Chronic Treatment with a Clinically Relevant Dose of Methylphenidate Increases Glutamate Levels in Cerebrospinal Fluid and Impairs Glutamatergic Homeostasis in Prefrontal Cortex of Juvenile Rats

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• 作者：Felipe Schmitz ; Paula Pierozan ; André F. Rodrigues…
• 关键词：Methylphenidate ; Juvenile rats ; Excitotoxicity glutamatergic ; Cerebrospinal fluid ; Prefrontal cortex ; α subunits of Na+ ; K+ ; ATPase
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：53
• 期：4
• 页码：2384-2396
• 全文大小：591 KB
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• 作者单位：Felipe Schmitz (1) <br> Paula Pierozan (1) <br> André F. Rodrigues (1) <br> Helena Biasibetti (1) <br> Daniella M. Coelho (2) <br> Ben Hur Mussulini (3) <br> Mery S. L. Pereira (3) <br> Mariana M. Parisi (4) <br> Florencia Barbé-Tuana (4) <br> Diogo L. de Oliveira (3) <br> Carmen R. Vargas (2) <br> Angela T. S. Wyse (1) <br><br>1. Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil <br> 2. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil <br> 3. Laboratório de Sinalização Glutamatérgica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil <br> 4. Laboratório de Biologia Molecular, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil <br>
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

The understanding of the consequences of chronic treatment with methylphenidate is very important since this psychostimulant is extensively prescribed to preschool age children, and little is known about the mechanisms underlying the persistent changes in behavior and neuronal function related with the use of methylphenidate. In this study, we initially investigate the effect of early chronic treatment with methylphenidate on amino acids profile in cerebrospinal fluid and prefrontal cortex of juvenile rats, as well as on glutamatergic homeostasis, Na+,K+-ATPase function, and balance redox in prefrontal cortex of rats. Wistar rats at early age received intraperitoneal injections of methylphenidate (2.0 mg/kg) or an equivalent volume of 0.9 % saline solution (controls), once a day, from the 15th to the 45th day of age. Twenty-four hours after the last injection, the animals were decapitated and the cerebrospinal fluid and prefrontal cortex were obtained. Results showed that methylphenidate altered amino acid profile in cerebrospinal fluid, increasing the levels of glutamate. Glutamate uptake was decreased by methylphenidate administration, but GLAST and GLT-1 were not altered by this treatment. In addition, the astrocyte marker GFAP was not altered by MPH. The activity and immunocontent of catalytic subunits (αb>1b>, αb>2b>, and αb>3b>) of Na+,K+-ATPase were decreased in prefrontal cortex of rats subjected to methylphenidate treatment, as well as changes in αb>1b> and αb>2b> gene expression of catalytic α subunits of Na+,K+-ATPase were also observed. CAT activity was increased and SOD/CAT ratio and sulfhydryl content were decreased in rat prefrontal cortex. Taken together, our results suggest that chronic treatment with methylphenidate at early age induces excitotoxicity, at least in part, due to inhibition of glutamate uptake probably caused by disturbances in the Na+,K+-ATPase function and/or in protein damage observed in the prefrontal cortex.