Inhibition of the glycine transporter GlyT‐1 potentiates the effect of risperidone, but not clozapine, on glutamatergic transmission in the rat medial prefrontal cortex
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Abstract Clinical studies suggest that the efficacy of the atypical antipsychotic drug (APD) risperidone (but not clozapine) can be augmented by adjunctive treatment with agonists at the glycine site of the N ‐methyl‐ D ‐aspartate (NMDA) receptor. By using intracellular recording, we have investigated the effect of the glycine transporter‐1 (GlyT‐1) inhibitor N [3‐(4′‐fluorophenyl)‐3‐(4′phenylphenylphenoxy) propyl] sarcosine (NFPS) on NMDA‐induced currents in pyramidal cells of the medial prefrontal cortex (mPFC), both when given alone and in combination with either risperidone or clozapine. Both risperidone and clozapine enhanced the NMDA‐induced currents. The concentration–response curves were biphasic, and the maximal effect of clozapine on the NMDA‐induced currents was significantly larger than the maximal effect of risperidone. NFPS also significantly potentiated the NMDA‐induced currents, when given alone. Moreover, NFPS (1 μM) augmented the effect of both the maximal (20 nM), and a submaximal (10 nM), concentration of risperidone. In contrast, NFPS did not potentiate either the effect of the maximal (100 nM) or a submaximal (80 nM) concentration of clozapine on the NMDA‐induced currents. These data may explain the beneficial clinical results of using glycine reuptake antagonists as adjuvant treatment to risperidone. Our findings also suggest that risperidone and clozapine may affect NMDA receptor‐mediated neurotransmission differently in the mPFC. Synapse 60:102–108, 2006. © 2006 Wiley‐Liss, Inc.Keywords:
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1. Streptomyces V-187 produces on minimal medium a mixture composed mainly of actinomycin C(1) (actinomycin D) and actinomycin A(1) (actinomycin I). If sarcosine is added to the medium, the micro-organism produces, in addition to actinomycins C(1) and A(1), actinomycin F(8) (actinomycin II) and actinomycin F(9) (actinomycin (III), characterized by the substitution by sarcosine of one or both the proline molecules present in actinomycin C(1). 2. Exogenous sarcosine seems to be incorporated as such by Streptomyces V-187 only in the sarcosine molecule(s) that replace proline in the actinomycins of the F group, whereas, for the synthesis of the other sarcosine molecules, the amino acid is first demethylated to glycine. 3. The incorporation of sarcosine and glycine into actinomycin by Streptomyces antibioticus appears to follow a similar pattern, except that a portion of the methyl group produced in the degradation of sarcosine is utilized as a source of the methyl groups of the antibiotic. This explains the previously reported lack of cross-dilution between glycine and sarcosine observed in the incorporation of these amino acids into actinomycin.
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The bacterium Pseudomonas PG2982 metabolizes glyphosate (N-(phosphonomethyl)glycine) by converting it to glycine, a one-carbon unit, and phosphate. Here we show that this conversion involves the intermediate formation of sarcosine. When cells are incubated with [14C]glyphosate, the 14C can be entrapped in glycine or sarcosine. With added sarcosine, 14C from all three carbons of glyphosate is recovered solely in sarcosine. In experiments with glycine, radioactivity from the carboxymethyl moiety of glyphosate is trapped in glycine as well as serine, whereas radioactivity from the phosphonomethyl carbon is only incorporated into serine. These results are consistent with a pathway involving the conversion of glyphosate to sarcosine by cleavage of its carbon-phosphorus (C-P) bond, followed by the oxidation of sarcosine to glycine and formaldehyde.
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Glycine cleavage system
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Abstract Glycine, methylglycine (sarcosine) and dimethylglycine can be quantitatively separated in starch columns using water‐alcohol 2:1 (v/v) as eluting agent. If amino acid hydrochlorides are to be separated, the eluting agent must be acidified with HCl. Likewise the partial separation of some peptides has been achieved by applying water‐alcohol 2:1.
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Objective:To understand the effects of antipsychotic,chlorderazin,clozapine and risperidone on blood glucose in patients with schizophrenia.Methods: Eighty eight patients first onset with schizophrenia were randomly divided into three groups,each group treated with chlorderazin,clozapine and Risperidone respectively for 8 weeks.The blood glucose,using Rayto-200c automatic biochemistry analyzer,was tested before treatment, at 4 and 8 weeks management.Results:The blood glucose level was higher in group clozapine than other two groups(P0.01),but no changes in group chlorderazin and Risperidone before and after drug treatment(P0.05).Conclusion: Clozapine can produce metabolic disorder of blood glucose.We should monitor it when initiate clozapine for patients.
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Objective: To compare serum concentrations of risperidone, 9‐hydroxy (OH) risperidone and risperidone plus 9‐OH risperidone, as well as the 9‐OH risperidone/risperidone ratio in patients receiving depot and oral risperidone. Method: Serum concentrations from 78 patients receiving three different doses of risperidone depot were measured and compared with serum concentrations from 82 patients taking three different doses of oral risperidone. Results: Patients receiving risperidone depot had significantly lower serum concentrations of risperidone plus 9‐OH risperidone than patients taking oral risperidone. More interestingly, the 9‐OH risperidone/risperidone ratio was also significantly lower in patients receiving risperidone depot than in patients taking oral risperidone. Conclusion: Serum concentrations of risperidone plus 9‐OH risperidone may be a rather poor indication of the antipsychotic efficacy of risperidone unless their ratio is also considered.
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治療抵抗性の統合失調症患者を対象に,clozapine 治療が抗精神病薬の頓用使用に 及ぼす影響について検討した。対象は,clozapine 治療開始前に慈圭病院に26週間以上入 院していた治療抵抗性統合失調症患者で,2017 年9月 30日までに clozapine を処方開始し た症例とした。抗精神病薬の頓用使用が 7 日間全くない週を無頓用週と定義して, clozapine 開始前後26週間(合計52週間)でその頻度を評価した。さらに,無頓用週以外 に,隔離あるいは拘束期間や,閉鎖あるいは開放病床使用期間,外来期間に関しても週単 位で評価した。結果,45例が研究対象となった。Clozapine 療法によって,無頓用週は有 意に増加し,その増加は投与後 5 週目には明らかになった。対象45例全体では,隔離や 拘束があった週が減少傾向を示し,開放病床を利用した週が有意に増加した。今回指標に 用いた無頓用週は,症状改善の指標というよりは病状の安定化の指標であり,本研究から clozapine の使用によって症状の安定化が投与後約 1 ヵ月頃から得られることが示唆され た。 臨床精神薬理 23:1029-1040, 2020 Key words ::clozapine, effectiveness, retrospective, treatment-resistant schizophrenia
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