The role of corticostrital neurons in schizoprenia modell  Page description

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Details of project

  
Identifier
43511
Type K
Principal investigator Hársing, László Gábor
Title in Hungarian A corticostriatalis pálya szerepének vizsgálata schizoprénia modellben in vitro
Title in English The role of corticostrital neurons in schizoprenia modell
Panel Neurosciences
Department or equivalent Laboratory of Molecular Pharmacology (Institute of Experimental Medicine)
Participants Jurányi, Zsolt
Starting date 2003-01-01
Closing date 2005-12-31
Funding (in million HUF) 3.864
FTE (full time equivalent) 0.00
state closed project





 

Final report

  
Results in Hungarian
Kortikostriátális agyszeletkészítményt fejlesztettünk ki, mely lehetővé teszi a Gluerg, GABAerg, DAerg neurotranszmisszió kölcsönhatásainak vizsgálatát a striátum állományában. A szuperfúziós rendszerben elkülönítve mértünk [3H]DA felszabadulást a striátum és a cortex állományából és a kéreg elektromos ingerlése [3H]DA felszabadulást váltott ki a striátumból. [3H]DA felszabadulást a potenciális antipszichotikum GlyT1 gátlók jelenlétében határoztuk meg. A GlyT1 gátlók potencírozzák a striátum NMDA receptorait, ezek a receptorok különböző neuronokban expresszálódhatnak, glicin iránti érzékenységük eltérő lehet. Közleményben foglaltuk össze a GlyT1 gátlók neurobiológiáját és medicinális kémiáját. [3H]5-HT felszabadulást vizsgáltunk patkány izolált rafe mag szeletben és meghatároztuk az 5-HT7 receptorok szerepet az e területről mérhető 5-HT felszabadulás szabályozásban. Az 5-HT7 receptorok a corticorafe Gluerg neuronok axon terminálisain expresszálódnak és heteroreceptorként vesznek részt a rafeból mérhető [3H]5-HT felszabadulás szabályozásában. Ezek a receptorok a rafe magban résztvésznek a Glu-5-HT neuronok közötti interakcióban és a rafe-kortikális 5-HTerg neuronok aktivitásának szabályozásában. A rafe neurotranszmisszióját review közleményben foglaltuk össze, bemutatva az 5-HT felszabadulásban az 5-HT1/2 receptor altípusok, valamint az 5-HT3/7 receptorok által megvalósuló gátlás és serkentés mechanizmusokat. E szabályzások alapját képezhetik a pszichózis 5-HT elméletének.
Results in English
We have developed a corticostriatal slice preparation in order to study interactions between glutamatergic, GABAergic and dopaminergic neurons. Release of [3H]dopamine from striatum was induced by cortical stimulation. This release was studied after impairment of dopaminergic terminals by 6-OHDA and hypoxic insults and also in the presence of the glycine transporter-1 (GlyT1) inhibitor Org-24461, a potential antipsychotic agents. Results obtained indicate that GlyT1 inhibitors may exert their antipsychotic effects by potentiation of striatal NMDA receptors with different locations and sensitivity towards the receptor coagonist glycine. A detailed review was prepared to analyse the neurobiology and medicinal chemistry of GlyT1 inhibitors. Moreover, [3H]5-HT release from raphe nuclei slices was also determined to demonstrate the role of 5-HT7 receptors in the regulation of raphe nuclei 5-HT projection neurons. We showed that 5-HT7 receptors in the raphe nuclei are heteroreceptors and are expressed in the membrane of cortico-raphe glutamatergic axon terminals. Although these receptors regulate local glutamatergic-serotonergic interaction in the raphe nuclei they alter activity of raphe-cortical 5-HT neurons. The neurotransmission in the raphe has been reviewed demonstrating feedback inhibition and stimulation of raphe 5-HT release by various subtypes of 5-HT1/2 receptors and also by 5-HT3/7 receptors. These interactions may be the base for 5-HTergic theory of psychotic states.
Full text http://real.mtak.hu/1109/
Decision
Yes





 

List of publications

  
Kapus, G., Kertesz S., Gigler, G., Simo, A., Vegh, M., Barkoczy, J., Harsing, L. G., Jr., Szabo, G., Levay, G.:: Comparison of the AMPA antagonist action of new 2,3-benzodiazepines in vitro and their neuroprotective effects in vivo., Pharm Res., 21, 317-323., 2004
Juranyi, Z., Sziray, N., Levay, G., Harsing, L. G., Jr.: AMPA receptor blockade potentiates the stimulatory effect of L-dopa on dopamine release in dopamine-deficient corticostriatal slice preparation, Critical Reviews in Neurobiology, 16, 129-139., 2004
Harsing, L. G., Prauda, I., Barkoczy, J., Matyus, P. Juranyi, Zs.: 5-HT7 heteroreceptor-mediated inhibition of [3H]serotonin release in raphe nuclei slices of the rat: evidence for a serotonergic-glutamatergic interaction, Neurochem. Res., 29, 1479-1489., 2004
Juranyi, Zs., Harsing, L. G. Jr.: Brain slice chambers designed for in vitro experiments with nervous tissue, In: Monoamine oxisase inhibitors, eds: Torok, T. L., Klebovich, I., Medicina, Budapest, pp. 281-308., 2004
Harsing, L. G., Jr.: Regulation of somatodendritic serotonin release in the midbrain raphe nuclei of the rat, In: Dendritic release of neurotransmitters, ed.: Mike Ludwig, Springer Publisher, New York, in press., 2004
Harsing, L. G., Jr., Juranyi, Zs.: Evidence for a reciprocal serotonergic-glutamatergic interaction in the raphe nuclei: involvement of 5-HT7 receptors, Proc. Austr. Neurosci. Soc.2004, 15, 78. 24th Annaul Meeting of the Australian Neurosci. Soc., Melbourne, Abstr. 120., 2004
Juranyi, Zs., Marko, B., Harsing, L. G., Jr.: Depletion of GABA decreased the evoked [3H]dopamine release in striatum in the presence of NMDA receptor blockade in corticostriatal slices, IBRO Workshop, Budapest, Abstr., 2004
Harsing, L. G. Jr., Gigler, G., Albert, M., Szenasi, G., Simo, A., Moricz, K., Varga, A., Ling, I., Bagdy, E., Kiraly, I., Solyom, S., Juranyi, Zs.: Neurotransmitter release in experimental stroke models: the role of glutamate-GABA interaction, In: Frontiers in Clinical Neuroscience: Neurodegeneration and Neuroprotection, ed.: L. Vecsei, Kluwer Publisher, New York, pp. 21-38., 2004
Juranyi, Z., Harsing, L. G., Jr.: Temperature-dependent [3H]glycine release in response to electrical stimulation and exogenous glycine in the presence of Org-24461, a glycine transporter1 inhibitor in rat hippocampal slices, 34th Annual Meeting, Society for Neuroscience, San Diego, Abst. 272.21., 2004
Kertesz, S., Kapus, G., Vegh, M., Szucs, Zs., Kovacs, G., Harsing, L. G., Levay, G.:: The AMPA potentiator benzothiazide S 18986, cyclothiazide and IDRA-21: a comperative in vitro study., IBRO Workshop, Budapest, 2004
Gressens, P., Spedding, M., Villa, P., Medja, F., Williamson, T., Kertesz S., Levay, G., Gigler, G., Szenasi, G., Barkoczy, J., Harsing, L. G., Jr.:: The effects of novel AMPA antagonists in models of neurodegeneration, Eur. J. Pharmacol., 519, 58-67., 2005
Hársing László Gábor:: Gyógyszerhatástan. Humán gyógyszerfejlesztés., Szerkesztette: Dinya Elek, Medicina Könyvkiadó Rt., 169-215., 2006
Matucz, E., Moricz, K., Gigler, G., Simo, A., Barkoczy, J., Levay, Gy., Harsing, L. G., Jr., Szenasi, G.:: Reduction of cerebral infarct size by non-competitive AMPA antagonists in rats subjected to permanent and transient focal ischemia., Brain Res., 1019, 210-216., 2004
Spedding, M., Neau, I., Harsing, L.:: Brain plasticity and pathology in psychiatric disease: sites of action for potential therapy., Curr. Opinion Pharm., 3, 1-8., 2003
Szenasi, G., Harsing, L. G., Jr.:: Pharmacology and prospective therapeutic usefulness of negative allosteric modulators of AMPA receptors., Drug Discovery Today: Therapeutic Strategies. 1, 69-76., 2004
Harsing, L.G., Jr., Gacsalyi, I., Schmidt, E., Szabo, G., Sziray, N., Sebban, C., Tesolin-Decros, B., Matyus, P., Spedding, M., Matyus, P., Levay, G.:: The glycine transporter 1 inhibitor NFPS and Org 24461: a pharmacological study., Pharm. Biochem. Behav., 74, 811-825., 2003
Harsing, L. G., Jr., Juranyi, Zs., Zigmond, M. J.:: Cortical stimulation influences striatal dopamine release via GABAergic neurons in corticostriatal slices of the rat., Soc. Neurosci., Abst. 705.8, 2003
Juranyi, Zs., Harsing, L. G., Jr., Zigmond, M. J.:: [3H]Dopamine release in striatum in response to cortical stimulation in a corticostriatal slice preparation., J. Neurosci. Methods, 126, 57-67., 2003
Szabo, G., Egyed, A., Harsing, L. G., Jr.:: A new and simple method for measuring neurotransporters. The GlyT1 transporter., FEBS Meeting, Brussels, Eur. J. Biochem., 270, PS01-1009., 2003
Szenasi, G., Gigler, G., Gacsalyi, I., Simo, A., Moricz, K., Sziray, N., Albert, M., Szabo, G., Schmidt, E., Egyed, A., Levay, G., Harsing, L. G., Jr.:: Beneficial and detrimental effects of Org 24461 and NFPS, two glycine transporter-1 inhibitors in rats and mice., 6th IBRO, Prague, Abstr. 3189., 2003
Szabo, G., Udvari, S., Egyed, A., Harsing, L. G. Jr.:: Biochemical characterization of Org 24461 and NFPS in synaptosomal fraction and in cos-7 cells expressing GlyT1 transporters., FEBS Congr., Warshaw, 32003444880., 2004
Harsing, L. G., Jr.:: 2,3-Benzodiazepines: multiple pharmacological actions and structure-activity relationship., Austrian-German-Hungarian-Italian-Polish-Spanish Joint Meeting on Medicinal Chemistry, eds.: P. Ettmayer, G. Ecker, Medimond, Italy, pp. 39-48., 2005
Harsing, L. G., Jr., Szabo, G., Agoston, M., Marko, B., Juranyi, Z., Haller, J., Gacsalyi, I.:: Further evidence for the antipsychotic properties of the glycine transporter1 inhibitor Org-24461., Proc. Austr. Neurosci. Soc., 16, 72., 2005
Harsing, L. G., Jr.:: 2,3-Benzodiazepines: multiple pharmacological actions and structure-activity relationship., Scientia Pharmaceutica, 73, Suppl. 1, S38., 2005
Harsing, L. G., Jr., Gigler, G., Moricz, K., Agoston, M., Marko, B., Szabo, G., Szenasi, G., Juranyi, Z.:: Antiischemic effects of Org-24461 and NFPS, two glycine transporter type-1 inhibitors., Soc. Neurosci., Abstr. 669.16., 2005
Szabo, G., Udvari, S., Egyed, A., Harsing, L. G., Jr.:: Biochemical characterization of Org 24461 and NFPS in synaptosomal fractions and in COS-7 cells expressing GlyT1 transporters., Eur. Brain Winter Conf. Arc, Abstr. 96., 2005
Kallo, I., Juranyi, Z., Jekkel, C., Jarasi, A., Wilhelm, T., Harsing, L., Liposits, Z.:: Effect of transient ischemia on glycine transporter 1 immunoreactivity in the rat forebrain., Soc. Neurosci., Abstr. 95.9., 2005
Harsing, L. G., Jr., Juranyi, Z., Tapolcsanyi, P., Czompa, A., Matyus, P.:: Glycine transporter type-1 and its inhibitors., Current Medicinal Chemistry, in press, 2006
Harsing, L. G., Jr.:: The pharmacology of the neurochemical transmission in the midbrain raphe nuclei of the rat., Current Neuropharmacology, submitted, 2006
Harsing, L. G. Jr., Juranyi, Z.:: Dual effect of the glycine transporter type-1 inhibitor Org-24461 on MK-801-induced [3H]dopamine release in rat corticostriatal slices., Proc. Austr. Neurosci. Soc.,17, 79., 2006
Juranyi, Z., Harsing, L. G., Jr.:: Amelioration of MK-801-enhanced [3H]dopamine release in rat corticostriatal slices by Org-24461, a glycine transporter1 inhibitor., Brain Res., in preparation, 2006
Megyeri, K., Marko, B., Sziray, N., Harsing, L. G., Jr., Levay, G.:: Effects of AMPA antagonists on dopamine turnover in parkinsonian rat striatum., Neurochem Res., in preparation, 2006
Benedek, A., Nagy, K., Albert, M., Szenasi, G., Matyus, P., Harsing, L. G., Jr., Juranyi, Z.:: [3H]Dopamine release in corticostriatal slices after transient cerebral ischemia in rats., Neurochem. Int., in preparation, 2006



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