GABAergic neurotransmission in globus pallidus and its involvement inneurologic disorders

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Journal Title:
Volume 56, Issue 04, 2004
Key Word:
globus pallidus;GABA;Parkinson's disease;seizure

Abstract: The globus pallidus occupies a critical position in the ‘indirect' pathway of the basal ganglia and, as such, plays an important role in the modulation of movement. In recent years, the importance of the globus pallidus in the normal and malfunctioned basal ganglia is emerging. However, the function and operation of various transmitter systems in this nucleus are largely unknown. GABA is the major neurotransmitter involved in the globus pallidus. By means of electrophysiological recording, immunohistochemistry and behavioral studies, new information on the distribution and functions of the GABAergic neurotransmission in the rat globus pallidus has been generated. Morphological studies revealed the existence of GABAA receptor, including its benzodiazepine binding site, and GABAB receptor in globus pallidus. At subcellular level, GABAA receptors are located at the postsynaptic sites of symmetric synapses (putative GABAergic synapses). However, GABAB receptors are located at both pre- and postsynaptic sites of symmetric, as well as asymmetric synapses (putative excitatory synapses). Consistent with the morphological results, functional studies showed that activation of GABAB receptors in globus pallidus reduces the release of GABA and glutamate by activating presynaptic auto- and heteroreceptors, and hyperpolarizes pallidal neurons by activating postsynaptic receptors. In addition to GABAB receptor, activation of GABAA receptor benzodiazepine binding site and blockade of GABA uptake change the activity of globus pallidus by prolonging the duration of GABA current. In agreement with the in vitro effect, activation of GABAB receptor, GABAA receptor benzodiazepine binding site and blockade of GABA uptake cause rotation in behaving animal. Furthermore, the GABA system in the globus pallidus is involved in the etiology of Parkinson's disease and regulation of seizures threshold. It has been demonstrated that the abnormal hypoactivity and synchronized rhythmic discharge of globus pallidus neurons associate with akinesia and resting tremor in parkinsonism. Recent electrophysiological and behavioral studies indicated that the new anti-epileptic drug, tiagabine, is functional in globus pallidus, which may present more information to understand the involvement of globus pallidus in epilepsy.

  • [1]Albin RL, Young AB, Penny JB. The functional anatomy of basal ganglia disorders. Trends Neurosci 1989; 12:366-375.
  • [2]Naito A, Kita H. The cortico-pallidal projection in the rat: an anterograde tracing study with biotinylated dextran amine. Brain Res 1994; 653:251-257.
  • [3]Bolam JP, Hanley JJ, Booth PA, Bevan MD. Synaptic organisation of the basal ganglia. J Anat 2000; 196:527-542.
  • [4]Mouroux M, Hassani OK, Feger J. Electrophysiological and Fos immunohistochemical evidence for the excitatory nature of the parafascicular projection to the globus pallidus. Neurosci 1997; 81:387-397.
  • [5]Bolam JP, Smith Y. The striatum and the globus pallidus send convergent synaptic inputs into single cells in the entopeduncular nucleus of the rat: a double anterograde labelling study combined with post-embedding immunocytochemistry for GAB A. J Comp Neurol 1992; 321:456-476.
  • [6]Filion M, Tremblay L. Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 1991; 547:142-151.
  • [7]Andre V, Pineau N, Moue J, Marescauz C, Nehlig A. Mapping of neuronal networks underlying generalized seizures induced by increasing doses of pentylenetetrazol in the immature and adult rat: a c-Fos mmunohistochemical study. Eur J Neurosci 1998; 10:2094-2106.
  • [8]Deransart C, Riban V, Le BT, Hechler V, Marescauz C, Depaulis A. Evidence for the involvement of the pallidum in the modulation of seizures in a genetic model of absence epilepsy in the rat.Neurosci Lett 1999; 265:131-134.
  • [9]McCormick SE, Stoessl AJ. Blockade of nigra and pallidal opioid receptors suppresses vacuous chewing movements in a rodent model of tardive dyskinesia. Neuroscience 2002; 112:851-859.
  • [10]McCormick SE, Stoessl AJ. Central administration of the neurotensin receptor antagonist SR48692 attenuates vacuous chewing movements in a rodent model of tardive dyskinesia.Neuroscience 2003; 119:547-555.
  • [11]Shink E, Smith Y. Differential synaptic innervation of neurons in the internal and external segments of the globus pallidus by the GABA- and glutamate-containing terminals in the squirrel monkey. J Comp Neurol 1995; 358:119-141.
  • [12]Sato F, Lavallee P, Levesque M, Parent A. Single-axon tracing study of neurons of the external segment of the globus pallidus in primate. J Comp Neurol 2000; 417:17-31.
  • [13]Kita H. Neostriatal and globus pallidus stimulation induced inhibitory postsynaptic potentials in entopeduncular neurons in rat brain slice preparations. Neuroscience 2001; 105:871-879.
  • [14]Bettler B, Kaupmann K, Bowery N. GABAB receptors: drugs meet clones. Curr Opin Neurobiol 1998; 8:345-350.
  • [15]Rudolph U, Crestani F, Mohler H. GABA(A) receptor subtypes:dissecting their pharmacological functions. Trends Pharmacol Sci 2001; 22:188-194.
  • [16]Zhang JH, Sato M, Tohyama M. Different postnatal development profiles of neurons containing distinct GABAA receptor beta subunit mRNAs in the rat forebrain. J Comp Neurol 1991;308:586-613.
  • [17]Wisden W, Laurie DJ, Monyer H, Seeburg PH. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain, I.Telencephalon, diencephalons, mesencephalon. J Neurosci 1992;12:1040-1062.
  • [18]Henderson Z. Expression of GABAA receptor subunit messenger RNA in non-cholinergic neurons of the rat basal forebrain. Neuroscience 1995; 65:1077-1086.
  • [19]Pehg Z, HauerB, Mihalek RM, Homanics GE, Sieghart W,Olsen RW, Houser CR. GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2subunits in the forebrain. J Comp Neurol 2002;446:179-197.
  • [20]Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G.GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 2000;101:815-850.
  • [21]Schwarzer C, Berresheim U, Pirker S, Wieselthaler A, Fuchs K,Sieghart W, Sperk G. Distribution of the major γ-aminobutyric acidA receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat. J Comp Neurol 2001;433:526-549.
  • [22]Waldvogel H J, Kubota Y, Fritschy J, Mohler H, Faull RL.Regional and cellular localization of GABAA receptor subunits in the human basal ganglia: An autoradiographic and immunohistochemical study. J Comp Neurol 1999; 415:313-340.
  • [23]Somogyi P, Fritschy JM, Benke D, Roberts JD, Sieghart W. The gamma 2 subunit of the GABAA receptor is concentrated in synaptic junctions containing the alpha 1 and beta 2/3 subunits in hippocampus, cerebellum and globus pallidus. Neuropharmacology 1996;35:1425-1444.
  • [24]Crossman AR, Mitchell IJ, Sambrook MA, Jackson A. Chorea and myoclonus in the monkey induced by gamma-aminobutyric acid antagonist in the lentiform complex. Brain 1988; 111:1211-1233.
  • [25]Matsumura M, Tremblay L, Richard H, Filion M. Activity of pallidal neurons in the monkey during dyskinesia induced by injection of bicuculline in the external pallidum. Neuroscience 1995; 65:59-70.
  • [26]Maneuf YP, Mitchell IJ, Crossman AR, Brotchie JM. On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus. Exp Neurol 1994; 125:65-71.
  • [27]Pan HS, Penney JB, Young AB. Gamma-aminobutyric acid and benzodiazepine receptor changes induced by unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. J Neurochem 1985; 45:1396-1404.
  • [28]Yu TS, Wang SD, Liu JC, Yin HS. Changes in the gene expression of GABA-A receptor alphal and alpha2 subunits and metabotropic glutamate receptor 5 in the basal ganglia of the rats with unilateral 6-hydroxydopamine lesion and embryonic mesencephalic grafts. Exp Neuro12001; 168:231-241.
  • [29]Schroeder JA, Schneider JS. GABA-A and mu-opioid receptor binding in the globus pallidus and endopeduncular nucleus of animals symptomatic for and recovered from experimental Parkinsonism. Brain Res 2002; 947:284-289.
  • [30]Caruncho HJ, Liste I, Rozas G, Lopez-Martin E, Guerra MJ,Labandeira-Garcia JL. Time course of striatal, pallidal and thalamic alpha 1, alpha 2 and beta 2/3 GABAA receptor subunit changes induced by unilateral 6-OHDA lesion of the nigrostriatal pathway. Brain Res Mol Brain Res 1997; 48:243-250.
  • [31]BamardEA, SkolinickP, OlsenRW, MohlerH, SieghartW, Biggio G, Braestrup C, Bateson AN, Langer SZ. International unionpharmacology. XV. Subtypes of γ-aminobutyric acidA receptors:Classification on the basis of subunit structure and receptor function. Pharmacol Rev 1998; 50:291-313.
  • [32]Lavoie AM, Twyman RE. Direct evidence for diazepam modulation of GABAA receptor microscopic affinity. Neuropharmacology 1996; 35:1383-1392.
  • [33]Mellor JR, Randall AD. Frequency-dependent actions of benzodiazepines on GABAA receptors in cultured murine cerebellar granule cells. J Physiol 1997; 503:353-369.
  • [34]Duncan GE, Breese GR, Criswell H.E, Mccown TJ, Herbert JS,Devaud L, Morrow AL. Distribution of [3H] zolpidem binding sites in relation to messenger RNA encoding the αl, β2 and y2subunits of GABAA receptors in rat brain. Neuroscience 1995;64:1113-1128.
  • [35]Chen L, Chan SCY, Yung WH. Electrophysiological and behavioral effects of zolpidem in rat globus pallidus. Exp Neuro12004;186;212-220.
  • [36]Bowery N, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 1987;20:365-383.
  • [37]Chu DMC, Albin RL. Young AB, Penney JB. Distribution and kinetics of GABAB binding sites in rat central nervous system: a quantitative autoradiographic study. Neuroscience 1990; 34:341-357.
  • [38]Benke D, Honer M, Michel C, Bettler B, Mohler H. γ-aminobutyric acid type B receptor splice variant proteins GBR 1a and GBR 1b are both associated with GBR 2 in situ and display differential regional and subcellular distribution. J Biol Chem 1999;274:27323-27330.
  • [39]Charara A, Heilman C, Levey AI, Smith Y. Pre- and postsynaptic localization of GABAB receptors in the basal ganglia in monkeys.Neuroscience 2000; 95:127-140.
  • [40]Smith Y, Charara A, Hanson JE, Paquet M, Levey AI. GABAB and group I metabotropic glutamate receptors in the striatopallidal complex in primates. J Anat 2000; 196: 555-576.
  • [41]Waldvogel HJ, Billinton A, White JH, Emson PC, Faull RL.Comparative cellular distribution of GABAn and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits. J Comp Neurol 2004; 470:339-356.
  • [42]Chen L, Boyes J, Yung WH, Bolam JP. Subcellular localization of GABAB receptor subunits in rat globus pallidus. J Comp Neurol 2004; 474:340-352.
  • [43]Chan SCY, Yung KKL, Yung WH. Pre- and postsynaptic distribution of GABAB receptors in rat globus pallidus revealed by immunocytochemistry and electrophysiology. Soc Neurosci Abstr 2000; 25:622.17.
  • [44]Chen L, Chan SCY, Yung WH. Rotational behavior and electrophysiological effects induced by GABAB receptor activation in rat globus pallidus. Neuroscience 2002; 114:417-425.
  • [45]Wichmann T, DeLong MR. Functional and pathophysiological models of the basal ganglia. Curr Opin Neurobiol 1996;6:751-758.
  • [46]Nini A, Feingold A, Slovin H, Bergman H. Neurons in the globus pallidus do not show correlated activity in the normal monkey,but phase-locked oscillations appear in the MPTP model of parkinsonism. J Neurophysiol 1995;74:1800-1805.
  • [47]Raz A, Vaadia E, Bergman H. Firing patterns and correlations of spontaneous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine vervet model of parkinsonism. J Neurosci 2000; 20:8559-8571.
  • [48]Magnin M, Morel A, Jeanmonod D. Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience 2000;96:549-564.
  • [49]Plenz D, Kitai ST. A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature 1999;400:677-682.
  • [50]Magill PJ, Bolam JP, Bevan MD. Relationship of activity in the subthalamic nucleus-globus pallidus network to cortical electroencephalogram. J Neurosci 2000;20:820-833.
  • [51]Magill PJ, Bolam JP, Bevan MD. Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network. Neuroscience 2001;106:313-330.
  • [52]Stanford IM. Independent neuronal oscillators of the rat globus pallidus. J Neurophysiol 2003; 89:1713-1717.
  • [53]El-Deredy W, Branston NM, Samuel M, Schrag A, Rothwell JC,Thomas DG, Quinn NP. Firing patterns of pallidal cells in parkinsonian patients correlate with their pre-pallidotomy clinical scores. Neuroreport 2000;11:3413-3418.
  • [54]Ruzicka E, Roth J, Jech R, Busek P. Subhypnotic doses of zolpidem oppose dopaminergic-induced dyskinesia in Parkinson's disease. Mov Disord 2000;15:734-735.
  • [55]Farver DK, Khan MH. Zolpidem for antipsychotic-induced Parkinsonism. Ann Pharmacother 2001 ;35: 435-437.
  • [56]Chadha A, Howell O, Atack JR, Sur C, Duty S. Changes in [3H]zolpidem and [3H]Ro 15-1788 binding in rat globus pallidus and substantia nigra pars reticulata following a nigrostriatal tract lesion.Brain Res 2000; 862:280-283.
  • [57]Chadha A, Sur C, Atack J, Duty S. The 5-HT1B receptor agonist,CP-93129, inhibits [3H]-GABA release from rat globus pallidus slices and reverses akinesia following intrapallidal injection in the reserpine-treated rat. Br J Pharmacol 2000;130:1927-1932.
  • [58]Olpe HR, Schellenberg H, Koella WP. Rotational behaviour induced in rats by intranigral application of GABA-related drugs and GABA antagonists. Eur J Phamacol 1977;45:291-294.
  • [59]Garant DS, Gale K. Lesions of substantia nigra protect against experimentally induced seizures. Brain Res 1983;273:156-161.
  • [60]Makulkin RF, Novytskyi SA, Korniienko TV. Role of globus pallidus in mechanisms of antiepileptic caudate-cortical effects.Fiziolog Zhur 1992;38:3-9.
  • [61]Iadarola MJ, Gale K. Substantia nigra: site of anti-convulsant activity mediated by gamma-aminobutyric acid. Science 1982;218:1237-1240.
  • [62]Depaulis A, Vergnes M, Marescaux C. Endogenous control of epilepsy: the nigral inhibitory system. Prog Neurobiol 1994; 42:33-52.
  • [63]Hayashi T. A physiological study of epileptic seizures following cortical stimulation in animals and its application to human clinics.Jpn J Physiol 1952; 3:46-64.
  • [64]Sabatino M, Grava nte G, Ferraro G, Savatteri V, La Grutta V.Inhibitory control by substantia nigra of generalized epilepsy in the cat. Epilepsy Res 1988; 2:380-386.
  • [65]Sawamura A, Hashizume K, Tanaka T. Electrophysiological,behavioral and metabolical features of globus pallidus seizures induced by a microinjection of kainic acid in rats. Brain Res 2002; 935:1-8.
  • [66]Suzdak PD, Foged C, Andersen KE. Quantitative autoradiographic characterization of the binding of [3H]tiagabine (NNC 05-328) to the GABA uptake carrier. Brain Res 1994; 647:231-241.
  • [67]Borden LA. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int 1996; 29:335-356.
  • [68]Fink-Jensen A, Suzdak PD, Swedberg MDB, Judge ME, Hansen L, Nielsen PG. The γ-aminobutyric acid (GABA) uptake inhibitor,tiagabine, increases extracellular brain levels of GABA in awake rats. Eur J Pharmacol 1992; 220:197-201.
  • [69]Chen L, Yung WH. Effects of GABA-uptake inhibitor tiagabine in rat globus pallidus. Exp Brain Res 2003; 152:263-269.
  • [70]Chen L, Chan YS, Yung WH. GABAB receptor activation in the rat globus pallidus potently suppresses pentylenetetrazol-induced tonic seizure. J Biomed Sci 2004; 11:457-464.
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