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S-Methyl-L-Cysteine Levels in Plasma and Striatum Following its Intraperitoneal Administration and The Effects on Striatal D-Serine Levels in Rats:An In Vivo Microdialysis Study

Mayu Onozato, Katsuyuki Ishimaru, Chihiro Nagashima, Minori Fukumoto, Hiromi Nakazawa, Miho Shishikura, Tatsuya Sakamoto, Hideaki Iizuka, Hideaki Ichiba, Takeshi Fukushima

Several recent studies have attempted to treat schizophrenia by increasing brain levels of D-serine (D-Ser), a co-agonist of N-methyld- aspartate receptors. Here, we intraperitoneally (i.p.) administered S-Methyl-L-cysteine (SMLC), an inhibitor of alanine-serine-cysteine transporter 1 (Asc-1), to male Sprague Dawley rats and investigated changes in plasma levels. Extracellular D-Ser levels and SMLC levels in the striatum were investigated using an in vivo microdialysis technique. Changes in endogenous L-serine (L-Ser), glycine (Gly), dopamine (DA), homovanillic acid (HVA), and 5-hydroxyindole acetic acid (HIAA) levels were also assessed. The maximum concentrations of SMLC in plasma and microdialysis samples were achieved within 60 and 90 min, respectively. SMLC was able to penetrate the blood-brain barrier and reach the striatum in a short time. It caused a dose-dependent increase in endogenous D-Ser levels, which then remained constant in the striatum, suggesting that peripheral administration of SMLC effectively increased endogenous D-Ser levels. SMLC also significantly increased L-Ser levels by inhibiting Asc-1, with limited effects on Gly, DA, HVA, and HIAA levels. These results suggest that the i.p. SMLC increased striatal D-Ser levels without affecting the release of other neurotransmitters.