A Behavioral Analysis of the Spatial Learning Deficit Induced by the NMDA Receptor Antagonist MK-801 (Dizocilpine) in the Rat

Åhlander, Matilda

doi:10.1016/s0893-133x(98)00116-x

Cited by 86 publications

(44 citation statements)

References 54 publications

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“…On the other hand, reduced activity of either of these two receptors causes cognitive deficits in this paradigm (Boess et al, 2007;Curzon et al, 2006;Morris, 2006;Wallace et al, 2011). More generally, treatment of experimental animals with glutamate receptor antagonists impairs performance in a variety of cognitive tasks (Ahlander et al, 1999;Hauber and Schmidt, 1989;Karasawa et al, 2008;Venable and Kelly, 1990), whereas endogenous or exogenous glutamate receptor agonists promote cognitive performance (Clem et al, 2008;Lynch et al, 2008;Singer et al, 2010). Although definitive confirmation will require further experimentation and additional brain areas may well be involved (Jo et al, 2007), the present findings suggest that the cognitive impairment caused by elevated KYNA was likely related to reductions in extracellular glutamate in the hippocampus, and that the cognition-enhancing effects of ESBA were the result of elevated extracellular glutamate.…”

Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

141

158

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Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

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Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

141

158

View full text Add to dashboard Cite

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“…Çalışmamızda, korunmalı güvenli alanda lokomotor aktivitede azalma görülmüştür. Bazı çalışmalarda NMDA reseptör blokajı ile lokomotor aktivitede artış ya da azalma gösterilmiştir (38,39). Limbik sistem yapılarıyla yakından ilişkili olan nükleus accumbenste NMDA reseptör blokajından sonra anksiyolitik etki ile birlikte lokomotor aktivitede artışın her zaman birlikte olmadığı gösterilmiştir (38,39).…”

Section: şEkil 6 Morris Su Havuzu Bellek Testinde Yüzme Hızı (Cm/sn)unclassified

“…Bazı çalışmalarda NMDA reseptör blokajı ile lokomotor aktivitede artış ya da azalma gösterilmiştir (38,39). Limbik sistem yapılarıyla yakından ilişkili olan nükleus accumbenste NMDA reseptör blokajından sonra anksiyolitik etki ile birlikte lokomotor aktivitede artışın her zaman birlikte olmadığı gösterilmiştir (38,39). Çalışmamızda görülen davranış özellikleri yani lokomotor aktivitede azalma, NMDA reseptör alt birimi NR2D'nin (GluRε4) mutasyona uğradığı farelerde gösterilmiştir (40).…”

Section: şEkil 6 Morris Su Havuzu Bellek Testinde Yüzme Hızı (Cm/sn)unclassified

The Effect of N-Methyl-D-Aspartate (NMDA) Receptor Blockade and Physical Environmental Enrichment During Childhood on Emotional and Cognitive Function in Adulthood in Balb/C Mice

Akıllıoğlu

Melik

Melik³

2012

Erciyes Med J

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“…Lesions or temporary inactivations of the dorsal hippocampus reliably disrupt performance on spatial tasks (Morris et al 1982;Sutherland et al 1982Sutherland et al , 1983McDonald and White 1994;Moser et al 1995;Duva et al 1997;Cassel et al 1998;Oswald et al 2003), suggesting a hippocampal contribution to spatial memory function. As well, impeding N-methyl-Daspartic acid receptor (NMDAr) function can mimic the effects of hippocampal lesions on a number of spatial tasks (Morris 1989;Robinson et al 1989;Heale and Harley 1990;Shapiro and Caramanos 1990;Ohno et al 1992;Bannerman et al 1995;Riekkinen and Riekkinen 1997;Ahlander et al 1999;Steele and Morris 1999;Holahan et al 2005).…”

mentioning

confidence: 99%

Effect of juvenile pretraining on adolescent structural hippocampal attributes as a substrate for enhanced spatial performance

Keeley¹,

Wartman²,

Häusler³

et al. 2010

Learn. Mem.

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Research has demonstrated that Long -Evans rats (LER) display superior mnemonic function over Wistar rats (WR). These differences are correlated with endogenous and input-dependent properties of the hippocampus. The present work sought to determine if juvenile pretraining might enhance hippocampal structural markers and if this would be associated with spatial processing improvements. Male and female WR and LER were either handled or trained on a water maze task from postnatal day 16 (p16) to p26 (pretraining). All animals were then trained on the task from p40 to p44 followed by immunohistochemical assessment of synaptophysin (to mark presynaptic terminals), MAP-2 (to mark dendrites), and the phosphorylated (activated) form of the extracellular signal-regulated kinase-1 (pERK1) in the hippocampus. From p19 to p20, LER (both male and female) showed a dramatic improvement in locating the hidden platform compared to their WR counterparts. On the first day of training at p40, all pretrained groups showed shorter latencies to locate the platform compared to groups without pretraining. Over the next 4 d, only pretrained male LER showed enhanced memory. Immunohistochemical analysis revealed fewer pERK1-labeled neurons in the CA3 hippocampal region in all pretrained groups and fewer pERK1-labeled neurons in the CA1 region of pretrained male LER. Pretrained male LER also showed more MAP-2 staining in CA1 and dentate gyrus regions. Synaptophysin staining revealed a pattern of axonal redistribution in the CA3 region in the pretrained groups. Results suggest a pattern of structural hippocampal alterations that may help to identify network malleability following pretraining protocols.

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A Behavioral Analysis of the Spatial Learning Deficit Induced by the NMDA Receptor Antagonist MK-801 (Dizocilpine) in the Rat

Abstract: This study analyzes whether the disruptive effects of the noncompetitive NMDA receptor antagonist

Cited by 86 publications

References 54 publications

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

The Effect of N-Methyl-D-Aspartate (NMDA) Receptor Blockade and Physical Environmental Enrichment During Childhood on Emotional and Cognitive Function in Adulthood in Balb/C Mice

Effect of juvenile pretraining on adolescent structural hippocampal attributes as a substrate for enhanced spatial performance

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