Methylphenidate Causes Behavioral Impairments and Neuron and Astrocyte Loss in the Hippocampus of Juvenile Rats.
Although the use, and misuse, of methylphenidate is increasing in childhood and adolescence, there is little information about the consequences of this psychostimulant chronic use on brain and behavior during development. The aim of the present study was to investigate hippocampus biochemical, histochemical, and behavioral effects of chronic methylphenidate treatment to juvenile rats. Wistar rats 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. Results showed that chronic methylphenidate administration caused loss of astrocytes and neurons in the hippocampus of juvenile rats. BDNF and pTrkB immunocontents and NGF levels were decreased, while TNF-α and IL-6 levels, Iba-1 and caspase 3 cleaved immunocontents (microglia marker and active apoptosis marker, respectively) were increased. ERK and PKCaMII signaling pathways, but not Akt and GSK-3β, were decreased. SNAP-25 was decreased after methylphenidate treatment, while GAP-43 and synaptophysin were not altered. Both exploratory activity and object recognition memory were impaired by methylphenidate. These findings provide additional evidence that early-life exposure to methylphenidate can have complex effects, as well as provide new basis for understanding of the biochemical and behavioral consequences associated with chronic use of methylphenidate during central nervous system development.
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Felipe
F
Schmitz
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Paula
P
Pierozan
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
André F
AF
Rodrigues
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Helena
H
Biasibetti
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Matheus
M
Grunevald
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.
Letícia F
LF
Pettenuzzo
Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
Giselli
G
Scaini
Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
Emilio L
EL
Streck
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.|Laboratório de Isquemia Cerebral e Psicobiologia dos Transtornos Mentais, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Carlos A
CA
Netto
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. wyse@ufrgs.br.|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. wyse@ufrgs.br.
Angela T S
ATS
Wyse
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008774:Methylphenidate / Q000633:toxicity*; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D021641:Recognition, Psychology; D015398:Signal Transduction; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D034961:Antigens, Nuclear; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D005904:Glial Fibrillary Acidic Protein; D008774:Methylphenidate; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D050825:Synaptosomal-Associated Protein 25; D014409:Tumor Necrosis Factor-alpha; C546339:Rbfox3 protein, rat
Cell survival pathways; Cytokines; Memory of object recognition; Methylphenidate; Neurotrophins; Synaptic proteins