Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Parkinson's disease, changes in GABAergic activity occurring downstream of the striatal dopamine loss are accompanied by reciprocal changes in GABA(A) receptor binding, the underlying molecular mechanisms for which are unknown. This study examined whether changes in expression of the genes encoding known GABA(A) receptor subunits (alpha(1-4), beta(1-3), gamma(1-3) and delta) could account for this receptor plasticity using a rodent model of Parkinson's disease with a 6-hydroxydopamine-induced nigrostriatal lesion. Analysis of autoradiograms of the basal ganglia and thalamus revealed changes in expression of only four of the 11 subunits studied. Expression of alpha1 and beta2 subunit genes was altered in a parallel manner following a 6-hydroxydopamine lesion; messenger RNA levels for both were significantly increased in the substantia nigra pars reticulata (11 +/- 4% and 17 +/- 1%, respectively), and significantly reduced in the globus pallidus (18 +/- 3% and 16 +/- 3%, respectively) and parafascicular nucleus (19 +/- 3% and 16 +/- 5%, respectively). Smaller changes in the messenger RNA levels encoding the alpha1 subunit in the lateral amygdala (8 +/- 1% decrease) and the alpha4 and gamma2 subunits in the striatum (10 +/- 2% and 6 +/- 1% increase, respectively) were also observed. No changes in expression were noted for any other subunits in any region studied. Clearly, both region- and subunit-specific regulation of GABA(A) receptor subunit gene expression occurs following a nigrostriatal tract lesion. The changes in expression of the alpha1 and beta2 subunit genes probably contribute to the documented changes in GABA(A) receptor binding following striatal dopamine depletion. Moreover, they provide a molecular basis by which the pathological changes in GABAergic activity in Parkinson's disease may be partially compensated.
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PMID:Effect of unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway on GABA(A) receptor subunit gene expression in the rodent basal ganglia and thalamus. 1061 68

Reciprocally connected glutamatergic subthalamic and GABAergic globus pallidus neurons have recently been proposed to act as a generator of low-frequency oscillatory activity in Parkinson's disease. To determine whether GABA(A) receptor-mediated synaptic potentials could theoretically generate rebound burst firing in subthalamic neurons, a feature that is central to the proposed oscillatory mechanism, we determined the equilibrium potential of GABA(A) current (E(GABA(A))) and the degree of hyperpolarization required for rebound firing using perforated-patch recording. In the majority of neurons that fired rebounds, E(GABA(A)) was equal to or more hyperpolarized than the hyperpolarization required for rebound burst firing. These data suggest that synchronous activity of pallidal inputs could underlie rhythmic bursting activity of subthalamic neurons in Parkinson's disease.
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PMID:Equilibrium potential of GABA(A) current and implications for rebound burst firing in rat subthalamic neurons in vitro. 1080 13

By using an animal model of parkinsonism, we examined the expression of GABA(A) receptor (R) and metabotropic glutamate receptor (mGluR) 5 in the basal ganglia after transplantation with dopamine-rich tissue. The adult rats were unilaterally lesioned by the injection of 6-hydroxydopamine to their left medial forebrain bundles. At 5-10 weeks following the dopaminergic denervation, the levels of GABA(A)R in the left caudate-putamen and globus pallidus were about 20 and 16% lower than that of the right intact (control) sides, as shown by [3H]flunitrazepam binding autoradiography on the brain sections. However, the receptor density increased to around 132 and 130% of control levels in the entopeduncular nucleus and substantia nigra pars reticulata of the lesioned sides. Furthermore, in situ hybridization analysis exhibited parallel trends of changes in the levels of the GABA(A)R alpha1 and alpha2 subunit and mGluR5 mRNAs in the neurons of the brain regions with that of the proteins detected by the binding assay. A number of the rats 5 weeks postlesion were transplanted with the ventral mesencephalon of the embryonic rat into their left striata. Five weeks later, the changes in the [3H]flunitrazepam binding seemed to be recovered by approximately 50-63% on the grafted sides of the areas. Moreover, the transplantation appeared to produce a nearly complete reversal of the lesion-induced alterations in the levels of the mRNAs. Thus, the data indicate the mechanism of gene regulation for the modified expression of the receptors and could implicate the participation of the receptors in the pathogenesis of Parkinson's disease.
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PMID:Changes in the gene expression of GABA(A) receptor alpha1 and alpha2 subunits and metabotropic glutamate receptor 5 in the basal ganglia of the rats with unilateral 6-hydroxydopamine lesion and embryonic mesencephalic grafts. 1125 11

The subthalamic nucleus (STN) influences the output of the basal ganglia, thereby interfering with motor behavior. The main inputs to the STN are GABAergic. We characterized the GABA(A) receptors expressed in the STN and investigated the response of subthalamic neurons to the activation of GABA(A) receptors. Cell-attached and whole cell recordings were made from rat brain slices using the patch-clamp technique. The newly identified epsilon subunit confers atypical pharmacological properties on recombinant receptors, which are insensitive to barbiturates and benzodiazepines. We tested the hypothesis that native subthalamic GABA(A) receptors contain epsilon proteins. Applications of increasing concentrations of muscimol, a selective GABA(A) agonist, induced Cl(-) and HCO currents with an EC(50) of 5 microM. Currents induced by muscimol were fully blocked by the GABA(A) receptor antagonists, bicuculline and picrotoxin. They were strongly potentiated by the barbiturate, pentobarbital (+190%), and by the benzodiazepines, diazepam (+197%) and flunitrazepam (+199%). Spontaneous inhibitory postsynaptic currents were also significantly enhanced by flunitrazepam. Furthermore, immunohistological experiments with an epsilon subunit-specific antibody showed that the epsilon protein was not expressed within the STN. Native subthalamic GABA(A) receptors did not, therefore, display pharmacological or structural properties consistent with receptors comprising epsilon. Burst firing is a hallmark of Parkinson's disease. Half of the subthalamic neurons have the intrinsic capacity of switching from regular-firing to burst-firing mode when hyperpolarized by current injection. This raises the possibility that activation of GABA(A) receptors might trigger the switch. Statistical analysis of spiking activity established that 90% of intact neurons in vitro were in single-spike firing mode, whereas 10% were in burst-firing mode. Muscimol reversibly stopped recurrent electrical activity in all intact neurons. In neurons held in whole cell configuration, membrane potential hyperpolarized by -10 mV whilst input resistance decreased by 50%, indicating powerful membrane shunting. Muscimol never induced burst firing, even in neurons that exhibited the capacity of switching from regular- to burst-firing mode. These molecular and functional data indicate that native subthalamic GABA(A) receptors do not contain the epsilon protein and activation of GABA(A) receptors induces membrane shunting, which is essential for firing inhibition but prevents switching to burst-firing. They suggest that the STN, like many other parts of the brain, has the physiological and structural features of the widely expressed GABA(A) receptors consisting of alphabetagamma subunits.
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PMID:Activation of GABA(A) receptors in subthalamic neurons in vitro: properties of native receptors and inhibition mechanisms. 1143 89

Inactivation of neurones in the subthalamic nucleus (STN) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated monkey model of Parkinson's disease has been shown to relieve parkinsonian motor symptoms. In patients with Parkinson's disease, neurones in the STN display hyperactive firing rates and rhythmic discharge activity such as tremor-related oscillations (3-8 Hz) and synchronous high-frequency oscillations (15-30 Hz). In this study, microinjections of lidocaine (n = 4) and muscimol, a GABA(A) receptor agonist (n = 2), were performed in the STN of six patients with Parkinson's disease to determine whether the focal suppression of STN neuronal activity can lead to an improvement in tremor, bradykinesia and rigidity. We also report the first use of microelectrode recording of the effects of microinjections on neuronal activity in the human brain (n = 2). Microinjections of 10-23 microl of lidocaine produced striking improvements in bradykinesia, limb tremor and rigidity in three out of three patients. These improvements were correlated with good therapeutic effects of subsequent STN deep brain stimulation performed in the same microelectrode trajectories as these injections. The most dramatic observation following lidocaine injections was the appearance of dyskinetic limb movements. In one patient, simultaneous microelectrode recording during an injection of 3.5 microl of lidocaine demonstrated a suppression of neuronal activity at distances of < 0.9 mm from the injection site, but no suppression was observed at > or = 1.2 mm from the injection site. Microinjections of 5-10 microl of muscimol in a region with tremor-related activity resulted in suppression of limb tremor in two out of two patients. Interestingly, in one of these patients, 4 Hz oscillatory activity was diminished in a neurone recorded 1.3 mm from the injection site, but there was no reduction in the mean firing rate or 20 Hz oscillatory activity. These results demonstrate that inactivation of neuronal activity in the STN of patients with Parkinson's disease improves motor symptoms. These findings also suggest that a focal block of the STN might alter the oscillatory activity of neurones located beyond the inhibited region.
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PMID:Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. 1157 Dec 26

The gamma-aminobutyric acid A (GABA(A)) receptor subunit expression of the dopaminergic cells of the substantia nigra (SN) was investigated in the present study. Especially the dopaminergic cells, located in the pars compacta of SN (SNc), are of great neurologic interest, because the functional deficit and depletion of these cells are the correlate of Parkinson's disease. We used a combination of in situ hybridization histochemistry (ISH) and immunohistochemistry (IHC) on sections of human postmortem mesencephalon to investigate the expression of GABA(A) receptor subunit messenger RNAs (mRNAs) and of the receptor protein in dopaminergic SN cells. Immunohistochemical detection of tyrosine hydroxylase (TH), the pivotal enzyme of dopamine synthesis, was used to define the boundaries of SN pars reticulata (SNr) and pars compacta subregions. In SNr, all neurons were labeled by subunit-specific oligonucleotide probes and the amount of GABA(A) receptor mRNA expression was quantified as alpha(1) = beta(2) > gamma(2) > alpha(3). In contrast, in SNc, only around 25% of neurons expressed mRNA transcripts of GABA(A) receptor subunits, quantified as alpha(1) = beta(2) > gamma(2) > alpha(3) > alpha(4) = beta(3). In approximately the same percentage of neurons, which were labeled by alpha(1)-subunit-specific probe, the alpha(1)-subunit also was detected at the protein level by a specific monoclonal antibody. We, therefore, could demonstrate that a subset of dopaminergic neurons in human SNc receive inhibitory synaptic input by means of GABA(A) receptors mainly of the alpha(1)beta(2)gamma(2) subtype. This might represent a negative feedback loop between the striatum and the SNc and be a target of pharmacologic interventions in neurodegenerative diseases such as Parkinson's disease.
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PMID:Human GABA A receptors on dopaminergic neurons in the pars compacta of the substantia nigra. 1235 18

High frequency stimulation (HFS) of deep brain regions such as globus pallidus internus or subthalamic nucleus can reverse Parkinson's symptoms probably through activation of gamma-aminobutyric acid (GABA)ergic neurotransmission. To prove the hypothesis, rat striatal slices were stimulated electrically (130 Hz) in vitro and dopamine (DA) outflow was measured using high performance liquid chromatography. HFS induced an attenuation in basal DA release in perfusate. Veratridine-induced DA outflow was blocked by the simultaneous application of HFS. Addition of bicuculline, a GABA(A) receptor antagonist, reversed the effect of HFS on DA outflow. In addition, destruction of striatal GABAergic neurons with kainic acid also reversed the effect of HFS. In conclusion, our present data provide strong evidence that HFS does not only need presynaptic GABA(A) receptors but also intact GABAergic nerve terminals coupled to GABA(A) receptors to exert an inhibitory effect and give a rationale of HFS effectiveness in the treatment of Parkinson's disease.
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PMID:Deep brain stimulation: response to neuronal high frequency stimulation is mediated through GABA(A) receptor activation in rats. 1267 43

Several years ago ubiquitin immunocytochemistry first demonstrated that ubiquitin protein conjugates are present in intraneuronal inclusions in all the major human chronic neurodegenerative diseases, as well as in inclusions in cerebellar astrocytomas and in hepatocytes in alcoholic liver disease. Unexpectedly, further studies showed that Lewy bodies are present in the cortex. Lewy bodies were originally described in the brain stem and are pathogonomic in the neuropathological diagnosis of Parkinson's disease. A balanced interpretation of further elegant experimental approaches, including transgenesis, suggests that the formation of intraneuronal inclusions is cytoprotective. Putative oligomeric proaggregates (prefibrillar entities) of cellular proteins inhibit the 26S proteasome and promote apoptosis. In the last few years a clutch of distinct experimental approaches have focused on the roles of ubiquitin-related processes in the development of the nervous system and neurohomeostasis. It is now clear that the ubiquitin/proteasome system (UPP) has a pivotal role in synaptogenesis, the formation of neuromuscular junctions and neurotransmitter receptor function. The inhibitory GABA(A) receptor, alpha1 glycine receptor, beta(2)-adrenergic receptor and arrestin, opiate receptors and the excitatory metabotropic glutamate receptor (mGluR1alpha) are regulated by the UPP. It is also increasingly clear that the regulation of long-term synaptic plasticity, and therefore memory, is dependent on both protein synthesis and protein degradation. Therefore, for the first time we have the opportunity to dissect the substrate of memory and the basis of cognitive decline in aging and in chronic neurodegenerative disease. Clearly, further understanding will provide a platform for novel drug development to treat chronic neurodegenerative diseases, including Alzheimer- and Parkinson-related conditions, and possibly psychiatric disorders.
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PMID:From neurodegeneration to neurohomeostasis: the role of ubiquitin. 1279 71

Previously, we have shown that GABA(A) receptors and glutamate receptors in substantia nigra play distinct roles in the regulation of somatodendritic dopamine release. GABAergic input to substantia nigra was found to be the primary determinant of the level of spontaneous somatodendritic dopamine release. In contrast, acute blockade of dopamine receptors by systemic haloperidol administration produced an increase in somatodendritic dopamine release in substantia nigra that was found to be dependent exclusively upon activation of nigral glutamate receptors. The focus of the present study was to identify anatomical structures that may participate in the differential regulation of somatodendritic dopamine release by GABA and glutamate under these two conditions. To this end, we pharmacologically inhibited the activity of either globus pallidus or subthalamic nucleus using microinfusion of the GABA(A) receptor agonist muscimol. The effects of these manipulations on spontaneous efflux of somatodendritic dopamine and on increases in this measure produced by systemic haloperidol administration were determined in ipsilateral substantia nigra using in vivo microdialysis. As observed previously, administration of haloperidol (0.5 mg/kg, i.p.) significantly increased extracellular dopamine in substantia nigra. Microinfusion of muscimol (400 ng/200 nl) into globus pallidus also produced a significant increase in somatodendritic dopamine efflux. When haloperidol was administered systemically in conjunction with microinfusion of muscimol into globus pallidus, an increase in nigral dopamine efflux was observed that was significantly greater than that which was produced singly by muscimol microinfusion into globus pallidus or by systemic haloperidol administration. The additive nature of the increases in somatodendritic dopamine release produced by these two manipulations indicates that independent neural circuitries may be involved. Inactivation of subthalamic nucleus by microinfusion of muscimol (200 ng/100 nl) had no effect on spontaneous somatodendritic dopamine efflux. Muscimol application into subthalamic nucleus, however, completely abolished the stimulatory effect of systemic haloperidol on dendritic dopamine efflux in substantia nigra. The present data extend our previous findings by demonstrating: 1) an important involvement of globus pallidus efferents in the GABAergic regulation of somatodendritic dopamine efflux in substantia nigra under normal conditions and, 2) an emergent predominant role of subthalamic nucleus efferents in the glutamate-dependent increase in somatodendritic dopamine efflux observed after systemic haloperidol administration. Thus, the relative influence of globus pallidus and subthalamic nucleus in the determination of the level of somatodendritic dopamine release in substantia nigra qualitatively varies as a function of dopamine receptor blockade. These findings are relevant to current models of basal ganglia function under both normal and pathological conditions, e.g. Parkinson's disease.
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PMID:Relative involvement of globus pallidus and subthalamic nucleus in the regulation of somatodendritic dopamine release in substantia nigra is dopamine-dependent. 1280 98

In Parkinson's disease the neurones of the subthalamic nucleus show increased synchrony and oscillatory burst discharge, thought to reflect a breakdown of parallel processing in basal ganglia circuitry. To understand better the mechanisms underlying this transition, we sought to mimic this change in firing pattern within sagittal slices of rat midbrain. The firing patterns of up to four simultaneously extracellularly recorded subthalamic nucleus (STN) neurones were analysed using burst and oscillation detection programs, and correlated activity between pairs of neurones assessed. In control conditions all but 11 of 488 (2%) neurones fired in a predominantly tonic pattern (with mean oscillation frequency >3 Hz), with no significantly cross-correlated activity in any of 393 pairs of neurones. The glutamate antagonists DL-2-amino-phosphonopentanoic acid (APV), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-methyl-2-(phenylethynyl)pyridine (MPEP) did not change the firing rate or pattern of these cells, providing no evidence for a role of glutamatergic collaterals within the STN under these conditions. The GABA(A) receptor antagonist bicuculline and GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl]phenylmethyl phosphinic acid (CGP 55845) were also without effect on firing rate or pattern in these cells, suggesting that there was no active input from other GABAergic basal ganglia nuclei in this slice. The dopamine receptor antagonist haloperidol caused no significant change to firing rate or pattern of firing in these cells, suggesting that there was no active dopaminergic input in this slice. Excitations of STN neurones by muscarine, (+)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), N-methyl-D-aspartic acid (NMDA) or dopamine were all unaccompanied by a change in firing pattern or any significant correlated activity between STN neurone pairs. Burst firing could be induced in STN neurones with either the potassium channel blocker tetraethylammonium (TEA; 10 mM; in 100/138 [72%] of cells) or with a combination of NMDA and the calcium-activated potassium channel blocker apamin (in 101/216 [47%] of cells). Burst firing in TEA was unchanged by CNOX and APV, MPEP, CGP55845, haloperidol, dopamine, and ACPD, although muscarine produced a significant increase in oscillation frequency. Burst firing in NMDA and apamin was unchanged by CNQX and APV, dopamine, muscarine and ACPD, although bicuculline caused a significant increase in oscillation frequency. Such burst firing was not accompanied by synchrony in any condition, either alone, or during application of excitatory agents or glutamate or GABA antagonists. As the bursting seen here was unaccompanied by the synchronous activity that has often been observed (pathologically) in vivo, it probably reflects solely intrinsic STN neuronal properties, rather than network activity. No functional role was found for glutamatergic collaterals within the STN, either when cells are firing tonically or burst firing. The circuitry needed to produce synchrony in the STN is most likely not intrinsic to the STN itself, but requires connections with other basal ganglia nuclei, and/or the cortex, which are not present in this preparation.
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PMID:Overwhelmingly asynchronous firing of rat subthalamic nucleus neurones in brain slices provides little evidence for intrinsic interconnectivity. 1466 53


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