in the rat

The lectin Phaseolus vulgaris leucoagglutinin (PHA-L) was used as an anterograde tracer to study the topographical distribution and synaptic organization of pallidonigral fibres in the rat. Injections of PHA-L in the lateral part of the globus pallidus led to anterograde labelling of a rich plexus of varicose fibres that arborized profusely in the central core of the rostral three quarters of the substantia nigra pars reticulata (SNr). However, few fibres were detected in SNr after PHA-L injection restricted to the most medial part of the globus pallidus. A small number of fibres was seen in the substantia nigra pars compacta after each injection. The most characteristic feature of the pallidonigral terminals was the formation of baskets around the perikarya and primary dendrites of SNr cells. Electron microscopic analysis revealed that the pallidonigral terminals contain pleomorphic vesicles and a large number of mitochondria and that they form symmetrical synaptic contacts. Furthermore, postembedding immunocytochemistry for gamma-aminobutyric acid (GABA) showed that they display GABA immunoreactivity. These findings demonstrate that, in the rat, the pallidonigral projection is a major source of GABA-containing terminals innervating pars reticulata cells and that the pattern of innervation is such that they may exert a powerful inhibitory control over these cells.     

Differential localization of GABAA receptor subunits within the substantia nigra of the human brain: an immunohistochemical study

Gamma-aminobutyric acid(A) (GABA(A)) receptors (GABA(A)R) are inhibitory heteropentameric chloride ion channels comprising a variety of subunits and are localized at postsynaptic sites within the central nervous system. In this study we present the first detailed immunohistochemical investigation on the regional, cellular, and subcellular localisation of alpha(1), alpha(2), alpha(3), beta(2,3), and gamma(2) subunits of the GABA(A)R in the human substantia nigra (SN). The SN comprises two major regions, the SN pars compacta (SNc) consisting of dopaminergic projection neurons, and the SN pars reticulata (SNr) consisting of GABAergic parvalbumin-positive projection neurons. The results of our single- and double-labeling studies demonstrate that in the SNr GABA(A) receptors contain alpha(1), alpha(3), beta(2,3), and gamma(2) subunits and are localized in a weblike network over the cell soma, dendrites, and spines of SNr parvalbumin-positive nonpigmented neurons. By contrast, GABA(A)Rs on the SNc dopaminergic pigmented neurons contain predominantly alpha(3) and gamma(2) subunits; however there is GABA(A)R heterogeneity in the SNc, with a small subpopulation (6.5%) of pigmented SNc neurons additionally containing alpha(1) and beta(2,3) GABA(A)R subunits. Also, in the SNr, parvalbumin-positive terminals are adjacent to GABA(A)R on the soma and proximal dendrites of SNr neurons, whereas linear arrangements of substance P-positive terminals are adjacent to GABA(A) receptors on all regions of the dendritic tree. These results show marked GABA(A)R subunit hetereogeneity in the SN, suggesting that GABA exerts quite different effects on pars compacta and pars reticulata neurons in the human SN via GABA(A) receptors of different subunit configurations.     

Intraventricular administration of GABAA receptor agonist muscimol attenuates the exo-focal change of the substantia nigra neurons following transient middle cerebral artery occlusion in rats

A therapeutic effect of the selective GABA_A receptor agonist muscimol on the ‘exo-focal postischemic death’ was examined in the substantia nigra pars reticulata (SNr) of rats. Continuous intraventricular infusion of muscimol (muscimol-infusion group) or saline (control group) was initiated from 24 h after the transient middle cerebral artery occlusion for 2 h. At 3 days postischemia, in accordance to a marked depletion of GABAergic afferent fibers in the ipsilateral substantia nigra, strong immunolabelling for 72 kDa heat shock protein (HSP72) appeared in the SNr neurons of the control rats. In contrast, there was no apparent HSP72 immunoreactivity in the ipsilateral SNr in the muscimol infusion group at this stage. In addition, cell density analysis showed that neuronal cell loss in the ipsilateral SNr was effectively prevented by muscinol infusion, as compared to that in the control group, at 15 days after ischemic insult. Thus, the GABA agonist could relieve the deafferented SNr neurons from the lethal metabolic changes responsible for induction of the stress response, which may occur in the course of exo-focal postischemic death.     

Cerebral cortical dysplasia: giant neurons show potential for increased excitation and axonal plasticity

Cerebral cortical dysplasia (CD) is a common cause of intractable childhood epilepsy. Five cases of CD were analyzed for GABA(A) receptor subunit beta (GABA(Abeta)), glutamate decarboxylase, AMPA receptor subunit 1 (GluR1) and subunit 2/3 (GluR2/3), and NMDA receptor 2 (NMDAR2) immunoreactivity. Antisera to the highly polysialylated neural cell adhesion molecule (PSA-NCAM) and human unc-33-like phosphoprotein 1 (hUlip 1) were used to identify neurons with 'developmentally immature' characteristics. Differences between CD and comparison tissue (n = 3) included: (1) prominent GABA(Abeta) immunoreactivity of the cytoplasm of dysmorphic neurons in the subcortical white matter and cortex in 1 CD case; (2) increased immunolabeling with anti-GluR1 and GluR2/3 antisera in dysmorphic neurons compared with more normal-appearing adjacent neurons and neurons from nondysplastic cortex; (3) varying numbers of cortical dysmorphic neurons stained for NMDAR2 in all 5 CD cases, in contrast to a complete lack of cellular immunoreactivity in 2/3 of the cases of nondysplastic cortex; (4) PSA-NCAM and hUlip 1 expression (usually observed only in populations of neurons that undergo axonal growth) was observed in CD tissue, but not in normal brain tissue. In summary, dysmorphic neurons in cases of CD have increased immunoreactivity for several excitatory neurotransmitter receptor subunits, show variable immunoreactivity for GABA(Abeta) and show expression of several proteins that are normally expressed only in immature neurons or those with the potential for synaptic plasticity. Copyright Copyright 1999 S. Karger AG, Basel     

Non-NMDA glutamate receptors are present throughout the primate hypothalamus

To determine the distributions of glutamate receptors throughout the macaque hypothalamus, we utilized highly specific antipeptide antibodies to visualize α-amino-3-hydroxy-5-methyl4-isoxazole propionate receptor subunits (GluRl, GluR2 and GluR3 {designated as GluR2/3}, and GluR4); kainate receptor subunits (GluR6 and GluR7, {Idesignated as GluR6/7}), and a metabotropic receptor (mGluRlα). The results indicate that these glutamate receptors are distributed differentially throughout the monkey hypothalamus. α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors are the dominant non-N-methyl-D-aspartate glutamate receptors within the monkey hypothalamus, and the GluR2 subunit is most abundant. GluR1-immunoreactive neurons and neuropil are observed predominantly in the tuberal and mammillary nuclei. GluR2/3-immunoreactive neurons and neuropil have a broader distribution within preoptic, anterior, tuberal, and caudal regions. Separate (but partially overlapping) distributions of GluRl- and GluR2/3-immunoreactive neurons were found, suggesting that the GluR1, GluR2, and/or GluR3 subunits may be coexpressed in subsets of hypothalamic neurons. In contrast, GluR4 immunoreactivity was expressed minimally within monkey hypothalamus. GluR6/7 immunoreactivity was enriched selectively within the suprachiasmatic nucleus. mGluRlα immunoreactivity was present in the mammillary complex. The localization of non-N-methyl-D-aspartate glutamate receptor subunits to neurons throughout the macaque hypothalamus provides further evidence for the glutamatergic regulation of neuroendocrine, autonomic, and limbic circuits. Differential distributions of glutaniate receptor subunits may increase the dynamic range of the effects of presynaptic glutamate, allowing for the regulation of several distinct functions subserved by hypothalamic neurons. © 1995 Wiley-Liss, Inc.     

Nigral GABAergic inhibition upon mesencephalic dopaminergic cell groups in rats

Synaptic inhibition from the substantia nigra pars reticulata (SNr) to the mesencephalic dopaminergic neurons, which was mediated by gamma (gamma)-amino-butyric acid (GABA), was investigated in a midbrain slice preparation of Wistar rats. Whole-cell patch-clamp recordings were used to record synaptic potentials/currents from the dopaminergic neurons (n = 93) located in the retrorubral field (n = 22), the substantia nigra pars compacta (n = 47) and the ventral tegmental area (n = 24). In the presence of ionotropic glutamate receptor antagonists electrical stimulation of the SNr induced inhibitory postsynaptic potentials (IPSPs) and/or currents (IPSCs) in 83 neurons. The IPSPs/IPSCs were comprised early and late components. The early IPSPs/IPSCs were mediated by chloride currents through GABA(A) receptors. The late IPSPs/IPSCs were mediated by potassium currents through GABA(B) receptors. Both GABA(A)- and GABA(B)-IPSPs were amplified by repetitive stimuli with frequencies between 25 and 200 Hz. This frequency range covers the firing frequencies of SNr neurons in vivo. It was observed that an application of a GABA(B) receptor antagonist increased the amplitude of the GABA(A)-IPSPs. The amplification was followed by a rebound depolarization that induced transient firing of dopaminergic neurons. These properties of the IPSPs were common in all of the three dopaminergic nuclei. These results suggest that postsynaptic GABA(A)- and GABA(B)-inhibition contribute to transient and persistent alternations of the excitability of dopaminergic neurons, respectively. These postsynaptic mechanisms may be, in turn, regulated by presynaptic GABA(B)-inhibition. Nigral GABAergic input may provide the temporospatial regulation of the background excitability of mesencephalic dopaminergic systems.     

Glutamate receptor subunit immunoreactivity in neurons of the rat rostral ventrolateral medulla

Immunohistochemical studies were conducted to assess the subunits of ionotropic and metabotropic glutamate receptor present in the rostral ventrolateral medulla (RVLM) of the rat. Double labeling the medullary sections with polyclonal GluR1, GluR2/3, GluR4, NMDAR1, NMDAR2A/B, mGluR1alpha, and mGluR2/3 antiserum and monoclonal tyrosine hydroxylase (TH) antiserum revealed nearly all TH immunoreactive (irTH) cells and many TH-negative neurons were immunoreactive to GluR2/3 (irGluR2/3), NMDAR1 (irNMDAR1), and NMDAR2A/B (irNMDAR2A/B). A few RVLM neurons were immunoreactive to GluR1 (irGluR1) and GluR4 (irGluR4), but they were generally TH-negative. Immunoreactivity to mGluR1alpha (irmGluR1alpha) appeared to be localized exclusively to fiber-like elements in the RVLM area. Our results show that neurons in the RVLM, including irTH, are endowed mainly with GluR2/3 and NMDAR1 or NMDAR2A/B ionotropic receptor subunits, and that irmGluR1alpha splice variant appears to be located on nerve fibers ramifying within the RVLM. Moreover, TH-negative neurons in the RVLM appear to bear similar subunits of ionotropic glutamate receptors.     

Electrophysiological effects of cholecystokinin on neurons in rat substantia nigra pars reticulata

The electrophysiological effects of car☐yterminal fragments of cholecystokinin (CCK) on neurons in the dorsal substantia nigra pars reticulata (SNr) were evaluated in anesthetized rats. Microiontophoretic administration of sulfated CCK octapeptide (CCK-8S, agonist for CCK-A and CCK-B receptors) and the selective CCK-B receptor agonists, CCK-4 and unsulfated CCK-8, inhibited the firing rates of a subpopulation of SNr neurons. This effect appears to be mediated by CCK-B receptors.     

Lesion of the substantia nigra pars compacta downregulates striatal glutamate receptor subunit mRNA expression

This is a study of the effect of the unilateral administration of dopamine (DA) in the pars compacta of the substantia nigra (SN) of the rat on striatal glutamate receptor subunit (GluR1, GluR2 and NMDAR1) gene expression determined by in situ hybridization. The location of the nigral lesion was determined by tyrosine hydroxylase (TH) immunohistochemistry and its extent by the striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. The DA-induced lesions produce significant bilateral reductions in the expression of GluR1 and NMDAR1 subunit mRNA in the medio-lateral striatum, whereas the expression of striatal GluR2 receptors was not changed. The reduction in GluR1 and NMDAR1 subunit mRNA may be the consequence of glutamatergic hyperactivity developed in the presence of a damaged nigro-striatal system and these may be associated with the genesis of some neurodegenerative diseases.