(R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism

Abstract Background Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine’s action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice. Methods The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. Results (R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine. Conclusions (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

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Modulation of extracellular d-serine content by calcium permeable AMPA receptors in rat medial prefrontal cortex as revealed by in vivo microdialysis

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145712001484 ◽

2013 ◽

Vol 16 (6) ◽

pp. 1395-1406 ◽

Cited By ~ 12

Author(s):

Sayuri Ishiwata ◽

Asami Umino ◽

Masakazu Umino ◽

Kazuko Yorita ◽

Kiyoshi Fukui ◽

...

Keyword(s):

Prefrontal Cortex ◽

Receptor Antagonist ◽

Medial Prefrontal Cortex ◽

Glutamate Receptor ◽

Ampa Receptor ◽

In Vivo Microdialysis ◽

Receptor Subtype ◽

Fluorometric Detection ◽

Brain Functions

Abstract In mammalian brains, d-serine has been shown to be required for the regulation of glutamate neurotransmission as an endogenous co-agonist for the N-methyl-d-aspartate type glutamate receptor that is essential for the expression of higher-order brain functions. The exact control mechanisms for the extracellular d-serine dynamics, however, await further elucidation. To obtain an insight into this issue, we have characterized the effects of agents acting at the α-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPA) type glutamate receptor on the extracellular d-serine contents in the medial prefrontal cortex of freely moving rats by an in vivo microdialysis technique in combination with high-performance liquid chromatography with fluorometric detection. In vivo experiments are needed in terms of a crucial role of d-serine in the neuron-glia communications despite the previous in vitro studies on AMPA receptor-d-serine interactions using the separated preparations of neurons or glial cells. Here, we show that the intra-cortical infusion of (S)-AMPA, an active enantiomer at the AMPA receptor, causes a significant and concentration-dependent reduction in the prefrontal extracellular contents of d-serine, which is reversed by an AMPA/kainate receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, and a calcium permeable AMPA receptor antagonist, 1-naphthyl acetyl spermine. The d-serine reducing effects of (S)-AMPA are augmented by co-infusion of cyclothiazide that prevents AMPA receptor desensitization. Our data support the view that a calcium permeable AMPA receptor subtype may exert a phasic inhibitory control on the extracellular d-serine release in the mammalian prefrontal cortex in vivo.

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Dysfunction of dopamine release in the prefrontal cortex of dysbindin deficient sandy mice: An in vivo microdialysis study

Neuroscience Letters ◽

10.1016/j.neulet.2009.12.071 ◽

2010 ◽

Vol 470 (2) ◽

pp. 134-138 ◽

Cited By ~ 30

Author(s):

Taku Nagai ◽

Yuko Kitahara ◽

Anna Shiraki ◽

Takao Hikita ◽

Shinichiro Taya ◽

...

Keyword(s):

Prefrontal Cortex ◽

Dopamine Release ◽

In Vivo Microdialysis ◽

Microdialysis Study

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Tyrosine Augments Acute Clozapine- but not Haloperidol-Induced Dopamine Release in the Medial Prefrontal Cortex of the Rat An in vivo Microdialysis Study

Neuropsychopharmacology ◽

10.1016/s0893-133x(01)00220-2 ◽

2001 ◽

Vol 25 (1) ◽

pp. 149-156 ◽

Cited By ~ 16

Author(s):

G Jaskiw

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Dopamine Release ◽

In Vivo Microdialysis ◽

Microdialysis Study

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Psychological stress increases serotonin release in the rat amygdala and prefrontal cortex assessed by in vivo microdialysis

Neuroscience Letters ◽

10.1016/0304-3940(93)90565-3 ◽

1993 ◽

Vol 162 (1-2) ◽

pp. 81-84 ◽

Cited By ~ 170

Author(s):

Hiroshi Kawahara ◽

Masami Yoshida ◽

Hideyasu Yokoo ◽

Masakatsu Nishi ◽

Masatoshi Tanaka

Keyword(s):

Prefrontal Cortex ◽

Psychological Stress ◽

In Vivo Microdialysis ◽

Serotonin Release

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Epigenetic Repression of the Adaptor Molecule LAT2 by the Leukemic Fusion Protein AML1/ETO.

Blood ◽

10.1182/blood.v110.11.987.987 ◽

2007 ◽

Vol 110 (11) ◽

pp. 987-987

Author(s):

Jesus Duque-Afonso ◽

Tobias Berg ◽

Olaf Heidenreich ◽

Michael Luebbert

Keyword(s):

Fusion Protein ◽

Molecular Mechanisms ◽

Hdac Inhibitors ◽

Histone H3 ◽

Chimeric Protein ◽

Dependent Manner ◽

U937 Cells ◽

Conditional Expression ◽

Dose Dependent

Abstract The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO, resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein represses transcription by recruiting a nuclear co-repressor complex containing HDACs and DNMT1 to its target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/WBSCR5), which is involved in FcεR I, c-Kit, B cell- and T cell receptor signalling. Notably, LAT2 is strongly repressed in AML1/ETO positive cells including primary AML blasts, which was confirmed by others in several large AML cohorts. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. AML1/ETO was induced by Ponasterone A in an ecdysone-inducible system in U937 cells (9/14/18 cell line). To deplete AML1/ETO in t(8;21)-positive cells, we electroporated Kasumi-1 cells with AML1/ETO siRNA. To interfere with epigenetic modifications more directly, cells were treated with the DNMT inhibitor decitabine (DAC) and 4 different HDAC inhibitors. LAT2 expression was determined by Northern Blot, qRT-PCR and Western Blot. HDAC occupation and the histone status of the LAT2 promoter was examined by chromatin immunoprecipitation (ChIP). LAT2 mRNA was downregulated already after 4 hours of conditional expression of AML1/ETO in 9/14/18 cells, and constitutively repressed in the AML1/ETO-positive Kasumi-1 and SKNO-1 cells. siRNA-mediated AML1/ETO depletion caused a 9-fold upregulation of LAT2 in Kasumi-1 cells, suggesting a possible direct mechanism of repression. To address this question, we performed ChIP assays for the LAT2 promoter after AML1/ETO induction in 9/14/18 cells. AML1/ETO inhibited acetylation of histone H3, H3K9 and H4, but did not affect trimethylation of H3K4. These changes were associated with the recruitment of HDAC2, but not HDAC1 and HDAC3, to the LAT2 promoter. The HDAC inhibitors MS-275, SAHA, TSA and valproic acid induced LAT2 mRNA in a dose-dependent manner in AML1/ETO-expressing Kasumi-1, with MS-275 being the most efficient inhibitor. MS-275 induced LAT2 expression also in t(8;21)-positive SKNO-1, but not in AML1/ETO-negative HL60 and U937 cells. LAT2 mRNA was also upregulated in a dose-dependent manner after DAC treatment in Kasumi-1 cells. The combination of DAC and MS-275 had a synergistic effect on inhibition of cell growth, acetylation of histones H3 and H4, and re-expression of LAT2 mRNA. MS-275-mediated re-expression of LAT2 was associated with an increase in acetylation of histone H3, H3K9, H4 and trimethylation of H3K4. The increase of activating histone modifications was associated with the release of HDAC1, HDAC2 and HDAC3 from the LAT2 promoter. In conclusion, the epigenetic changes of the LAT2 promoter caused by AML1/ETO could be pharmacologically reverted by inhibition of histone acetylation.

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Effects of Conditioned Fear Stress on Dopamine Release from Ra1 Prefrontal Cortex as measured by in Vivo Microdialysis.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)37349-4 ◽

1996 ◽

Vol 71 ◽

pp. 277

Author(s):

Machiko Matsumoto ◽

Mitsuhiro Yoshioka ◽

Hiroko Togashi ◽

Hideya Saito

Keyword(s):

Prefrontal Cortex ◽

Dopamine Release ◽

Conditioned Fear ◽

In Vivo Microdialysis ◽

Conditioned Fear Stress

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Characterization of dopamine release in the rat medial prefrontal cortex as assessed by in vivo microdialysis: Comparison to the striatum

Neuroscience ◽

10.1016/0306-4522(90)90009-s ◽

1990 ◽

Vol 36 (3) ◽

pp. 669-676 ◽

Cited By ~ 67

Author(s):

B. Moghaddam ◽

R.H. Roth ◽

B.S. Bunney

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Dopamine Release ◽

In Vivo Microdialysis

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Inhibition of Metastatic Uveal Melanoma Cell Proliferation by the Histone Deacetylase 6 Inhibitor, Ricolinostat, is Linked to Altered Microphthalmia-associated Transcription Factor and Phospho-ERK Expression

10.1101/2021.10.28.466226 ◽

2021 ◽

Author(s):

Husvinee Sundaramurthi ◽

Sandra Garcia-Mulero ◽

Kayleigh Slater ◽

Simone Marcone ◽

Josep M. Piulats ◽

...

Keyword(s):

Transcription Factor ◽

Cell Survival ◽

Histone Deacetylase ◽

Uveal Melanoma ◽

Molecular Mechanisms ◽

Dependent Manner ◽

Histone Deacetylase 6 ◽

Dose Dependent

Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase 6 inhibitor (HDAC6i), to attenuate MUM cell growth in vitro and in vivo, and elucidate the underlying molecular mechanisms. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo regression of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry analysis revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0006) following 24 hours of treatment and significant apoptosis was triggered in a time- and dose-dependent manner (p = <0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome-profiling, attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329, significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of MUM cells and are potential therapeutic options for MUM.

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