The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate

Anis, Nabil A.; Berry, Stephen C.; Burton, N.R.; Lodge, David

doi:10.1111/j.1476-5381.1983.tb11031.x

Cited by 1,329 publications

(567 citation statements)

References 45 publications

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“…Ketamine is a dissociative anesthetic that produces anesthesia, analgesia, suppression of fear and anxiety, and amnesia and its effects are mediated by antagonism of NMDA receptors (NMDARs) (Anis et al, 1983). Activation of NMDARs is essential for long-term potentiation and spatial learning and memory (Malenka and Bear, 2004), and NMDAR blockade results in impaired synaptic plasticity manifested as adverse effects on learning and memory (Sakimura et al, 1995;Shimizu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Cuevas

Trickler

Guo

et al. 2013

Neurotoxicology and Teratology

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Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) type glutamate receptors is commonly used as a pediatric anesthetic. Multiple studies have shown ketamine to be neurotoxic, particularly when administered during the brain growth spurt. Previously, we have shown that ketamine is detrimental to motor neuron development in the zebrafish embryos. Here, using both wild type (WT) and transgenic (hb9:GFP) zebrafish embryos, we demonstrate that ketamine is neurotoxic to both motor and sensory neurons. Drug absorption studies showed that in the WT embryos, ketamine accumulation was approximately 0.4% of the original dose added to the exposure medium. The transgenic embryos express green fluorescent protein (GFP) localized in the motor neurons making them ideal for evaluating motor neuron development and toxicities in vivo. The hb9:GFP zebrafish embryos (28 h post fertilization) treated with 2 mM ketamine for 20 h demonstrated significant reductions in spinal motor neuron numbers, while co-treatment with acetyl L-carnitine proved to be neuroprotective. In whole mount immunohistochemical studies using WT embryos, a similar effect was observed for the primary sensory neurons. In the ketamine-treated WT embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced compared to that in controls. However, acetyl L-carnitine co-treatment prevented ketamine-induced adverse effects on the RB neurons. These results suggest that acetyl L-carnitine protects both motor and sensory neurons from ketamine-induced neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Cuevas

Trickler

Guo

et al. 2013

Neurotoxicology and Teratology

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“…The crystals were dried and crystallized at [21] 158 °C, [22] 207−208.5 °C, [22] 207−209 °C, [22] 207−209 °C (HCl × H 2 O, [14] 207 °C [20] ). 1 …”

Section: Synthesis Proceduresmentioning

confidence: 99%

Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2‐diphenylethyl isomers

Wallach

Kavanagh

McLaughlin

et al. 2014

Drug Testing and Analysis

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Substances with the diphenylethylamine nucleus represent a recent addition to the product catalog of dissociative agents sold as ‘research chemicals’ on the Internet. Diphenidine, i.e. 1‐(1,2‐diphenylethyl)piperidine (1,2‐DEP), is such an example but detailed analytical data are less abundant. The present study describes the synthesis of diphenidine and its most obvious isomer, 1‐(2,2‐diphenylethyl)piperidine (2,2‐DEP), in order to assess the ability to differentiate between them. Preparation and characterization were also extended to the two corresponding pyrrolidine analogues 1‐(1,2‐diphenylethyl)‐ and 1‐(2,2‐diphenylethyl)pyrrolidine, respectively. Analytical characterizations included high‐resolution electrospray mass spectrometry (HR‐ESI‐MS), liquid chromatography ESI‐MS/MS, gas chromatography ion trap electron and chemical ionization MS, nuclear magnetic resonance spectroscopy (NMR) and infrared spectroscopy. Differentiation between the two isomeric pairs was possible under GC‐(EI/CI)‐MS conditions and included the formation of distinct iminium ions, such as m/z 174 for 1,2‐DEP and m/z 98 for 2,2‐DEP, respectively. The pyrrolidine counterparts demonstrated similar phenomena including the expected mass difference of 14 Da due to the lack of one methylene unit in the ring. Two samples obtained from an Internet vendor provided confirmation that diphenidine was present in both samples, concurring with the product label. Finally, it was confirmed that diphenidine (30 μM) reduced N‐methyl‐D‐aspartate‐mediated field excitatory postsynaptic potentials (NMDA‐fEPSPs) to a similar extent to that of ketamine (30 μM) when using rat hippocampal slices. The appearance of 1,2‐ diphenylethylamines appears to reflect the exploration of alternatives to arylcyclohexylamine‐type substances, such as methoxetamine, PCP and PCPy‐based analogues that also show NMDA receptor activity as demonstrated here for diphenidine. Copyright © 2014 John Wiley & Sons, Ltd.

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“…27,28 In 'normal' animals, PPI is disrupted by the administration of drugs such as apomorphine (Apo) that acts as an agonist at D1 and D2 family dopamine receptors and amphetamine (Amp) that releases and inhibits reuptake of dopamine, 29,30 as well as the noncompetitive N-methyl-D-aspartic acid (NMDA)/ glutamate receptor antagonist phencyclidine (PCP). 29,31 The availability of Oxt knockout (À/À) mice provided an opportunity to assess, in the PPI model, the hypothesis that Oxt can act as a 'natural' antipsychotic. We predicted that OxtÀ/À mice would be more susceptible to the PPI-disrupting doses of psychotomimetics.…”

Section: Introductionmentioning

confidence: 99%

Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice

2008

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It has been previously suggested that oxytocin (Oxt) may act as a natural antipsychotic. To test this hypothesis, we investigated whether disruption of the oxytocin gene (OxtÀ/À) made mice more susceptible to the psychosis-related effects of amphetamine (Amp), apomorphine (Apo) and phencyclidine (PCP). We examined drug-induced changes in the prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating deficits characteristic of several psychiatric and neurological disorders, including schizophrenia. We found that treatment with Amp, Apo and PCP all had effects on PPI. However, in OxtÀ/À mice, but not Oxt þ / þ mice, PCP treatment resulted in large PPI deficits. As PCP is a noncompetitive N-methyl-D-aspartic acid receptor antagonist, these findings suggest that the absence of Oxt alters the glutamatergic component of the PPI.

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The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate

Cited by 1,329 publications

References 45 publications

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2‐diphenylethyl isomers

Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice

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