Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus

Graef, John D.; Newberry, Kimberly; Newton, Amy; Pieschl, Rick L.; Shields, Eric; Luan, F; Simmermacher, Jean; Luchetti, David; Schaeffer, Eric; Li, Yuwen; Kiss, László; Bristow, Linda J.

doi:10.1016/j.brainres.2015.03.019

Cited by 37 publications

(31 citation statements)

References 41 publications

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“…Consistent with former studies [ 43 – 46 ] that ketamine and memantine have similar effects on synaptic plasticity, we revealed that both compounds have a concentration window (1 μM-10 μM) that selectively reduces cLTD without impairing LTP. It is likely that selectively blocking synaptic depression and maintaining normal synaptic potentiation could be beneficial for learning and memory at the synaptic level, since LTP deficits and enhancement of LTD are reported in AD pathology [ 26 ] and also in the aging process [ 47 ].…”

Section: Resultssupporting

confidence: 91%

Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

et al. 2016

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NMDA receptors have been widely reported to be involved in the regulation of synaptic plasticity through effects on long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD have been implicated in learning and memory processes. Besides synaptic plasticity, it is known that the phenomenon of gamma oscillations is critical in cognitive functions. Synaptic plasticity has been widely studied, however it is still not clear, to what degree synaptic plasticity regulates the oscillations of neuronal networks. Two NMDA receptor antagonists, ketamine and memantine, have been shown to regulate LTP and LTD, to promote cognitive functions, and have even been reported to bring therapeutic effects in major depression and Alzheimer’s disease respectively. These compounds allow us to investigate the putative interrelationship between network oscillations and synaptic plasticity and to learn more about the mechanisms of their therapeutic effects. In the present study, we have identified that ketamine and memantine could inhibit LTD, without impairing LTP in the CA1 region of mouse hippocampus, which may underlie the mechanism of these drugs’ therapeutic effects. Our results suggest that NMDA-induced LTD caused a marked loss in the gamma power, and pretreatment with 10 μM ketamine prevented the oscillatory loss via its inhibitory effect on LTD. Our study provides a new understanding of the role of NMDA receptors on hippocampal plasticity and oscillations.

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Section: Resultssupporting

confidence: 91%

Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

et al. 2016

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“…We next showed that BMS-986169 robustly elevated ex vivo hippocampal LTP measured 24 hours after treatment. As evidence of synaptic strengthening, this finding is consistent with the hypothesis that rapid-acting antidepressants enhance synaptic plasticity (Wohleb et al, 2017) and with results for ketamine and the structurally distinct GluN2B NAM CP-101,606 in this assay (Burgdorf et al, 2013;Graef et al, 2015). The effect is thought to arise from increased expression of synaptic proteins, such as GluR1 and PSD95, and at least two mechanisms downstream of NMDA receptor inhibition may be involved: 1) disinhibition of pyramidal glutamate neurons leading to activity-dependent brain-derived neurotrophic factor release and activation of extracellular signal-regulated kinase/ AKT/mTORC1 signaling, and/or 2) activity-independent blockade of extrasynaptic, postsynaptic NMDA receptors leading to reduced eEF2 kinase activity, decreased eEF2 phosphorylation, and desuppression of brain-derived neurotrophic factor and synaptic protein translation (Miller et al, 2016;Murrough et al, 2017).…”

Section: Discussionsupporting

confidence: 87%

Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder

Bristow

Gulia

Weed

et al. 2017

J Pharmacol Exp Ther

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()-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3,4)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate -methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (K = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human -methyl-d-aspartate receptor subtypes (IC = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC = 28.4 M) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.

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“…Indeed, using hippocampal LTP as a measure of plasticity it was recently reported that LTP is robustly enhanced in slice preparations taken from animals dosed 24 h previously with i.v. ketamine or NR2B NAMs (Graef et al, 2015). This effect contrasts sharply with the LTP impairment seen following direct application of NMDA antagonists to hippocampal slices (Shipton and Paulsen, 2014).…”

Section: Discussionmentioning

confidence: 88%

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

Weed

Bookbinder

Polino

et al. 2015

Neuropsychopharmacol

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Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a nonspecific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.

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Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus

Cited by 37 publications

References 41 publications

Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

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