Nagendra S Singh1, Michel Bernier2, Simonetta Camandola3, Mohammed A Khadeer1, Ruin Moaddel1, Mark P Mattson3, Irving W Wainer1. 1. Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. 2. Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. 3. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Abstract
BACKGROUND AND PURPOSE: Patients with major depressive disorder receiving racemic ketamine, (R,S)-ketamine, experience transient increases in Clinician-Administered Dissociative States Scale scores and a coincident drop in plasma d-serine levels. The results suggest that (R,S)-ketamine produces an immediate, concentration-dependent pharmacological effect on d-serine plasma concentrations. One potential source of this effect is (R,S)-ketamine-induced inhibition of the transporter ASCT2, which regulates intracellular d-serine concentrations. In this study, we tested this hypothesis by examining the effect of (S)- and (R)-ketamine on ASCT2-mediated transport of d-serine in PC-12 and 1321N1 cells and primary neuronal cells in culture. EXPERIMENTAL APPROACH: Intracellular and extracellular d-serine levels were determined using capillary electrophoresis-laser-induced fluorescence and liquid chromatography-mass spectrometry respectively. Expression of ASCT2, Asc-1 and serine racemase was determined utilizing Western blotting. KEY RESULTS: (S)-Ketamine produced a concentration-dependent increase in intracellular d-serine and reduced extracellular d-serine accumulation. In contrast, (R)-ketamine decreased both intracellular and extracellular d-serine levels. The ASCT2 inhibitor, benzyl-d-serine (BDS), and ASCT2 gene knockdown mimicked the action of (S)-ketamine on d-serine in PC-12 cells, while the Asc-1 agonist d-isoleucine reduced intracellular d-serine and increased extracellular d-serine accumulation. This response to d-isoleucine was not affected by BDS or (S)-ketamine. Primary cultures of rat neuronal cells expressed ASCT2 and were responsive to (S)-ketamine and BDS. (S)- and (R)-ketamine increased the expression of monomeric serine racemase in all the cells studied, with (S)-ketamine having the greatest effect. CONCLUSIONS AND IMPLICATIONS: (S)-Ketamine decreased cellular export of d-serine via selective inhibition of ASCT2, and this could represent a possible source of dissociative effects observed with (R,S)-ketamine. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
BACKGROUND AND PURPOSE:Patients with major depressive disorder receiving racemic ketamine, (R,S)-ketamine, experience transient increases in Clinician-Administered Dissociative States Scale scores and a coincident drop in plasma d-serine levels. The results suggest that (R,S)-ketamine produces an immediate, concentration-dependent pharmacological effect on d-serine plasma concentrations. One potential source of this effect is (R,S)-ketamine-induced inhibition of the transporter ASCT2, which regulates intracellular d-serine concentrations. In this study, we tested this hypothesis by examining the effect of (S)- and(R)-ketamine on ASCT2-mediated transport of d-serine in PC-12 and 1321N1 cells and primary neuronal cells in culture. EXPERIMENTAL APPROACH: Intracellular and extracellular d-serine levels were determined using capillary electrophoresis-laser-induced fluorescence and liquid chromatography-mass spectrometry respectively. Expression of ASCT2, Asc-1 and serine racemase was determined utilizing Western blotting. KEY RESULTS:(S)-Ketamine produced a concentration-dependent increase in intracellular d-serine and reduced extracellular d-serine accumulation. In contrast, (R)-ketamine decreased both intracellular and extracellular d-serine levels. The ASCT2 inhibitor, benzyl-d-serine (BDS), and ASCT2 gene knockdown mimicked the action of (S)-ketamine on d-serine in PC-12 cells, while the Asc-1 agonist d-isoleucine reduced intracellular d-serine and increased extracellular d-serine accumulation. This response to d-isoleucine was not affected by BDS or (S)-ketamine. Primary cultures of rat neuronal cells expressed ASCT2 and were responsive to (S)-ketamine and BDS. (S)- and(R)-ketamine increased the expression of monomeric serine racemase in all the cells studied, with (S)-ketamine having the greatest effect. CONCLUSIONS AND IMPLICATIONS: (S)-Ketamine decreased cellular export of d-serine via selective inhibition of ASCT2, and this could represent a possible source of dissociative effects observed with (R,S)-ketamine. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
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