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PubMed1984

Dopamine attenuates the effects of GABA on single unit activity in the globus pallidus.

Studies were conducted to assess whether stimulation of dopamine receptors located in the globus pallidus might play a role in mediating the enhanced pallidal activity seen after systemic administration of dopamine agonists or D-amphetamine. Dopamine, applied iontophoretically, had modest effects on the activity of pallidal neurons; the baseline firing rates of 32% of cells recorded increased by an average of 23 +/- 2%, 18% decreased in rate and the remaining cells showed no significant rate change. More significantly, dopamine consistently attenuated the inhibitory actions of gamma-aminobutyric acid (GABA) in the globus pallidus. When dopamine was simultaneously iontophoresed with GABA, GABA's effectiveness at inhibiting pallidal activity was reduced by an average of 50%. Norepinephrine or acetylcholine, applied iontophoretically at equimolar concentrations and ejected at the same current as dopamine, caused no consistent attenuation of pallidal responses to GABA's rate effects. To determine whether the attenuation of GABA's inhibitory action by iontophoresed dopamine could be mimicked by systemic drug administration, apomorphine, 80 micrograms/kg, or D-amphetamine, 0.8 mg/kg, was given i.v. while GABA was iontophoresed. Apomorphine markedly decreased pallidal responses to the inhibitory effects of GABA in 75% of the cells by an average of 50%; haloperidol reversed this effect. Modulatory interactions between GABA and D-amphetamine were also observed in 5 of the 11 pallidal cells tested; GABA's inhibitory effect on pallidal cell activity was reduced by an average of 66% on these neurons. These results suggest that one way in which dopamine and dopamine agonists may affect basal ganglia function is by modulating GABAergic transmission in the globus pallidus.

Acetylcholine↗

PubMedDate not supplied

GABA-B receptor activation in the rat globus pallidus potently suppresses pentylenetetrazol-induced tonic seizures.

To determine the involvement of the globus pallidus in mediating epilepsy, the effects of microinjection of a GABA uptake blocker (tiagabine), a benzodiazepine agonist (zolpidem) and a GABA-B receptor agonist (baclofen) on pentylenetetrazol (PTZ)-induced tonic seizure were examined in adult rats. Administration of PTZ induced tonic seizures in all control animals, accompanied with a 100% mortality rate. Pretreatment with bilateral intrapallidal microinjection of tiagabine (1 mM) suppressed the incidence of tonic seizures to 67.7% and reduced the mortality rate to 16.7%. Furthermore, the latency to tonic seizures was 1,275 +/- 277 s, which was significantly longer than that of the corresponding control animals (319 +/- 225 s). On the other hand, administration of zolpidem (1 mM) was without significant effects on the mortality rate, the incidence and latency of the tonic seizure. In sharp contrast, microinjection of baclofen (1 mM) completely suppressed PTZ-induced tonic seizures and reduced the mortality rate to 0%. This effect was largely abolished by co-injection of the GABA-B receptor antagonist CGP55845. To elucidate the direct cellular action of baclofen, the excitability and membrane potential of globus pallidus neurons were studied by cell-attached and whole-cell patch-clamp recordings in the brain slice. Bath application of baclofen (50 microM) significantly reduced the firing of these neurons, and was often accompanied by a clear membrane hyperpolarization, in a CGP55845-sensitive manner. These data suggest that activation of GABA-B receptors in globus pallidus could significantly modulate PTZ-induced tonic seizures.

Action Potentials↗

PubMed1995

Heterogeneous and compartmental distribution of zinc in the striatum and globus pallidus of the rat.

The distribution of vesicular or chelatable zinc was analysed in the dorsal and ventral subdivisions of the striatum and globus pallidus of the rat with Danscher's selenium method. Acetylcholinesterase and Calbindin-D28k were used as striatal and pallidal markers in order to analyse the possible compartmentalization of the distribution of zinc in the striatum and globus pallidus. The main findings of this study are the following: (1) The distribution of vesicular zinc in the dorsal striatum was heterogeneous. A peripheral rim of tissue heavily stained for zinc was detected in the medial, dorsal and lateral striatal areas, along most of the rostrocaudal extent of the striatum. addition, patch-like zones intensely stained for zinc were prominent in the rostral half of the caudate-putamen complex. (2) In some regions of the rostral half of the caudate-putamen complex, the staining for zinc appeared to follow the well-known striatal patches (striosomes)/matrix organization. However, in other regions of the rostral half of the striatum such a relation was not detected. (3) The ventral striatum also showed a heterogeneous staining for zinc. Thus, in the most ventral part of the caudate-putamen complex, both subdivisions of the nucleus accumbens and parts of the olfactory tubercle displayed different patterns of compartmentalized distribution of zinc. In the dorsal half of the shell of the nucleus accumbens, some patches with an intense reaction for zinc seemed to overlap with acetylcholinesterase-poor patches. (4) There was a remarkable absence of staining for zinc in the globus pallidus. This histochemical study illustrates, on the one hand, the high content of vesicular zinc in the dorsal and ventral subdivisions of the striatum, which was distributed following different patterns of chemical compartmentalization, and on the other hand, the absence of vesicular zinc in the globus pallidus of the rat.

Acetylcholinesterase↗

PubMed1994

Acute toluene exposure decreases extracellular gamma-aminobutyric acid in the globus pallidus but not in striatum: a microdialysis study in awake, freely moving rats.

Intracerebral brain microdialysis was performed in awake, freely moving rats to study the effect of acute inhalation exposure of toluene (2000 ppm, 2 h) on extracellular levels of gamma-aminobutyric acid (GABA) within the globus pallidus and the striatum. GABA within the globus pallidus decreased (20%) during and after (26%) exposure to toluene, while no reduction was seen in the striatal GABA level during exposure. After the exposure there was a tendency towards an increase (maximally 37%) in striatal GABA. 2 h of perfusion with tetrodotoxin (10(-6) M) decreased (32%) the extracellular GABA levels within the globus pallidus. The results suggest that the effect of acute toluene exposure varies with brain region and that the GABA output from the striatum to globus pallidus is more affected by the exposure than the GABA release within the striatum.

Administration, Inhalation↗

PubMed1980

Nucleus accumbens to globus pallidus GABA projection subserving ambulatory activity.

The present experiments investigated the hypothesis of a projection relating to the release of gamma-aminobutyric acid (GABA) from the nucleus accumbens to the globus pallidus subserving ambulatory activity in the rat. The GABA antagonist picrotoxin, microinjected into the globus pallidus, elicited dose-dependent increases in ambulatory activity. The administration of dopamine into the nucleus accumbens had a synergistic effect and further stimulated ambulatory activity. GABA injected into the ventral posterior globus pallidus significantly attenuated the ambulatory activity stimulated by injecting dopamine into the nucleus accumbens. These observations provide evidence of a GABAergic projection from the nucleus accumbens to the globus pallidus and implicate it in the initiation of ambulatory activity.

Animals↗

PubMed1999

GABAergic control of rat substantia nigra dopaminergic neurons: role of globus pallidus and substantia nigra pars reticulata.

Dopaminergic neurons in vivo fire spontaneously in three distinct patterns or modes. It has previously been shown that the firing pattern of substantia nigra dopaminergic neurons can be differentially modulated by local application of GABA(A) and GABA(B) receptor antagonists. The GABA(A) antagonists, bicuculline or picrotoxin, greatly increase burst firing in dopaminergic neurons whereas GABA(B) antagonists cause a modest shift away from burst firing towards pacemaker-like firing. The three principal GABAergic inputs to nigral dopaminergic neurons arise from striatum, globus pallidus and from the axon collaterals of nigral pars reticulata projection neurons, each of which appear to act in vivo primarily on GABA(A) receptors (see preceding paper). In this study we attempted to determine on which afferent pathway(s) GABA(A) antagonists were acting to cause burst firing. Substantia nigra dopaminergic neurons were studied by single unit extracellular recordings in urethane anesthetized rats during pharmacologically induced inhibition and excitation of globus pallidus. Muscimol-induced inhibition of pallidal neurons produced an increase in the regularity of firing of nigral dopaminergic neurons together with a slight decrease in firing rate. Bicuculline-induced excitation of globus pallidus neurons produced a marked increase in burst firing together with a modest increase in firing rate. These changes in firing rate were in the opposite direction to what would be expected for a monosynaptic GABAergic pallidonigral input. Examination of the response of pars reticulata GABAergic neurons to similar manipulations of globus pallidus revealed that the firing rates of these neurons were much more sensitive to changes in globus pallidus neuron firing rate than dopaminergic neurons and that they responded in the opposite direction. Pallidal inhibition produced a dramatic increase in the firing rate of pars reticulata GABAergic neurons while pallidal excitation suppressed the spontaneous activity of pars reticulata GABAergic neurons. These data suggest that globus pallidus exerts significant control over the firing rate and pattern of substantia nigra dopaminergic neurons through a disynaptic pathway involving nigral pars reticulata GABAergic neurons and that at least one important way in which local application of bicuculline induces burst firing of dopaminergic neurons is by disinhibition of this tonic inhibitory input.

Action Potentials↗

PubMed1997

Reduced eticlopride-induced Fos expression in caudate-putamen and globus pallidus after unilateral frontal cortex injury: relation to neglect.

Unilateral ablation of medial agranular cortex in rats results in neglect of contralateral stimuli and reductions in amphetamine-induced expression of the immediate early gene, c-fos, in both caudate-putamen and globus pallidus. Both unilateral neglect and the reductions in dopamine agonist induction of subcortical Fos immunoreactivity dissipate over a matter of weeks. Dopamine agonism induces Fos predominantly in striatonigral cells and in globus pallidus via striatopallidal disinhibition, whereas Fos is induced in striatopallidal cells by administration of antagonists of the D2 dopamine receptor subfamily. To examine more directly effects of cortical injury on striatopallidal function, induction of striatal Fos by the D2 antagonist eticlopride (0.1 mg/kg, s.c.) was examined in rats with medial agranular cortex ablation. In the same animals, eticlopride-induced Fos in globus pallidus was also examined. Five days after unilateral cortex injury, in rats showing neglect, the numbers of Fos immunoreactive nuclei induced by eticlopride were reduced by 50% in caudate-putamen and 25% in globus pallidus of the ipsilateral hemisphere. These lesion effects were restricted to dorsolateral caudate-putamen and dorsal pallidum. Three or more weeks after cortical injury, in rats recovered from neglect, eticlopride-induced Fos was normalized in caudate-putamen, but still decreased by 20% in globus pallidus. Along with previous findings, these results suggest that behavioral recovery from neglect produced by cortical injury may be at least partially mediated by normalizations of function of both striatopallidal and striatonigral neurons. In addition, the present findings suggest that normalization of function of pallidal cells activated by eticlopride is not necessary for behavioral recovery from frontal cortex ablation. Lingering reductions in excitatory cortico-subthalamo-pallidal input may be responsible for the longer-lasting dysfunctions of these pallidal cells.

Animals↗

PubMed1978

Opiate receptor agonists as modulators of gamma-aminobutyric acid turnover in the nucleus caudatus, globus pallidus and substantia nigra of the rat.

The injection of various doses of morphine, subcutaneously, or of beta-endorphin, intraventricularly, changes the turnover rate of gamma-aminobutyric acid (TRGABA) in the substantia nigra, globus pallidus and nucleus caudatus. The TRGABA decreases in N. caudatus but increases in globus pallidus and substantia nigra. These changes are dose related and can be inhibited by naltrexone. The increased TRGABA in globus pallidus elicited by these opioid receptor agonists may be associated with catalepsy since muscimol, a specific GABA receptor agonist, injected into the globus pallidus causes a dose-related catalepsy. Since this GABA receptor agonist injected into the substantia nigra fails to cause catalepsy, one can exclude that the increase in the TRGABA of substantia nigra elicited by opiate receptor agonists is operative in mediating the catalepsy elicited by opioids.

Animals↗

PubMed1993

The distribution of the globus pallidus neurons with input from various cortical areas in the monkeys.

Single neuron activities of the globus pallidus were recorded in awake monkeys. Electrical stimulation of various cortical areas (the prefrontal, premotor, supplementary motor and arcuate premotor areas, and the motor cortex) inhibited spontaneous discharge of pallidal neurons. This inhibitory response was considered to be mediated through the striatum. Considerable number of pallidal neurons responded to the stimulation of more than one cortical areas. However, the neurons receiving inputs from the motor cortex and/or arcuate premotor area and those receiving inputs from the prefrontal, premotor and/or supplementary motor areas were segregated. The former neurons were located ventrolaterally in the caudal part of the globus pallidus, while the latter ones were located dorsomedially in the rostral part of the globus pallidus.

Animals↗

PubMed2006

Globus pallidus deep brain stimulation in dystonia.

Globus pallidus deep brain stimulation (GPi-DBS) is a useful alternative in the treatment of dystonia. Patients selected for GPi-DBS were prospectively rated with the Unified Dystonia Rating Scale (UDRS). Also, "blinded" videotape assessments were performed. Eleven patients were identified. Compared with pre-DBS scores, there were improvements in mean total UDRS score (15.3%) and in the following subscores: neck (18.18%), trunk (32.9%), arm (17.9%), and leg (19.9%). One patient developed a skin infection and erosion requiring surgical debridement. GPi-DBS is a safe and effective treatment for generalized dystonia in patients who remained impaired, despite optimal medical therapy.

Adolescent↗

PubMedDate not supplied

Hyperactive behavior of rats after lesions of the globus pallidus.

Following bilateral lesions of the globus pallidus, rats living in a residential maze were hyperactive during the 12 hr dark cycle but not during the 12 hr light cycle. Lesioned rats were less exploratory during the light cycle than control rats but not during the dark cycle. Exploratory behavior of rats was photographed for 15 min during the light cycle. The duration of 6 behavior acts was significantly shorter than controls (scratching, grooming, sitting, sniffing, standing and rearing). The number of initiations of grooming, scratching, sniffing and smelling decreased while looking and walking increased in frequency. The linkage of behavior acts into sequences was diminished compared with controls. Similar, but not identical, changes were found when the structure of exploratory behavior of naive rats was compared with the exploratory behavior of experienced rats. It is concluded that naive control rats are hyperactive relative to experienced rats in this exploratory situation and that rats with pallidal lesions display changes in their behavior which are characteristic of hyperactive animals even when other tests under similar conditions, such as exploration during the light cycle in a maze, show the pallidal rats as hypoactive relative to control rats.

Animals↗

PubMed2000

Effects of feeding on extracellular levels of glutamate in the medial and lateral portion of the globus pallidus of freely moving rats.

The globus pallidus (GP) is considered to be part of the basal ganglia and previous research has determined that it might be involved in feeding behavior. For example, it has been shown that the GP becomes active during feeding and that disinhibition of this nucleus, by locally injecting a GABA antagonist, is sufficient to induce feeding in a satiated rat. However, few studies have measured extracellular levels of glutamate during free feeding in the GP of rats. For this reason brain microdialysis coupled to capillary electrophoresis with laser-induced fluorescence was used to determine FTC-glutamate levels, either in the medial or lateral portion of the GP, of freely moving rats. Retrograde labeling of the neurons projecting to the two areas was also examined in an attempt to gain some insight on the identity of the neurons that released glutamate in the GP during feeding. Extracellular levels of glutamate-FTC differentially increased in both portions of the GP during a 2-min interval of free feeding. Retrograde labeling also showed that both areas received projections from different brain areas suggesting that each of the GP portions could be involved in separate aspects of the feeding behavior.

Animals↗

PubMed2003

Independent neuronal oscillators of the rat globus pallidus.

In vivo, neurons of the globus pallidus (GP) and subthalamic nucleus (STN) resonate independently around 70 Hz. However, on the loss of dopamine as in Parkinson's disease, there is a switch to a lower frequency of firing with increased bursting and synchronization of activity. In vitro, type A neurons of the GP, identified by the presence of I(h) and rebound depolarizations, fire at frequencies (<or=80 Hz) in response to glutamate pressure ejection, designed to mimic STN input. The profile of this frequency response was unaltered by bath application of the GABA(A) antagonist bicuculline (10 microM), indicating the lack of involvement of a local GABA neuronal network, while cross-correlations of neuronal pairs revealed uncorrelated activity or phase-locked activity with a variable phase delay, consistent with each GP neuron acting as an independent oscillator. This autonomy of firing appears to arise due to the presence of intrinsic voltage- and sodium-dependent subthreshold membrane oscillations. GABA(A) inhibitory postsynaptic potentials are able to disrupt this tonic activity while promoting a rebound depolarization and action potential firing. This rebound is able to reset the phase of the intrinsic oscillation and provides a mechanism for promoting coherent firing activity in ensembles of GP neurons that may ultimately lead to abnormal and pathological disorders of movement.

Action Potentials↗

PubMed1995

Glucose-sensitive neurons of the globus pallidus: II. Complex functional attributes.

The globus pallidus (GP) is intimately involved in regulation of various aspects of hunger- and thirst-motivated behaviors. Our parallel neurochemical studies demonstrated the existence of GP neurons whose discharge rates are suppressed by glucose applied microelectrophoretically. In the present series of experiments, we aimed to provide complex, feeding-associated functional characterization--similar to that previously accomplished in the case of lateral hypothalamic and amygdaloid chemosensitive neurons--of these glucose-sensitive (GS) and the glucose-insensitive (GIS) pallidal cells. To do so, extracellular single neuron activity of the GP was recorded in anesthetized rats and anesthetized or awake rhesus monkeys by means of carbon fiber, multibarreled glass microelectrodes during: a) microelectrophoretic administration of chemicals, b) gustatory, and c) olfactory stimulations. In alert primates, activity changes were also recorded during presentation of food and nonfood objects as well as during the performance of a conditioned, high fixed-ratio bar-press feeding task. The half of pallidal cells examined showed firing rate changes during phases of the conditioned alimentary task. In both species, about 1/7 of all neurons tested proved to be GS, while the proportion of cells responding to gustatory and olfactory stimulations was 19% and 16%, respectively. Task-related and taste- and smell-responsive units were mainly found among the GS neurons of the pallidum. These data, along with previous findings, indicate that chemosensitive cells of the GP, in an apparent overlap with units of the central gustatory representation, are involved in a hierarchically organized glucose-monitoring neural network, through which pallidal neurons exert their integrative functions in the central feeding control.

Animals↗

PubMed1988

Motor dominance and lateral asymmetry of the globus pallidus.

Animal experiments suggest that neurochemical and anatomic asymmetries exist within the basal ganglia, particularly the globus pallidus, and that these asymmetries correlate with both preferred direction of rotation and limb preference in lever pressing. Human neurotransmitter studies have also revealed a significant asymmetry within the globus pallidus, the left containing greater amounts of dopamine and choline acetyltransferase than the right. Recent anatomic studies of human subcortical regions, limited to the striatum, have failed to show a size asymmetry. We examined 18 normal brains in subjects ranging in age from 26 weeks gestation to 86 years for volumetric asymmetry of the globus pallidus. We found a significant asymmetry, the left side measuring larger in 16 of 18 brains. Considering the role of the basal ganglia in motor control, this data may reflect a structural basis of either axial or limb motor dominance in humans.

Adolescent↗

PubMed2000

Functional mapping of the human globus pallidus: contrasting effect of stimulation in the internal and external pallidum in Parkinson's disease.

Our objective was to elaborate a functional map of the globus pallidus by correlating the intrapallidal localization of quadripolar electrodes implanted in parkinsonian patients with the clinical effect of the stimulation of each contact. Five patients with L-DOPA-responsive Parkinson's disease presenting severe motor fluctuations and L-DOPA-induced dyskinesias were treated by continuous bilateral high-frequency stimulation of the globus pallidus. The effects of stimulation on parkinsonian disability were tested through each of the four stimulating contacts of each electrode. The anatomical localization of each of the stimulating contacts was determined by confronting the pre- and post-operative magnetic resonance imaging with the anatomical atlas of Schaltenbrand and Wharen.(34) The registration procedure comprised digitization of the atlas, the use of deformation tools to fit atlas sections with magnetic resonance imaging sections, and three-dimensional reconstruction of both the atlas and the magnetic resonance imaging sections. Analysis of the 32 stimulating contacts tested did not reveal a somatotopic organization in the pallidal region investigated but demonstrated that high-frequency stimulation had contrasting effects depending on whether it was applied to the external or the internal pallidum. Akinesia was improved by stimulation of the external pallidum but worsened by stimulation of the internal pallidum. In contrast, parkinsonian rigidity was improved by stimulation of either part of the pallidum. The areas in the internal pallidum where stimulation worsened akinesia were those in which stimulation reduced or suppressed L-DOPA-induced dyskinesias. Conversely, stimulation applied to the external pallidum induced dyskinesias. The fact that rigidity was improved by stimulation of the internal and external pallidum suggests that the neuronal bases of parkinsonian rigidity are different from those of akinesia and dyskinesias. The effect on akinesia and dyskinesias is in agreement with the current model of basal ganglia circuitry(10) if high-frequency stimulation activates rather than inhibits pallidal neurons, a possibility which is very likely since there are marked anatomical, biochemical and electrophysiological differences between the globus pallidus and the subthalamic nucleus. This study demonstrates that high-frequency stimulation of the globus pallidus in parkinsonian patients has contrasting effects depending on whether it is applied to the external or the internal part of this nucleus. The effect on akinesia and dyskinesias suggests that stimulation activates pallidal neurons, a result which challenges the generally accepted concept that high-frequency stimulation inactivates neurons in the region stimulated.

Adult↗

PubMed1990

Elevation of Met-enkephalin-like immunoreactivity in the rat striatum and globus pallidus following the focal injection of excitotoxins.

The present study examined the effects of excitotoxins which activate distinct excitatory amino acid (EAA) receptor subtypes on the levels of Methionine-enkephalin-like immunoreactivity (ME-i.r.) in the striatum and globus pallidus, with a view to developing a model of the striatopallidal enkephalin deficit that prevails in Huntington's disease (HD). Each of the 4 excitotoxins, N-methyl-D-aspartate (NMDA, 50-150 nmol), quisqualate (QUIS, 26.5-102 nmol), kainate (KA, 0.5-7 nmol) and quinolinate (QUIN, 18-288 nmol), were unilaterally infused into the right striatum under halothane anaesthesia. Seven days after the injection, levels of ME-i.r. in the ipsilateral and contralateral striatum or globus pallidus were measured by radioimmunoassay (RIA). Injection of each of the 4 excitotoxins produced dose-related and bilateral elevations in ME-i.r. in both brain regions. Generally, the excitotoxin-induced contralateral response mirrored that on the ipsilateral side and the globus pallidus showed a greater change in ME-i.r. levels than did the striatum. The rank order of apparent efficacy for these 4 agents, based on the magnitude of the maximal effect produced by the excitotoxin, was QUIN = KA greater than NMDA = QUIS. In contrast, the rank order of apparent potency, based on the doses producing a maximal effect, was KA greater than QUIS greater than QUIN greater than NMDA. Histological examination of brain sections revealed that in all cases of excitotoxin injection, the dose producing a maximal increase in ME-i.r. was associated with tissue damage in the injection area. However, no tissue damage was apparent in the globus pallidus or the contralateral striatum. To determine the involvement of EAA receptors in the observed elevations of ME-i.r., the action of 3 EAA antagonists was evaluated in co-injection experiments. Kynurenate (KYN), but not CNQX, antagonized the actions of QUIS on pallidal ME-i.r. levels. Both KYN and CPP, a potent NMDA receptor antagonist, blocked the effect of QUIN. The possibility that contralateral changes in the striatum or globus pallidus were due to mobilization of an endogenous EAA was investigated by injection of CPP into the striatum contralateral to the QUIN infusion. This injection of CPP (1.8-3.6 nmol) did not block the QUIN-induced contralateral response, but reduced the elevation in ME-i.r. in the ipsilateral pallidum. Although the excitotoxin-induced changes in ME-i.r. levels do not appear to correspond to the enkephalin deficit seen in HD, such a deficit may be discernible in different parameters of enkephalinergic cell function.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Differential neuronal activity in segments of globus pallidus in Parkinson's disease patients.

Microelectrode trajectories through the globus pallidus of 6 Parkinson's disease (PD) patients yielded neurophysiological 'landmarks' which enabled the identification of neurones located in the external segment (GPe) and internal segments, exterior (GPi,e) and interior (GPi,i) of globus pallidus and the surrounding borders (Bor). Firing rate histograms and inter-spike interval time histograms were constructed for neurones in each region. The neuronal activity in GPi,i was higher than in the other segments, and a high degree of bursting was found in GPe and GPi neurones. This profile of neuronal activity is similar to that observed in monkeys treated with MPTP, suggesting that the observed level of activity of neurones in GPi,i is excessive, and contributes to the bradykinesia and rigidity of PD patients.

Aged↗