NMDA antagonists produce site-selective impairment of accuracy in a delayed nonmatch-to-sample task in rats

Willmore, Catherine B.; LaVecchia, Kari L.; Wiley, Jenny L.

doi:10.1016/s0028-3908(01)00143-5

Cited by 20 publications

(7 citation statements)

References 31 publications

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“…Because memantine does not block Ab binding, inhibition of cell death implies that neuronal apoptosis is triggered by receptor activation. Although memantine has proven to be an effective therapy in Alzheimer's disease, studies in rodents have shown that memantine can diminish learning (23,34). Because it is likely that there will be long-term consequences to continuous administration of memantine in humans, we are most excited by the observation that D-peptide can mediate neuronal sparing.…”

Section: Discussionmentioning

confidence: 99%

Immunity and behavior: Antibodies alter emotion

Huerta

Kowal

DeGiorgio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

258

226

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Systemic lupus erythematosus is an autoimmune disease in which most patients express Abs that bind double-stranded DNA. Recent work has shown that a subset of lupus Abs can crossreact with the NR2A and NR2B subunits of the NMDA receptor. This receptor is expressed in neurons throughout the brain but is at highest density within cells of the hippocampus, amygdala, and hypothalamus. The neurons in the CNS are normally protected from brain-reactive Abs by the blood-brain barrier (BBB); however, a breach in the barrier's integrity exposes neurons to potentially pathogenic Abs. Previously, we have shown that mice that are immunized with a peptide mimetope of DNA produce lupus-like Abs that crossreact with DNA and the NMDA receptor. Moreover, after abrogation of the BBB by treatment with lipopolysaccharide, the immunized mice display hippocampal neuron damage with ensuing memory impairment. Given that rises in epinephrine can increase cerebral blood flow and can cause leaks in the BBB, we decided to investigate whether epinephrine could act as a permissive agent for Ab-mediated neurotoxicity. Here, we show that peptide-immunized mice, given epinephrine to open the BBB, lose neurons in the lateral amygdala and develop a behavioral disorder characterized by a deficient response to fear-conditioning paradigms. Thus, the agent used to open the BBB determines which brain region is made vulnerable to neurotoxic Abs, and Abs that penetrate brain tissue can cause changes not only in cognitive competence, but also in emotional behavior.amygdala ͉ anti-NMDA receptor antibody ͉ anti-DNA antibody ͉ fear conditioning ͉ systemic lupus erythematosus

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Section: Discussionmentioning

confidence: 99%

Immunity and behavior: Antibodies alter emotion

Huerta

Kowal

DeGiorgio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

258

226

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“…JNJ-55511118 showed impairment in V-maze, MWM, and DNMTP. However, compared with effects following systemic administration of the NMDA receptor antagonists dizocilpine or phencyclidine (Willmore et al, 2001), or the muscarinic antagonist scopolamine (Chudasama and Muir, 1997), the impairment induced by JNJ-55511118 was relatively small. Our data are in line with those reported for GluA1 knockout mice, which also show relatively mild learning and memory impairments compared with animals with hippocampal lesions (Sanderson and Bannerman, 2012).…”

Section: Tarp-g8-selective Ampar Modulatorsmentioning

confidence: 94%

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8

Maher

Ravula

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

153

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Members of the a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediate the majority of fast synaptic transmission within the mammalian brain and spinal cord, representing attractive targets for therapeutic intervention. Here, we describe novel AMPA receptor modulators that require the presence of the accessory protein CACNG8, also known as transmembrane AMPA receptor regulatory protein g8 (TARP-g8). Using calcium flux, radioligand binding, and electrophysiological assays of wild-type and mutant forms of TARP-g8, we demonstrate that these compounds possess a novel mechanism of action consistent with a partial disruption of the interaction between the TARP and the pore-forming subunit of the channel. One of the molecules, 5-[2-chloro-6-(trifluoromethoxy)phenyl]-1,3-dihydrobenzimidazol-2-one (JNJ-55511118), had excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration. This molecule showed strong, dose-dependent inhibition of neurotransmission within the hippocampus, and a strong anticonvulsant effect. At high levels of receptor occupancy in rodent in vivo models, JNJ-55511118 showed a strong reduction in certain bands on electroencephalogram, transient hyperlocomotion, no motor impairment on rotarod, and a mild impairment in learning and memory. JNJ-55511118 is a novel tool for reversible AMPA receptor inhibition, particularly within the hippocampus, with potential therapeutic utility as an anticonvulsant or neuroprotectant. The existence of a molecule with this mechanism of action demonstrates the possibility of pharmacological targeting of accessory proteins, increasing the potential number of druggable targets.

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“…These compounds have been of interest because an NMDA receptor blockade prevents hippocampal long-term potentiation, which is linked to learning and memory, and because they have been shown to interfere with a variety of memory tasks (see Bannerman, Rawlins, & Good, 2006, for a review). Perhaps surprisingly, although NMDA antagonists interfere with DMTS accuracy, they generally do so only in a delay-independent fashion (Dix, Gilmour, Potts, Smith, & Tricklebank, 2010; Pontecorvo, Clissold, White, & Ferkany, 1991; Smith et al, 2011; Willmore, LaVecchia, & Wiley, 2001). So it is of some interest that both MacQueen et al, (2011) and Galizio, Deal, Hawkey, and April (2013) found that the non-competitive NMDA antagonist MK-801 (dizocilpine) impaired OST accuracy at doses that had no effect on a simple odor discrimination.…”

mentioning

confidence: 99%

Behavioral pharmacology of the odor span task: Effects of flunitrazepam, ketamine, methamphetamine and methylphenidate

Galizio¹,

April²,

Deal³

et al. 2016

J Exper Analysis Behavior

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The Odor Span Task is an incrementing non-matching-to-sample procedure that permits the study of behavior under the control of multiple stimuli. Rats are exposed to a series of odor stimuli and selection of new stimuli is reinforced. Successful performance thus requires remembering which stimuli have previously been presented during a given session. This procedure has been frequently used in neurobiological studies as a rodent model of working memory; however, only a few studies have examined the effects of drugs on performance in this task. The present experiments explored the behavioral pharmacology of a modified version of the Odor Span Task by determining the effects of stimulant drugs methylphenidate and methamphetamine, NMDA antagonist ketamine, and positive GABAA modulator flunitrazepam. All four drugs produced dose-dependent impairment of performances on the Odor Span Task, but for methylphenidate and methamphetamine, these occurred only at doses that had similar effects on performance of a simple odor discrimination. Generally, these disruptions were based on omission of responding at the effective doses. The effects of ketamine and flunitrazepam were more selective in some rats. That is, some rats tested under flunitrazepam and ketamine showed decreases in accuracy on the Odor Span Task at doses that did not affect simple discrimination performance. These selective effects indicate disruption of within-session stimulus control. Overall, these findings support the potential of the Odor Span Task as a baseline for the behavioral pharmacological analysis of remembering.

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NMDA antagonists produce site-selective impairment of accuracy in a delayed nonmatch-to-sample task in rats

Cited by 20 publications

References 31 publications

Immunity and behavior: Antibodies alter emotion

Immunity and behavior: Antibodies alter emotion

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8

Behavioral pharmacology of the odor span task: Effects of flunitrazepam, ketamine, methamphetamine and methylphenidate

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