Effects of muscimol and picrotoxin on single unit activity of substantia nigra neurons

Intravenous administration of the GABA agonist, muscimol, caused dose-dependent increases in the unit activity of substantia nigra pars compacta (dopamine) neurons and an inhibition of nigral pars reticulata cells. The depressant effects of the drug upon reticulata neurons were reversible by subsequent administration of the GABA antagonists, picrotoxin and bicuculline HCl. However, the stimulatory effects of i.v. muscimol upon dopamine neurons were not abolished by these agents. Intravenous administration of picrotoxin alone caused only moderate increases in the activity of dopamine neurons (31% over baseline at 7.0 mg/kg), but markedly stimulated the firing of pars reticulata cells (154% over baseline at 7.0 mg/kg). In spite of the stimulation of dopamine neurons after i.v. muscimol, microiontophoresis of GABA and muscimol could inhibit the firing of both pars compacta and pars reticulata cells, although the reticulata neurons were much more sensitive to the inhibitory actions of these agents than the dopamine neurons. Considered together, these studies suggest that a population of neurons in the substantia nigra pars reticulata have the capacity to be more affected by a major GABA input to the nigra than the pars compacta dopamine neurons. The results further suggest that if the dopamine cells are regulated by GABAergic neurons of the striatonigral pathway, their regulation must be indirect and could involve a second inhibitory neuron within the nigra.     

Sub-chronic treatment with classical but not atypical antipsychotics produces morphological changes in rat nigro-striatal dopaminergic neurons directly related to "early onset" vacuous chewing

In the present work, we investigated if an impairment of dopaminergic neurons after subchronic haloperidol treatment might be a possible physiopathologic substrate of the "early onset" vacuous chewing movements (VCMs) in rats. For this purpose, different antipsychotics were used to analyse a possible relationship between VCMs development and morphological alterations of tyrosine-hydroxylase-immunostained (TH-IM) neurons. Rats treated twice a day with haloperidol displayed a significant increase of VCMs that was both time- (2-4 weeks) and dose (0.1-1 mg/kg) dependent. Immunocytochemical analysis showed a shrinkage of TH-IM cell bodies in substantia nigra pars compacta and reticulata and a reduction of TH-immunostaining in the striatum of haloperidol treated rats with the arising of VCMs. No differences were observed in TH-IM neurons of ventral tegmental area and nucleus accumbens vs. control rats. The atypical antipsychotics risperidone (2 mg/kg, twice a day), amisulpride (20 mg/kg, twice a day) and clozapine (10 mg/kg, twice a day) did not produce any nigro-striatal morphological changes or VCMs. TH-IM nigro-striatal neuron morphological alterations and VCMs were still present after three days of withdrawal in rats treated for four weeks with haloperidol (1 mg/kg). Both the main morphological changes and the behavioural correlate disappeared after three weeks of withdrawal. These results suggest that haloperidol induces a morphological impairment of the dopaminergic nigro-striatal neurons which is directly associated with the arising, permanency and disappearance of VCMs in rats.     

Delta(9)-tetrahydrocannabinol decreases extracellular GABA and increases extracellular glutamate and dopamine levels in the rat prefrontal cortex: an in vivo microdialysis study

Cannabinoid modulation of prefrontal cortex and hippocampus neuronal functioning has been correlated to the disruptive action of marijuana on memory tasks. This study investigates the effects of delta(9)-tetrahydrocannabinol (delta(9)-THC) on dopamine, glutamate and GABA levels in vivo by brain microdialysis in the prefrontal cortex. Delta(9)-THC (1 mg/kg, i.v.) significantly increased extracellular dopamine and glutamate levels and decreased GABA levels. These effects were prevented by the cannabinoid antagonist SR141716A (1 mg/kg, i.v.), which per se was ineffective. These results suggest that delta(9)-THC disrupt the normal interplay between neurotransmitters in this area and may bear relevance in understanding neuronal mechanisms underlying cannabinoid-induced cognitive deficits.     

N-methyl-D-aspartate receptor blockade attenuates D1 dopamine receptor modulation of neuronal activity in rat substantia nigra

It has been proposed that dopamine and glutamate affect basal ganglia output, in part, through interactions between D1 receptors and NMDA receptors. The present study examined whether N-methyl-D-aspartate (NMDA) receptor antagonists affect the neurophysiological responses of substantia nigra pars compacta (SNpc; dopaminergic) and pars reticulata (SNpr; non-dopaminergic) neurons to a systemically administered D1 dopamine agonist in two animals models of Parkinson's disease, reserpine treatment and nigrostriatal lesion. Previous studies using extracellular single unit recording techniques have shown that the D1 dopamine agonist SKF 38393 (10 mg/kg) exerts different effects on the firing rates of SNpr neurons after these two dopamine-depleting treatments, suggesting the involvement of multiple mechanisms. SKF 38393 consistently increased the firing rates of SNpr neurons in rats treated subchronically with reserpine, and markedly decreased SNpr firing rates in rats with nigrostriatal damage. Pretreatment with the non-competitive NMDA antagonist MK-801 (0.15 mg/kg i.v.) blocked, and the competitive NMDA antagonist (±)-CPP (30 mg/kg i.p.) attenuated, the rate effects of SKF 38393 in both dopamine-depleted preparations. SKF 38393 consistently inhibited the firing rate of SNpc dopamine neurons after acute reserpine treatment (10 mg/kg, 4–7 hours), an effect specifically mediated by D1 receptors. Pretreatment with MK-801 (0.1 mg/kg i.v.) or the competitive NMDA antagonist (+)-HA-966 (30 mg/kg i.v.) also effectively attenuated SKF 38393's inhibitory effect on SNpc dopamine neurons. Therefore, NMDA receptor blockade markedly reduces the ability of D1 receptor stimulation to modulate firing rates of both dopaminergic and non-dopaminergic cells in the substantia nigra. Although multiple mechanisms appear to underlie D1-mediated effects on substantia nigra firing rates in reserpine and 6-OHDA-treated rats, these results demonstrate a common dependence on glutamatergic transmission and a permissive role for NMDA receptor activation in the ability of D1 receptor stimulation to both enhance and reduce neuronal activity in the substantia nigra. Synapse 30:18–29, 1998. Published 1998 Wiley-Liss, Inc.     

Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration

Systemic administration of the selective D1 agonist, SKF 38393, to rats with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway induces contralateral turning and reduces firing rates of substantia nigra pars reticulata neurons. Previous studies have shown that chronically administered levodopa diminishes the contralateral turning induced by SKF 38393 in these animals. The present study demonstrates that twice daily injections (45-50 mg/kg, i.p.) of levodopa for 19 days also diminishes the effects of SKF 38393 on substantia nigra pars reticulata activity. Concomitant with this change, chronic levodopa injections reversed the lesion-induced supersensitivity of substantia nigra pars reticulata neurons to iontophoresed GABA. Neither of these effects were produced by the continuous infusion of levodopa (90-100 mg/kg/day, i.p. by osmotic pump) for 19 days, a treatment that produces average daily blood levodopa levels similar to those produced by chronic levodopa injection. These results suggest that large variations in circulating levodopa levels in 6-hydroxydopamine lesioned rats may desensitize the behavioral responses to D1 dopamine agonist administration by down-regulating D1 and GABA receptor-mediated mechanisms of basal ganglia output through the substantia nigra pars reticulata.     

Nigral reticulata neurons: potentiation of reponsiveness to amphetamine with long-term treatment

Single-unit activity was recorded in the substantia nigra pars reticulata of rats in response to intravenous challenge injections of d-amphetamine. The animals were pretreated with saline or 5.0 mg/kg d-amphetamine twice daily for 6 consecutive days. Whereas the large majority of saline controls (6 to 8) showed no consistent response to amphetamine at doses up to 2.0 mg/kg, amphetamine pretreated rats (7 of 10) responded with a progressive increase in firing rate. Both groups of animals responded to a subsequent injection of 5.0 mg/kg clozapine with a depression of firing rate. The remaining control rats were inhibited by amphetamine and this aberrant response was enhanced with long-term treatment. In this unusual cells, clozapine accelerated firing rate. Taken together, these results indicate that unlike dopaminergic neurons in the compacta region of the nigra, reticulata neurons increase their responsiveness to amphetamine with repeated administration.     

Compartmental distribution of ventral striatal neurons projecting to the mesencephalon in the rat.

The ventral striatum is characterized by an intricate neurochemical compartmentation that is reflected in the distribution of most of its afferent fiber systems. In the present study, the compartmental relationships of ventral striatal neurons projecting to the mesencephalon were studied by combining tract tracing with the immunohistochemical localization of leu-enkephalin. Injections of the retrograde tracer cholera toxin subunit B were placed at various sites in the ventral mesencephalon. The anterograde tracer Phaseolus vulgaris leucoagglutinin was injected in single compartments in the rostrolateral part of the nucleus accumbens. The projections from the ventral striatum to the dopaminergic cell groups in the ventral mesencephalon and those to the substantia nigra pars reticulata originate from distinct subpopulations of ventral striatal neurons that respect neurochemically defined compartmental boundaries. In the "shell" of the nucleus accumbens, neurons that project to the dopaminergic cell groups are located outside areas of high cell density and weak enkephalin immunoreactivity (ENK-IR). Rostrolaterally in the "core" of the nucleus accumbens, neurons inside large areas of strong ENK-IR surrounding the anterior commissure project to the dorsomedial part of the substantia nigra pars reticulata, whereas neurons outside these areas innervate the ventral tegmental area and/or the medial part of the substantia nigra pars compacta. By contrast, more caudally in the dorsal part of the nucleus accumbens and in the ventral part of the caudate-putamen, the relationships are reversed: neurons in- or outside small patches of strong ENK-IR project respectively to the pars compacta or the pars reticulata of the substantia nigra. Since the thalamic and cortical afferents of the ventral striatum are compartmentally ordered as well, the present results imply that through the ventral striatal compartments information from disparate combinations of cortical and thalamic sources may be conveyed to distinct mesencephalic targets. The component of the ventral striatomesencephalic system reaching the dopaminergic cell groups A10, A9, and A8 may modulate the dopaminergic input to virtually the entire striatum. The other component can, by way of the pars reticulata of the substantia nigra, participate in nigrothalamic and nigrotectal output pathways of the basal ganglia.     

Morphine-induced alterations of local cerebral glucose utilization in the basal ganglia of rats

The actions of various doses of morphine on the local cerebral glucose utilization (LCGU) were studied by means of the autoradiographic [¹⁴C]2-deoxyglucose technique. Morphine (1–15 mg/kg i.p.) decreased LCGU in most areas of the basal ganglia (caudate nucleus, globus pallidus, nucleus accumbens), but not in the substantia nigra pars compacta. LCGU was also decreased in limbic nuclei, such as septum, hippocampus and amygdala, and in most thalamic areas. In most cortical regions, a decrease was found as well. Findings in some efferent nuclei seemed of particular interest, namely in the substantia nigra pars reticulata, anteroventral and lateral nucleus of the thalamus and the subthalamic nucleus, where decrease in LCGU were found after administration of 7.5 mg/kg or sometimes lower doses, but not after 15 mg/kg of morphine. The decreases seem to reflect a general depressory effect of morphine on neuronal activity which is known from electrophysiological studies. Part of these effects might be, in addition, due to an activation of dopaminergic neurons, since dopamine mainly acts as an inhibitory neurotransmitter. This dopaminergic activation leads to characteristic behavioral effects after lower doses of morphine. The largest dose used (15 mg/kg) produces muscular rigidity, probably by a direct action on the striatum. This effect antagonizes and masks the dopaminomimetic effects. The results suggest that it also antagonizes the functional alterations in some efferent nuclei of the basal ganglia manifest after lower doses of morphine. Local injections of morphine (15 μg) led to decreases of LCGU in the various parts of the striatum, but to increases in lateral and anteroventral thalamus. These increases in LCGU in two thalamic areas seem to support the above hypothesis that the rigidity is accompanied, at least in part of the efferent nuclei of the basal ganglia, by increases in LCGU antagonizing the inhibitory effects described above.     

Effects of D1 and D2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D1/D2 coactivation induces potentiated responses

Extracellular single unit recording techniques were used to compare the effects of selective and non-selective dopamine agonists on substantia nigra pars reticulata activity in rats with 6-hydroxydopamine induced lesions of the nigrostriatal dopamine pathway. As previously shown, apomorphine (0.32 mg/kg), a dopamine agonist that interacts with both D1 and D2 dopamine receptor subtypes, produced consistent inhibitions of substantia nigra pars reticulata activity in these animals. The D1-receptor agonist, SKF 38393 (RS-SKF 38393, 10 mg/kg), also induced significant inhibitions in the activity of these neurons in 6-hydroxydopamine lesioned rats, although less consistently than did apomorphine. The effects of SKF 38393 were reversed by the D1-antagonist, SCH 23390. The D2 selective agonist quinpirole was considerably less effective than apomorphine at inhibiting substantia nigra pars reticulata activity at doses up to 1 mg/kg. Since comparable experiments have shown that quinpirole is as effective as apomorphine at producing dopamine D2-autoreceptor-mediated effects on dopamine neuron activity, quinpirole's lack of efficacy in the present study relative to that of apomorphine does not appear to be related to differences in relative potency for central D2-receptors using this route of administration. Rather, the relative effectiveness of SKF 38393 on pars reticulata activity suggests that selective stimulation of D1-receptors is at least, if not more, efficacious than selective stimulation of D2-receptors at inducing alterations in the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats. The simultaneous stimulation of both receptors, however, was considerably more effective than selective stimulation of either receptor subtype: doses of SKF 38393 and quinpirole which had no significant effect on nigral activity when administered alone brought about marked inhibition of the firing of these cells when administered simultaneously. No such inhibition was seen when the inactive enantiomer, S-SKF 38393, was substituted for the racemic form of SKF 38393 in this protocol. These observations in 6-hydroxydopamine lesioned rats support other recent findings indicating that the two dopamine receptor subtypes can interact in a synergistic way to affect basal ganglia output.     

Opioid receptors in midbrain dopaminergic regions of the rat II. Kappa and delta receptor autoradiography

Summary Opiates and opioid peptides are known to influence the dopaminergic (DA) neurons in the midbrain. The purpose of this study was to map and quantify the density of kappa and delta opioid receptor subtypes in the retrorubral field, substantia nigra, and ventral tegmental area and related nuclei, which contain DA nuclei A8, A9, and A10, respectively. Sections through the rostral-caudal extent of the rat midbrain were stained with an antibody against tyrosine hydroxylase, as a DA cell marker, and comparable sections were processed for in vitro receptor autoradiography using the kappa-selective ligand, U-69593, and the delta-selective ligand, D-Pen², D-Pen⁵-enkephalin. In general, both kappa and delta ligands exhibited low levels of specific binding in regions occupied by the midbrain DA neurons.Kappa binding (4–8 fmol/mg tissue) was high throughout the rostral-caudal extent of the substantia nigra, in rostral portions of the ventral tegmental area, and in the nucleus paranigralis; low binding occurred in the retrorubral field and central linear nucleus raphe.Delta binding (6–18 fmol/mg tissue) was high in the caudal portion of the substantia nigra pars reticulata, and in the medial terminal nucleus of the accessory optic system (a region previously shown to contain DA dendrites). The kappa and delta receptor binding is heterogeneously distributed in regions occupied by midbrain dopaminergic neurons, and several fold lower than the binding of mu opioid receptors in the same brain regions.     

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.     

Substance P synaptic interactions with GABAergic and dopaminergic neurons in rat substantia nigra: An ultrastructural doublelabeling immunocytochemical study

The distribution of substance P (SP), tyrosine hydroxylase (TH), and glutamic acid decarboxylase (GAD) immunoreactivity in the substantia nigra of the rat was studied by means of an ultrastructural double-labeling immunocytochemical method. Direct synaptic contact between SP-immunoreactive terminals and GAD-positive nigral neurons was more often observed in the pars lateralis than the pars reticularis and was rarely observed in the pars compacta. Substance P-positive terminals also formed synapses with cell bodies and dendrites of TH-positive, dopaminergic neurons in the pars compacta and pars reticulata. Multiple SP-immunoreactive terminals were often observed with symmetrical and, less frequently, asymmetrical synapses on individual TH-containing dendrites. Evidence of SP-containing terminals contacting both GABAergic and dopaminergic neurons in the substantia nigra suggests a direct excitatory action upon nigral projection neurons.     

Substantia nigra pars reticulata lesion facilitates kainic acid-induced seizures

The administration of subconvulsive doses of kainic acid (5 mg/kg, intraperitoneally) to rats, with lesion of the substantia nigra pars reticulata (1 week), produced high frequency wet dog shakes and severe convulsive behavior (observed in 60% of the rats). The behavior was not observed in rats treated with kainic acid but without reticulata lesion. The results show that rats with unilateral lesion of the substantia nigra pars reticulata are more vulnerable to seizure stimuli.     

Nigral dopaminergic neurons: differential sensitivity to apomorphine following long-term treatment with low and high doses of amphetamine

Twice daily injections of 1.0 or 5.0 mg/kg D-amphetamine for 6 consecutive days differentially affected the response of dopaminergic neurons in the substantia nigra pars compacta to challenge injections of apomorphine on the following day. Thus, whereas treatment with the high amphetamine dose produced a dramatic shift to the right of the apomorphine dose-response curve, rats treated with 1.0 mg/kg D-amphetamine responded to apomorphine in the same way as saline-treated controls. These results support the view that long-term treatment with relatively high amphetamine doses is required to produce autoreceptor subsensitivity in the substantia nigra.     

Microtopography of methionine-enkephalin, dopamine and noradrenaline in the ventral mesencephalon of human control and Parkinsonian brains

The topographical distributions of Met-enkephalin, dopamine and noradrenaline were determined in serial frontal sections of human substantia nigra (pars compacta and pars reticulata) and ventral tegmental area. Met-enkephalin was identified by Biogel and thin layer chromatography and assayed by a specific radioimmunoassay. In the substantia nigra (pars compacta and pars reticulata), the levels of Met-enkephalin increased progressively from the rostal to the caudal part of the structure. This pattern closely resembled that of dopamine levels, particularly in the pars compacta. Noradrenaline levels in the substantia nigra and those of Met-enkephalin, dopamine, and noradrenaline in the ventral tegmental area, exhibited only limited fluctuations from the anterior to the posterior part of each structure.Highly significant decreases in Met-enkephalin, dopamine and noradrenaline levels were observed in the substantia nigra and ventral tegmental area of Parkinsonian brains. This observation, together with the close topographical association of dopamine and Met-enkephalin in the substantia nigra, further supports the likely existence of important functional relationships between dopaminergic and enkephalinergic neurons in the human brain.     

Expression of ErbB4 in substantia nigra dopamine neurons of monkeys and humans

Abnormal neuregulin-1 signaling through its receptor (ErbB4) might be associated with schizophrenia, although their neuropathological contribution remains controversial. To assess the role of neuregulin-1 in the dopamine hypothesis of schizophrenia, we used in situ hybridization and immunoblotting to investigate the cellular distribution of ErbB4 mRNA in the substantia nigra of Japanese monkeys (Macaca fuscata) and human postmortem brains. In both monkeys and humans, significant signal for ErbB4 mRNA was detected in substantia nigra dopamine neurons, which were identified by melanin deposits. The expression of ErbB4 mRNA in nigral dopamine neurons was confirmed with an independent RNA probe, as well as with combined tyrosine hydroxylase immunostaining. Immunoblotting appeared to support the observation of in situ hybridization. Immunoreactivity for ErbB4 protein was much more enriched in substantia nigra pars compacta containing dopamine neurons than in neighboring substantia nigra pars reticulata. These observations suggest that ErbB4 is expressed in the dopaminergic neurons of primate substantia nigra and ErbB4 abnormality might contribute to the dopaminergic pathology associated with schizophrenia or other brain diseases.     

Effect of delta9-tetrahydrocannabinol on phosphorylated CREB in rat cerebellum: an immunohistochemical study

Several converging lines of evidence indicate that drugs of abuse may exert their long-term effects on the central nervous system by modulating signaling pathways controlling gene expression. Cannabinoids produce, beside locomotor effects, cognitive impairment through central CB1 cannabinoid receptors. Data clearly indicate that the cerebellum, an area enriched with CB1 receptors, has a role not only in motor function but also in cognition. This immunohistochemical study examines the effect of delta9-tetrahydrocannabinol (delta9-THC), the principal psychoactive component of marijuana, on the levels of phosphorylated CREB (p-CREB) in the rat cerebellum. Acute treatments with delta9-THC at doses of 5 or 10 mg/kg induced a significant increase of p-CREB in the granule cell layer of the cerebellum, an effect blocked by the CB1 receptor antagonist SR 141716A. Following chronic delta9-THC administration (10 mg/kg/day for 4 weeks), the density of p-CREB was markedly attenuated compared to controls, and this attenuation persisted 3 weeks after withdrawal from delta9-THC. These data provide evidence for the involvement of cerebellar granule cells in the adaptive changes occurring during acute and chronic delta9-THC exposure. This might be a mechanism by which delta9-THC interferes with motor and cognitive functions.     

D1 dopamine receptor stimulation inhibits firing activity of midbrain dopamine neurons in reserpine treated rats: An effect eliminated after hemitransection of diencephalon

It has been reported that systemic administration of the D₁ dopamine (DA) receptor agonist SKF 38393 inhibits the firing rate of substantia nigra pars compacta (SNC, A9) DA neurons after repeated reserpine treatment in locally anesthetized rats, although SKF 38393 induces little effect on the firing of midbrain DA neurons in normal rats. The present study found that local pressure microejection of SKF 38393 (10⁻² M, 20–100 nl) to SNC or substantia nigra pars reticulata (SNR) failed to influence the firing of SNC DA neurons in reserpinized rats (reserpine 1 mg/kg × 6 days, s.c.); subsequent intravenous (i.v.) injection of SKF 38393 (4 mg/kg), however, inhibited their firing and the inhibition was reversed by the D₁ receptor antagonist SCH 23390. Similarly, systemic administration of SKF 38393 (4 mg/kg, i.v.) inhibited the firing of ventral tegmental area (VTA, A10) DA cells in reserpinized rats, while local microejection of SKF 38393 (10⁻² M, 30–60 nl) did not affect their firing. Furthermore, the inhibitory effect of systemic SKF 38393 on firing rate of either SNC or VTA DA neurons in reserpinized rats was eliminated after hemitransection of diencephalon. These results suggest that repeated reserpine treatment renders midbrain DA neurons responsive to D₁ receptor stimulation and that D₁ receptor agonist-induced inhibition of midbrain DA cell firing in reserpinized rats may require the involvement of long-loop feedback pathways. © 1996 Wiley-Liss, Inc.     

Distribution of the major gamma-aminobutyric acid(A) receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat

Within the basal ganglia, gamma-aminobutyric acid (GABA) exerts a fundamental role as neurotransmitter of local circuit and projection neurons. Its fast hyperpolarizing action is mediated through GABA(A) receptors. These ligand-gated chloride channels are assembled from five subunits, which derive from multiple genes. Using immunocytochemistry, we investigated the distribution of 12 major GABA(A) receptor subunits (alpha1-5, beta1-3, gamma1-3, and delta) in the basal ganglia and associated limbic brain areas of the rat. Immunoreactivity for an additional subunit (subunit alpha6) was not observed. The striatum, the nucleus accumbens, and the olfactory tubercle displayed strong, diffuse staining for the subunits alpha2, alpha4, beta3, and delta presumably located on dendrites of the principal medium spiny neurons. Subunit alpha1-, beta2-, and gamma2-immunoreactivities were apparently mostly restricted to interneurons of these areas. In contrast, the globus pallidus, the entopeduncular nucleus, the ventral pallidum, the subthalamic nucleus, and the substantia nigra pars reticulata revealed dense networks of presumable dendrites of resident projection neurons, which were darkly labeled for subunit alpha1-, beta2-, and gamma2-immunoreactivities. The globus pallidus, ventral pallidum, entopeduncular nucleus, and substantia nigra pars reticulata, all areas receiving innervations from the striatum, displayed strong subunit gamma1-immunoreactivity compared to other brain areas. In the substantia nigra pars compacta and in the ventral tegmental area, numerous presumptive dopaminergic neurons were labeled for subunits alpha3, gamma3, and/or delta. This highly heterogeneous distribution of individual GABA(A) receptor subunits suggests the existence of differently assembled, and presumably also functionally different, GABA(A) receptors within individual nuclei of the basal ganglia and associated limbic brain areas.     

Spreading of slow cortical rhythms to the basal ganglia output nuclei in rats with nigrostriatal lesions

A high proportion of neurons in the basal ganglia display rhythmic burst firing after chronic nigrostriatal lesions. For instance, the periodic bursts exhibited by certain striatal and subthalamic nucleus neurons in 6-hydroxydopamine-lesioned rats seem to be driven by the approximately 1 Hz high-amplitude rhythm that is prevalent in the cerebral cortex of anaesthetized animals. Because the striatum and subthalamic nucleus are the main afferent structures of the substantia nigra pars reticulata, we examined the possibility that the low-frequency modulations (periodic bursts) that are evident in approximately 50% nigral pars reticulata neurons in the parkinsonian condition were also coupled to this slow cortical rhythm. By recording the frontal cortex field potential simultaneously with single-unit activity in the substantia nigra pars reticulata of anaesthetized rats, we proved the following. (i) The firing of nigral pars reticulata units from sham-lesioned rats is not coupled to the approximately 1 Hz frontal cortex slow oscillation. (ii) Approximately 50% nigral pars reticulata units from 6-hydroxydopamine-lesioned rats oscillate synchronously with the approximately 1 Hz cortical rhythm, with the cortex leading the substantia nigra by approximately 55 ms; the remaining approximately 50% nigral pars reticulata units behave as the units recorded from sham-lesioned rats. (iii) Periodic bursting in nigral pars reticulata units from 6-hydroxydopamine-lesioned rats is disrupted by episodes of desynchronization of cortical field potential activity. Our results strongly support that nigrostriatal lesions promote the spreading of low-frequency cortical rhythms to the substantia nigra pars reticulata and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.