The effect of dizocilpine (MK-801) on conditional discrimination learning in the rat

Tk, Murray; Rm, Ridley

doi:10.1097/00008877-199710000-00002

Cited by 40 publications

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“…In adult rats and mice, the systemic MK-801 administration studies (Bardgett, et al, 2003; Murray, Ridley, Snape, & Cross, 1995), in conjunction with lesion studies, have clearly established a role for the hippocampal system in spatial discrimination reversal learning (Bardgett, et al, 2003; Kimble, 1968; Kimble & Kimble, 1965; Oliveira, et al, 1997). Systemic MK-801 administration also impairs other forms of spatial learning in adult rats, including Morris Water Maze learning and reversal (Ahlander, Misane, Schott, & Ogren, 1999), spatial serial reversal (van der Meulen, Bilbija, Joosten, de Bruin, & Feenstra, 2003), radial arm maze learning (Caramanos & Shapiro, 1994; Shapiro & O’Connor, 1992; Woodside, Borroni, Hammonds, & Teyler, 2004), conditional visuo-spatial learning (Murray & Ridley, 1997), cognitive-set shifting (Stefani & Moghaddam, 2005a; Stefani & Moghaddam, 2005b), spontaneous alternation in a radial arm maze (Homayoun, Stefani, Adams, Tamagan, & Moghaddam, 2004), and spatial delayed alternation (Hauber, 1993; Locchi, Dall’olio, Gandolfi, & Rimondini, 2007; Verma & Moghaddam, 1996). The results from these studies combined provide support for the well-accepted theory of the role of the hippocampus in spatial learning tasks.…”

Section: Methodsmentioning

confidence: 99%

Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats

Watson

Stanton

2009

Neurobiology of Learning and Memory

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Systemic administration of MK-801, an NMDA receptor antagonist, impairs reversal learning in weanling rats (Chadman, Watson, & Stanton, 2006). The brain systems responsible for this effect are not known in either adult or young animals. This study tested the hypothesis that hippocampal NMDA receptors are engaged in weanling-age rats during spatial discrimination reversal training in a T-maze. In Experiment 1, 26-day-old Long-Evans rats (P26) showed a dose-related impairment on this task following bilateral intrahippocampal administration of either 2.5 or 5.0 μg MK-801 or saline vehicle during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but received intrahippocampal MK-801 (2.5 μg) during acquisition, reversal, both, or neither. MK-801 failed to impair acquisition, ruling out nonspecific "performance effects" of the drug. MK-801 impaired reversal irrespective of drug treatment during acquisition. NMDA receptor antagonism in the hippocampus is sufficient to account for the previously reported effects of systemic MK-801 on reversal of T-maze position discrimination. KeywordsDevelopment; Reversal Learning; Hippocampus; MK-801; Rat; Spatial LearningThe N-methyl-D-Aspartate (NMDA) receptor subtype of glutamate receptors plays a substantial role in neural physiology, synaptic plasticity, and behavioral learning and memory. These roles include, but are not limited to, the molecular/cellular basis of short-and long-term memory formation, the induction and maintenance of long-term potentiation (LTP), as well spatial learning and memory that depends upon the hippocampus (Morris, Anderson, Lynch, & Baudry, 1986;O'Keefe & Nadel, 1978;Shapiro, 2001).NMDA receptors are heavily concentrated in the hippocampal formation, cortex, and striatum (Wong, Kemp, Priestley, Knight, Woodruff, & Iversen, 1986;Wong, Knight, & Woodruff, 1988). These same brain regions are essential for spatial learning and memory, contextual memory, and higher-order cognitive learning tasks in adult animals. It is currently unknown if these same brain regions are involved in reversal learning during early ontogeny.Corresponding author: Deborah J. Watson, Department of Psychology, University of Delaware, Newark, DE 19716, Ph: (302) Fax (302) 831-3645, E-mail: dwatson@psych.udel.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurobiol Learn Mem. Author manuscript; available in PMC 2010 July 1. Published in final edited form as:Neurobiol Learn Mem. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscrip...

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Section: Methodsmentioning

confidence: 99%

Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats

Watson

Stanton

2009

Neurobiology of Learning and Memory

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“…Learning ability was tested as described previously 13 in a wooden Y-maze with three arms. 9 The whole area of the arms was covered by black or white inserts.…”

Section: Y-maze Learning Testmentioning

confidence: 99%

Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts

et al. 2005

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Patients with liver disease with overt or minimal hepatic encephalopathy show impaired intellectual capacity. The underlying molecular mechanism remains unknown. Rats with portacaval anastomosis or with hyperammonemia without liver failure also show impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanine monophosphate (glutamate-NO-cGMP) pathway in brain. We hypothesized that pharmacological manipulation of the pathway in order to increase cGMP content could restore learning ability. We show by in vivo brain microdialysis that chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, normalizes the function of the glutamate-NO-cGMP pathway and extracellular cGMP in brain in vivo in rats with portacaval anastomosis or with hyperammonemia. Moreover, sildenafil restored the ability of rats with hyperammonemia or with portacaval shunts to learn a conditional discrimination task.

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“…Learning ability was tested, as described by Murray and Ridley (1997), in a wooden Y-maze, which had three arms of equal size (60 cm long, 11.5 cm wide, and 25 cm high). The arm where the rats were placed at the beginning of each trial was considered the start arm.…”

Section: Y-maze Learning Testmentioning

confidence: 99%

The function of the glutamate–nitric oxide–cGMP pathway in brain in vivo and learning ability decrease in parallel in mature compared with young rats

Piedrafita¹,

Cauli²,

Montoliú³

et al. 2007

Learn. Mem.

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Aging is associated with cognitive impairment, but the underlying mechanisms remain unclear. We have recently reported that the ability of rats to learn a Y-maze conditional discrimination task depends on the function of the glutamate-nitric oxide-cGMP pathway in brain. The aims of the present work were to assess whether the ability of rats to learn this task decreases with age and whether this reduction is associated with a decreased function of the glutamate-nitric oxide-cGMP pathway in brain in vivo, as analyzed by microdialysis in freely moving rats. We show that 7-mo-old rats need significantly more (192 ± 64%) trials than do 3-mo-old rats to learn the Y-maze task. Moreover, the function of the glutamate-nitric oxide-cGMP pathway is reduced by 60 ± 23% in 7-mo-old rats compared with 3-mo-old rats. The results reported support the idea that the reduction in the ability to learn the Y-maze task (and likely other types of learning) of mature compared with young rats would be a consequence of reduced function of the glutamate-nitric oxide-cGMP pathway.Aging is associated with cognitive impairment, but the underlying mechanisms remain unclear. The molecular bases for different types of learning are not well known. NMDA receptors play a crucial role in some types of learning. Activation of NMDA receptors leads to increased calcium in the post-synaptic neuron. Calcium binds to calmodulin and activates neuronal nitric oxide synthase (nNOS) in those neurons, which express both the NMDA receptors and this enzyme, increasing nitric oxide (NO). NO, in turn, activates soluble guanylate cyclase, increasing cGMP. Part of this cGMP is released to the extracellular fluid through cGMP transporters present in the cell membrane (Sager 2004).Several reports indicate that activation of this glutamate-NO-cGMP pathway is involved in some forms of learning (Danysz et al. 1995;Chen et al. 1997;Meyer et al. 1998). NO seems to mediate at least part of the role of NMDA receptors in learning. This is supported by studies showing that inhibition of NO synthase reduces learning of some spatial tasks (Ingram et al. 1998a,b;Zou et al. 1998) The role of NO in learning may be mediated by its activation of soluble guanylate cyclase and the increase in cGMP. Some reports indicate that soluble guanylate cyclase and cGMP are important in learning and memory. Bernabeu et al. (1996Bernabeu et al. ( , 1997 showed that, in rats, passive avoidance learning was associated with a time-dependent, learning-specific increase in cGMP (Bernabeu et al. 1996) and in cGMP-dependent protein kinase activity in hippocampus (Bernabeu et al. 1997) The same group also showed that administration of a membrane permeable analog of cGMP facilitated memory consolidation (Bernabeu et al. 1996), while bilateral intrahippocampal administration of an inhibitor of soluble guanylate cyclase caused full amnesia for inhibitory avoidance learning when given immediately after training (Bernabeu et al. 1997). These data indicate that the increase in cGMP produced by guanylate cycla...

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The effect of dizocilpine (MK-801) on conditional discrimination learning in the rat

Cited by 40 publications

References 0 publications

Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats

Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats

Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts

The function of the glutamate–nitric oxide–cGMP pathway in brain in vivo and learning ability decrease in parallel in mature compared with young rats

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