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PubMed1998

Serotonergic regulation of neuropeptide and glutamic acid decarboxylase mRNA levels in the rat striatum and globus pallidus: studies with fluoxetine and DOI.

The serotonergic regulation of neuropeptide and glutamic acid decarboxylase (GAD) mRNA level in the rat basal ganglia was investigated by determining the effects of chronic treatment with the serotonin uptake blocker fluoxetine and the serotonin 5-HT2 agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI). Fluoxetine (10 mg/kg) induced a reduction of preproenkephalin and GAD65 mRNA levels in the caudate-putamen and nucleus accumbens core and shell after 5 days of treatment. In addition, GAD65 mRNA levels were reduced in the globus pallidus. These changes appeared to be transient as they were not found after 15 days of fluoxetine treatment. DOI (7 mg/kg), administered for 9 days, induced a decrease of preprodynorphin mRNA levels in the caudate-putamen and the nucleus accumbens core and shell. No regional differentiation in the effects of fluoxetine and DOI was observed. Based on the present results, we propose that an increased 5-HT tone may reduce enkephalin and GABA mRNA levels in striatal regions and in the globus pallidus. Our results further show that preproenkephalin mRNA is not affected by chronic 5-HT2 receptor stimulation, indicating that the fluoxetine-induced decrease in preproenkephalin mRNA levels involves other 5-HT receptors than the 5-HT2 receptor. Preprodynorphin mRNA levels, on the other hand, were found to be reduced after chronic 5-HT2 receptors than stimulation. This observation, together with our previous finding that the 5-HT2 antagonist ritanserin tends to increase preprodynorphin mRNA levels, suggests a 5-HT2-mediated tonic inhibition of preprodynorphin mRNA levels.

Amphetamines↗

PubMed2005

Modulation of torsinA expression in the globus pallidus internus is associated with levodopa-induced dyskinesia in hemiparkinsonian rats.

TorsinA is the causative protein of DYT1 dystonia, a major representative of hyperkinetic movement disorders. In this study, the distribution of torsinA was investigated in the basal ganglia of hemiparkinsonian rats with or without levodopa-induced dyskinesia (LID). Two months after 6-hydroxydopamine (OHDA) treatment, Wistar-albino rats were subjected to intermittent intraperitoneal injection of levodopa/benserazid (LID-group, n=5) or vehicle (control, n=5) for 21 days. Immunohistochemical analysis disclosed that in the caudal portion of the entopeduncular nucleus (EP), homologous to the globus pallidus internus (GPi) in primates, on the parkinsonian side, there was a significant decrease of torsinA-immunopositive neurons in rats with LID, but not in those without LID. However, Nissl-staining showed no loss of GPi neurons in rats with LID. In both groups, there was no significant difference between ipsi- and contralateral sides with respect to the density of torsinA-positive neuronal cells in the striatum, globus pallidus externus, and subthalamic nucleus. Ours are the first data to demonstrate the specific modulation of torsinA expression in the basal ganglia of the hyperkinesia model, suggesting that GPi neurons containing torsinA possess pathologic plasticity for LID.

Animals↗

PubMed2004

Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation-induced cellular defects in the rat striatum and globus pallidus.

This study examined the effects of prolonged (4 days) high frequency stimulation (HFS) of the subthalamic nucleus (STN), in comparison with those of STN lesion, on the dopamine denervation-mediated cellular changes in the basal ganglia in a Wistar rat model of Parkinson's disease. STN HFS counteracted the dopamine lesion-induced increase in GAD67 mRNA expression in the output structures of the basal ganglia, as shown previously after STN lesion, providing cellular support for the similar antiparkinsonian benefits produced by the two surgical procedures. The dopamine denervation-induced increase in GAD67 mRNA levels in the globus pallidus was partially antagonized after HFS and totally reversed after ibotenate-induced STN lesion. The overexpression of striatal enkephalin mRNA tended to be further increased by HFS but was antagonized by STN lesion. The decrease in striatal substance P mRNA levels was affected neither by STN HFS nor lesion. As STN HFS for two hours was previously found not to interfere with the effects of dopamine lesion in the globus pallidus and striatum, the present data provide strong evidence that the effects of STN surgery in these structures involve long-term adaptive processes and that the rearrangements mediated by HFS and lesion are, at least in part, different.

Animals↗

PubMed1998

Effects of full D1 dopamine receptor agonists on firing rates in the globus pallidus and substantia nigra pars compacta in vivo: tests for D1 receptor selectivity and comparisons to the partial agonist SKF 38393.

Many studies have used the D1 agonist SKF 38393 to characterize D1 receptor influences on firing rates in basal ganglia nuclei in vivo. However, SKF 38393 is a partial agonist and so may not be ideal for delineating D1 receptor effects. This study characterizes the effects of four full D1 agonists, SKF 82958 (chloro-APB), SKF 81297 (6-chloro-PB), dihydrexidine and A-77636, on the firing rates of midbrain dopamine and globus pallidus neurons. Recordings were done in fully anesthetized or paralyzed, locally anesthetized rats, and drugs were given systemically intravenously. Dihydrexidine, SKF 81297 and A-77636 were free of rate effects on midbrain dopamine neurons (up to 10.2 mg/kg) and also did not antagonize the inhibitory effects of quinpirole. In contrast, SKF 82958 strongly inhibited dopamine cells through activation of D2 autoreceptors (ED50 = 0.70 mg/kg). Of these drugs, SKF 82958 also was the only one to increase pallidal unit firing rates when given alone (at 5.0 but not 1.0 mg/kg); the other compounds appeared to be selective for postsynaptic D1 receptors. The results suggest that SKF 82958 may be more properly classified as a mixed D1/D2 agonist. In addition, all four agonists strongly potentiated the pallidal response to quinpirole, demonstrating a D1 receptor potentiation of D2 receptor effects. The results support the role of D1 receptors in the midbrain and globus pallidus as previously characterized with SKF 38393. The similar actions of partial and full D1 agonists in these systems support evidence for a D1 receptor reserve and possibly an effector system other than adenylate cyclase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1981

In vivo release of enkephalin from the globus pallidus.

Push-pull cannulae were acutely positioned through previously implanted guides in the globus pallidus of unanesthetized freely moving cats and rats. During slow-flow perfusions, enkephalin release was detected in resting conditions and increased more than 3-fold when both 50 mM K+ and 1.8 mM Ca2+ were present in the perfusing medium. Local perfusion with veratrine also enhanced enkephalin release. Furthermore, in vivo, electrical stimulation of the rat caudo-putamen enhanced enkephalin release in the pallidum. This latter finding is consistent with a functional strio-pallidal enkephalin-containing pathway previously postulated by immunohistochemical or lesion experiments.

Animals↗

PubMed2004

Severity of negative symptoms in schizophrenia correlated to hyperactivity of the left globus pallidus and the right claustrum. A PET study.

Schizophrenia has been characterized as a complex disease, in which various cerebral regions may be affected. The purpose of this study was to compare the cerebral regions that are involved in mild and severe negative symptoms, and to determine whether the degree of severity can be related to specific dysfunctional areas of the brain. The PANS Scale was used to form two groups of patients with prevalence of negative symptoms: Mildly Affected (MA), and Severely Affected (SA). Brain PETs were obtained in resting conditions, and SPM (Statistical Parametric Mapping) was used to perform statistical comparisons. The MA-group showed increased activity in: posterior cingulate gyrus, middle frontal gyrus, precentral gyrus, middle occipital gyrus, cuneus and post-central gyrus; decreased activity in inferior frontal gyrus, orbitofrontal and fusiform gyrus. The SA-group showed increased activity in: globus pallidus, insular cortex, cuneus, claustrum, post-central gyrus and pre-central gyrus; decreased activity in fusiform gyrus and superior temporal gyri. These results permit correlation of negative symptomatology with abnormalities in the cortico-striato-pallido-thalamic neural circuit. Severity of negative symptoms is clearly correlated to abnormal left external pallidal activation, evidencing the relevance of this nucleus for cognitive, planning and social capabilities. Specific therapeutic strategies might be derived from pallidal neurotransmitter systems studies. Key words: schizophrenia, negative symptoms, severity, PET, globus pallidus, claustrum.

Adolescent↗

PubMed1999

Tremor-frequency (3-6 Hz) activity in the sensorimotor arm representation of the internal segment of the globus pallidus in patients with Parkinson's disease.

Neurons in the internal segment of the globus pallidus (GPi) oscillate at approximately the frequency of parkinsonian tremor. However, the correlation of that activity with tremor has not previously been studied. We now describe the relationship between single neuron activity in the arm sensorimotor portion of GPi and upper extremity tremor in patients with Parkinson's disease. There was a significant concentration of power in the tremor-frequency range (3-6 Hz) for 11/44 GPi neurons. However, pallidal tremor-frequency activity correlated significantly with electromyogram (EMG) activity during tremor for only a single GPi neuron. These data are most consistent with the hypothesis that the output of neurons in GPi is transformed in thalamus by a non-linear mechanism, before transmission via the cortex to the spinal motorneurons that drive movement.

Brain Mapping↗

PubMed2000

Long-term follow-up study of chronic globus pallidus internus stimulation for posttraumatic hemidystonia.

The authors report the first case of chronic globus pallidus internus (GPi) stimulation for treatment of medically intractable hemidystonia for which long-term follow-up data are available. The patient had developed left-sided low-frequency tremor and hemidystonia after a severe head trauma sustained at 15 years of age. He experienced relief of the tremor but not of the hemidystonia after a thalamotomy was performed in the right hemisphere 3 years postinjury. When the patient was 24 years old, the authors performed a magnetic resonance-guided stereotactic implantation of a monopolar electrode in the right-sided posteroventral GPi. Chronic deep brain stimulation resulted in remarkable improvement of dystonia-associated pain, phasic dystonic movements, and dystonic posture, which was accompanied by functional gain. Postoperative improvement was sustained after 4 years of follow up. Chronic GPi stimulation appears to be a valuable treatment option for posttraumatic dystonia.

Adult↗

PubMed2003

Activation of group III metabotropic glutamate receptors presynaptically reduces both GABAergic and glutamatergic transmission in the rat globus pallidus.

To investigate the role of group III metabotropic glutamate receptors (mGluRs) in the globus pallidus (GP), whole-cell recordings were performed using rat brain slice preparations. Application of the group III mGluRs specific agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) suppressed the amplitude of striatal stimulation-induced IPSCs and internal capsule stimulation-induced EPSCs in most of the GP neurons that were capable of generating repetitive firing without spike accommodation. The suppression of IPSCs and EPSCs was accompanied by an increase in the paired-pulse ratio. The L-AP4 effects were antagonized by (R,S)-alpha-cyclopropyl-4-phosphophenylglycine, a blocker for group II/III mGluRs. L-AP4 reduced the frequency of mIPSCs and mEPSCs without changing their amplitude distribution. L-AP4 failed to change iontophoretic glutamate induced responses. These results suggest that the subthalamo-pallidal glutamatergic input might homo- and hetero-synaptically control GABAergic and glutamatergic transmission in the GP.

Animals↗

PubMed1983

Neuronal responses to 5-hydroxytryptamine and dorsal raphe stimulation within the globus pallidus of the rat.

The projection from the dorsal raphe nucleus (DRN) to the globus pallidus (GP) was investigated electrophysiologically, in the urethane-anesthetized rat together with the responsiveness of cells in the GP to 5-hydroxytryptamine (5-HT) and noradrenaline (NA). The majority of spontaneously active cells in the GP had high regular firing rates. They were unaffected by both DRN stimulation (69/83 cells) and iontophoretically applied 5-HT (38/63 units) or NA (30/42 units) but were inhibited by GABA. A few cells (N = 10) were recorded from, that were spontaneously active but with a much lower and less regular firing rate, which, however, seemed to be much more responsive to 5-HT. In addition, DL-homocysteic acid (DLH) was used to activate silent cells and all seven cells activated in this manner were inhibited by 5-HT. In addition 5/6 cells that had their firings maintained by DLH were inhibited by stimulation of the dorsal raphe. The results show a lack of responsiveness to both 5-HT and DRN stimulation of the typically regular spontaneously active pallidal neurons. There seems to be a small population of normally quiescent cells, however, that is sensitive to 5-HT and receives an input from the DRN.

Animals↗

PubMed1995

A defective control of small-amplitude movements in monkeys with globus pallidus lesions: an experimental study on one component of pallidal bradykinesia.

The effects of globus pallidus (GP) lesion were examined in two monkeys trained to perform a visually guided pointing movement in simple and choice reaction time tasks involving small and large amplitude movements. The reaction time (RT) and the movement time (MT) were measured. The Y-axis error (EY) was also analyzed in order to assess the movement accuracy. Unilateral GP lesion was made by locally injecting an excitatory amino acid, quisqualic acid. GP lesion led to little change in the RTs (simple and choice RTs) and in the EY, whereas a large increase in the MT occurred. The MT impairments seem to have been correlated with the movement amplitude, since they were larger in the case of small-amplitude than large-amplitude movements. These results suggest that the GP may be involved in the control of small-amplitude rather than large-amplitude movements. As various studies have shown that proprioceptive cues are more strongly involved in the control of discrete than large-amplitude movements, the MT deficit, i.e., the bradykinesia observed here, may reflect a defective integration of proprioceptive information occurring after GP lesion.

Animals↗

PubMed1995

D1 dopamine receptors influence Fos immunoreactivity in the globus pallidus and subthalamic nucleus of intact and nigrostriatal-lesioned rats.

Studies of the globus pallidus (GP) and subthalamic nucleus (STN) have emphasized the role of D2 dopamine receptors, although effects of D1 receptor activation on GP firing rate and STN metabolism have been reported, especially in rats with nigrostriatal lesions. This study systematically investigated the effects of D1 and D2 receptor activation on the activity of the GP and STN in intact and 6-OHDA-lesioned rats using immunostaining for the immediate-early gene Fos. In intact rats, the D1 agonist SKF 38393 (20.0 mg/kg) produced a five-fold potentiation of the GP Fos expression due to the D2 agonist quinpirole produced significant Fos expression. In rats with prior nigrostriatal lesions, SKF 38393 (4.0 or 20.0 mg/kg) increased Fos immunostaining in both the GP and STN, while quinpirole increased it only in the GP. SKF 38393 effects in the GP and STN of nigrostriatal-lesioned rats were blocked completely by SCH 23390, and unaffected by eticlopride. These results are a novel demonstration of control of Fos expression by dopaminergic drugs in the STN and by D1 agonists in the GP.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1982

An autoradiographic study of efferent connections of the globus pallidus in Macaca mulatta.

Radioactive amino acids were injected into restricted regions of the globus pallidus of rhesus macaques to allow identification of the organization and courses of efferent pallidal projections. The previously identified projection of the internal pallidal segment (GPi) to ventral thalamic nuclei showed a topographic organization, with the predominant projection from ventral GPi being to medial and caudal ventralis anterior (VA) and lateralis (VL) and from dorsal GPi to lateral and rostral VA and VL. Pallidal efferent fibers also extended caudally and dorsally into pars caudalis of VL, but they spared the portion of pars oralis of VL shown by others to receive input from the cerebellum. In addition to centromedian labeling in all animals, the parafascicular nucleus was also labeled when isotope was injected into dorsal GPi. The medial route from GPi to the midbrain tegmentum was more substantial than has been shown before, and along this route there was an indication that some fibers terminated in the prerubral region. The projection to the pedunculopontine nucleus was extensive, and fibers continued caudally into the parabrachial nuclei. Pallidal projections to the thalamus seem to be topographically organized but spare thalamic regions that interact with area 4. Caudally directed efferent fibers follow multiple routes and extend more caudally than to the pedunculopontine nuclei.

Animals↗

PubMed1995

Double dissociation of passive avoidance and milk maze performance deficits with discrete lesions of substantia innominata or globus pallidus of rats.

In three experiments, small bilateral lesions of the substantia innominata (SI), globus pallidus (GP) and central nucleus of the amygdala (ACe) produced deficits in passive avoidance of drinking (dPA) or escape performance in a milk maze (MM). Severe deficits in dPA were produced by electrolytic lesions in lateral SI or rostral ACe, and by electrolytic or ibotenic acid lesions in the heart of the SI. Such lesions produced no effects on MM performance. Lesions of the rostral SI produced no, or mild, deficits in dPA and MM performance. However, lesions of the rostral GP produced an extreme deficit in MM performance but not dPA. The milder MM deficits produced by rSI lesions appeared to reflect a spatial navigation deficit, while the more severe impairment produced by rGP lesions appeared to represent a broader disruption of instrumental behavior. SI lesions also produced a temporary cessation of drinking and a chronic decrease in body weight, both of which were associated with impaired oromotor function. Eating and drinking deficits were less severe when lesions were more lateral or rostral in SI, and absent with lesions in rostral GP or amygdala. The most important finding, however, was a double dissociation of MM performance deficits following rostral GP lesions versus passive avoidance deficits produced by SI lesions.

Animals↗

PubMed1999

Reversal of experimental parkinsonism by using selective chemical ablation of the medial globus pallidus.

OBJECT: Symptoms from Parkinson's disease improve after surgical ablation of the medial globus pallidus (GPm). Although, in theory, selective chemical ablation of neurons in the GPm could preserve vital structures jeopardized by surgery, the potential of this approach is limited when using traditional techniques of drug delivery. The authors examined the feasibility of convection-enhanced distribution of a neurotoxin by high-flow microinfusion to ablate the neurons of the GPm selectively and reverse experimental Parkinson's disease (akinesia, tremor, and rigidity). METHODS: Initially, to test the feasibility of this approach, the GPms of two naive rhesus macaques were infused with kainic acid or ibotenic acid through two cannulas that had been placed using the magnetic resonance imaging-guided stereotactic technique. Two weeks later the animals were killed and their brains were examined histologically to determine the presence of neurons in the GPm and the integrity of the optic tract and the internal capsule. To examine the therapeutic potential of this paradigm, unilateral experimental Parkinson's disease was induced in six macaques by intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and their behavior was studied for 12 weeks after chemopallidotomy was performed using kainic acid (three animals) or control infusion (three animals). CONCLUSIONS: Chemopallidotomy using kainic acid permanently reversed the stigmata of MPTP-induced parkinsonism. By contrast, the control animals exhibited a transient recovery following intrapallidal infusion and then relapsed back to their baseline state. The use of high-flow microinfusion of selectively active toxins has the potential for treatment of Parkinson's disease and, by expanding the range of approachable targets to include large nuclei, for broad applications in clinical and experimental neuroscience.

Animals↗

PubMed1989

Effects of excitotoxic lesions of the substantia innominata, ventral and dorsal globus pallidus on visual discrimination acquisition, performance and reversal in the rat.

Rats received infusions of ibotenic acid into the substantia innominata, in the region of the nucleus basalis of Meynert (nbM), before and after training on simple (simultaneous) and conditional visual discriminations. The ibotenate infusions reduced cortical choline acetyltransferase (ChAT) levels by about 20%, destroyed many ChAT-immunoreactive neurons in the nbM, but also caused the loss of many neurons in the substantia innominata and adjacent areas. These lesions did not impair the acquisition and performance of a simple visual discrimination, but did impair reversal of the discrimination and the performance of a conditional visual discrimination. However, the degree of impairment was unrelated to the degree of cortical ChAT loss. Ibotenic acid lesions to the dorsal globus pallidus also impaired reversal of discrimination but left acquisition and performance unaffected. Striatal dopamine depletion produced by 6-hydroxydopamine (6-OHDA) infusions into the mid-ventral caudate nucleus impaired performance of the simultaneous visual discrimination. Cortical noradrenaline depletion produced by 6-OHDA lesions of the dorsal noradrenergic bundle either alone or in combination with ibotenic acid lesions of the substantia innominata had no effect on acquisition of the discrimination. It is concluded that ibotenic acid lesions of the substantia innominata or to the dorsal globus pallidus affect learning and performance of conditional visual discrimination performance and impair reversal learning without affecting the capacity to discriminate visual events. These results are compared to those following cortical noradrenaline depletion or striatal dopamine loss.

Animals↗

PubMedDate not supplied

Iron-induced susceptibility effect at the globus pallidus causes underestimation of flow and volume on dynamic susceptibility contrast-enhanced MR perfusion images.

BACKGROUND AND PURPOSE: Age-related iron accumulation in extrapyramidal nuclei causes T2 shortening, which may result in decreased signal intensity in these areas on MR images. Because the dynamic susceptibility contrast-enhanced technique uses heavily T2*- or T2-weighted images, the iron-induced susceptibility may have direct impact on perfusion imaging. The purpose of this study was to assess the effect of iron-induced susceptibility on the calculated perfusion parameters. The difference of this effect between gradient-echo and spin-echo sequences was also assessed. METHODS: Dynamic susceptibility contrast-enhanced MR perfusion imaging data of 12 patients were used for this study. Perfusion images were obtained using a single shot spin-echo echo-planar imaging sequence in seven patients and a gradient-echo echo-planar imaging sequence in five patients. Region of interest measurements of relative cerebral blood flow, relative cerebral blood volume, and mean transit time were obtained at various parts of the gray matter, including the globus pallidus, putamen, caudate nucleus, thalamus, and cerebral cortex of temporal, frontal, and occipital lobes. The baseline signal intensity on the source images and the magnitude of signal change (DeltaR2* or DeltaR2) were also assessed. RESULTS: The globus pallidus had statistically significantly lower values of relative cerebral blood flow, relative cerebral blood volume, baseline signal intensity, and magnitude of signal change compared with other parts of the gray matter for both gradient-echo and spin-echo sequences (P <.05). Underestimations of these values were more prominent for the gradient-echo than for the spin-echo sequence. Little variance in the measured mean transit time was noted. CONCLUSION: Iron-induced susceptibility effect may lead to underestimation of relative cerebral blood flow and relative cerebral blood volume in the basal ganglia.

Aged↗

PubMed1996

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 alpha-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.

Afferent Pathways↗