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Review
. 2015 Feb;240(2):145-55.
doi: 10.1177/1535370214549531. Epub 2014 Sep 21.

Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans

Ke Xu  1 , Robert H Lipsky  2
Affiliations
Review

Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans

Ke Xu et al. Exp Biol Med (Maywood). 2015 Feb.

Abstract

For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.

Keywords: N-Methyl-d-aspartic acid (NMDA) receptor; gene expression; ketamine administration; ketamine-associated psychosis.

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Figures

Figure 1
Figure 1
Gene structure and annotation for GRIN1 (a), GRIN2A (b), and GRIN2B (c). Data are from the University of California Santa Cruz (UCSC) Genome Browser. Panel (a): the human GRIN1 gene has seven transcripts. At the 5’ end, there is a high methylation region with high density of H3K27Ac (a histone modification mark), and a CpG island. Interestingly, this critical region contains six conserved transcription factor binding sites including CREB that may involve the mechanism of neuroplasticity and addiction. A long RNA is identified across this region. Within this region, 13 common SNPs are identified. The SNP rs11146020 maps close to this region and was found associated with schizophrenia in some studies; Panel (b): GRIN2A has four transcripts. A possible regulatory region is located in intron 7. The region contains a high density of H3K27Ac marks, multiple conserved transcription factor binding sites, long RNA sequence found by ENCODE. A (TC)17 polymorphism is identified within this region; (c) GRIN2B has one mRNA transcript. The second intron has a high density of histone modification marks with conserved transcription factor binding sites, suggesting a potential regulation region. Multiple microsatellite polymorphisms are identified in GRIN2B. (A color version of this figure is available in the online journal.)
Figure 1
Figure 1
Gene structure and annotation for GRIN1 (a), GRIN2A (b), and GRIN2B (c). Data are from the University of California Santa Cruz (UCSC) Genome Browser. Panel (a): the human GRIN1 gene has seven transcripts. At the 5’ end, there is a high methylation region with high density of H3K27Ac (a histone modification mark), and a CpG island. Interestingly, this critical region contains six conserved transcription factor binding sites including CREB that may involve the mechanism of neuroplasticity and addiction. A long RNA is identified across this region. Within this region, 13 common SNPs are identified. The SNP rs11146020 maps close to this region and was found associated with schizophrenia in some studies; Panel (b): GRIN2A has four transcripts. A possible regulatory region is located in intron 7. The region contains a high density of H3K27Ac marks, multiple conserved transcription factor binding sites, long RNA sequence found by ENCODE. A (TC)17 polymorphism is identified within this region; (c) GRIN2B has one mRNA transcript. The second intron has a high density of histone modification marks with conserved transcription factor binding sites, suggesting a potential regulation region. Multiple microsatellite polymorphisms are identified in GRIN2B. (A color version of this figure is available in the online journal.)
Figure 2
Figure 2
A proposed molecular mechanism describing initial ketamine use (left) and chronic abuse (right): initial ketamine use may involve altering two pathways: NMDA and dopamine receptors. Ketamine blocks NMDA receptor-dependent activation of NF-κB and CREB that promote synaptic plasticity via BDNF. However, ketamine also enhances dopamine function, via increased dopamine release and intracellular signaling, leading to activation of CREB. Increased CREB activation enhances BDNF transcription. In addition, ketamine enhances translation of BDNF mRNA, leading to increased neuroplasticity and addiction. Chronic ketamine exposure induces compensatory GRIN1 up-regulation that causes an influx of extracellular Ca2+ into the intracellular compartment. The overloaded Ca2+ infux produces superoxide anion that activates NF-κB, to promote Bax gene expression which is critical to active caspase, leading to apoptosis. (A color version of this figure is available in the online journal.)
See this image and copyright information in PMC

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