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Objectives: To evaluate oxidative damage through the thiobarbituric acid-reactive species (TBARS) and protein carbonyl groups; antioxidant enzymatic system - superoxide dismutase (SOD) and catalase (CAT); and energetic metabolism in the brain of spontaneously hypertensive adult rats (SHR) after both acute and chronic treatment with methylphenidate hydrochloride (MPH)., Methods: Adult (60 days old) SHRs were treated during 28 days (chronic treatment), or 1 day (acute treatment). The rats received one i.p. injection per day of either saline or MPH (2 mg/kg). Two hours after the last injection, oxidative damage parameters and energetic metabolism in the cerebellum, prefrontal cortex, hippocampus, striatum and cortex were evaluated., Results: We observed that both acute and/or chronic treatment increased TBARS and carbonyl groups, and decreased SOD and CAT activities in many of the brain structures evaluated. Regarding the energetic metabolism evaluation, the acute and chronic treatment altered the energetic metabolism in many of the brain structures evaluated., Conclusion: We observed that both acute and chronic use of methylphenidate hydrochloride (MPH) in adult spontaneously hypertensive rats (SHRs) was associated with increased oxidative stress and energetic metabolism alterations. These data also reinforce the importance of the SHR animal model in further studies regarding MPH.

Objective: Methylphenidate hydrochloride is the most widely used medication for treatment and management of attention-deficit hyperactivity disorder. However, the chronic effects of methylphenidate hydrochloride on anxiety- and depressive-like rat behaviors remain poorly investigated. In this context, the present study evaluated the effects of treatment with methylphenidate hydrochloride on anxiety- and depressive-like behaviors using young and adult rats during the light and the dark cycle., Method: Male Wistar rats (25 or 60 days old) received a once-daily (in either the light or dark cycle) methylphenidate hydrochloride (2mg/kg) or saline intraperitoneal injection for 28 days. We performed elevated plus maze and forced swimming test two hours after the last injection., Results: The light/dark cycle was a significant factor in the anxiety-like behaviors; however, no significant interaction between all three factors (cycle, age and methylphenidate hydrochloride) was found. Nevertheless, we observed a nominally significant interaction between the light/ dark cycle and age in the forced swimming test., Conclusion: Our results have shown that age and the light/dark cycle are more significant modulators of anxiety- and depressive-like behaviors than methylphenidate hydrochloride treatment.

Methylphenidate (MPH) is a very effective treatment option for children and adolescents with attention-deficit/hyperactivity disorder. Nevertheless, there have been inconsistent reports regarding the effects of MPH on learning and memory. The aim of this study was to evaluate whether the treatment with MPH during the morning differs from that during the night on learning and memory (short and long term) in young and adult male Wistar rats. The animals received once daily intraperitoneal injection of either MPH (2 mg/kg) or saline (0.9%) for 28 days (either in the morning or at night). The animals underwent two behavioral tasks to evaluate learning and memory: inhibitory avoidance task and continuous multiple trials step-down inhibitory avoidance (CMIA). Young rats treated in the morning showed significant impaired long-term memory for inhibitory avoidance training and facilitated acquisition in the CMIA. Adult rats treated in the night showed impaired long-term retention in the CMIA. We observed similar performances in both tests for young rats treated at night or adult rats treated in the morning. Our results suggest that age and time of treatment can alter the MPH effects in learning and memory.

Methylphenidate is a central nervous system stimulant used for the treatment of attention-deficit hyperactivity disorder. Na(+), K(+)-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that methylphenidate effects on central nervous system metabolism are poorly known and that Na(+), K(+)-ATPase is essential to normal brain function, the purpose of this study was to evaluate the effect of this drug on Na(+), K(+)-ATPase activity in the cerebrum of young and adult rats. For acute administration, a single injection of methylphenidate (1.0, 2.0, or 10.0 mg/Kg) or saline was given to rats on postnatal day 25 or postnatal day 60, in the young and adult groups, respectively. For chronic administration, methylphenidate (1.0, 2.0, or 10.0 mg/Kg) or saline injections were given to young rats starting at postnatal day 25 once daily for 28 days. In adult rats, the same regimen was performed starting at postnatal day 60. Our results showed that acute methylphenidate administration increased Na(+), K(+)-ATPase activity in hippocampus, prefrontal cortex, and striatum of young and adult rats. In young rats, chronic administration of methylphenidate also enhanced Na(+), K(+)-ATPase activity in hippocampus and prefrontal cortex, but not in striatum. When tested in adult rats, Na(+), K(+)-ATPase activity was increased in all cerebral structures studied. The present findings suggest that increased Na(+), K(+)-ATPase activity may be associated with neuronal excitability caused by methylphenidate.

The prescription of methylphenidate (MPH) has dramatically increased in this decade for attention deficit hyperactivity disorder (ADHD) treatment. The action mechanism of MPH is not completely understood and studies have been demonstrated that MPH can lead to neurochemical adaptations. Superoxide radical anion is not very reactive per se. However, severe species derived from superoxide radical anion mediate most of its toxicity. In this study, the superoxide level in submitochondrial particles was evaluated in response to treatment with MPH in the age-dependent manner in rats. MPH was administrated acutely or chronically at doses of 1, 2 or 10 mg/kg i.p. The results showed that the acute administration of MPH in all doses in young rats increased the production of superoxide in the cerebellum and only in the high dose (10mg/kg) in the hippocampus, while chronic treatment had no effect. However, acute treatment in adult rats had no effect on production of superoxide, but chronic treatment decreased the production of superoxide in the cerebellum at the lower doses. Our data suggest that the MPH treatment can influence on production of superoxide in some brain areas, but this effect depends on age of animals and treatment regime with MPH.

In this study age-, circadian rhythm- and methylphenidate administration- effect on open field habituation and object recognition were analyzed. Young and adult male Wistar rats were treated with saline or methylphenidate 2.0 mg/kg for 28 days. Experiments were performed during the light and the dark cycle. Locomotor activity was significantly altered by circadian cycle and methylphenidate treatment during the training session and by drug treatment during the testing session. Exploratory activity was significantly modulated by age during the training session and by age and drug treatment during the testing session. Object recognition memory was altered by cycle at the training session; by age 1.5 h later and by cycle and age 24 h after the training session. These results show that methylphenidate treatment was the major modulator factor on open-field test while cycle and age had an important effect on object recognition experiment.

Dopamine may alter the phosphorylation state of DARPP-32 that plays a central role in the dopaminergic neurons biology. Studies have shown that DARPP-32/protein phosphatase 1 cascade is a major target for psychostimulants drugs. Methylphenidate is a psychostimulant that acts blocking the dopamine transporter has been used as an effective treatment for Attention Deficit Hyperactivity Disorder. We investigated if methylphenidate could alter DARPP-32 expression in five brain regions (striatum, hippocampus, prefrontal cortex, cortex and cerebellum) in young and adult rats. Our results showed that methylphenidate treatment is able to alter DARPP-32 expression in rat brain. Acute methylphenidate treatment has reduced hippocampal DARPP-32 protein levels in old rats, while chronic methylphenidate treatment has decreased them in old rat hippocampus and young rat cerebellum. It was found an increased cortical expression after chronic methylphenidate administration in old rats. Our results provide the first experimental demonstration that methylphenidate induces changes in total DARPP-32 expression that are posology- and age-related in some rat brain areas, although further studies are needed to shed more light on the mechanisms behind these findings.

Aims: The high prevalence of Attention Deficit/Hyperactivity Disorder (ADHD) and the increased therapeutic use of methylphenidate (MPH) raise some concerns regarding its long-term side effects and safety profile. Considering that MPH effects on brain metabolism are poorly known and that creatine kinase (CK) plays an important role in cell energy homeostasis, we evaluated CK activity in the brain of young and adult rats following acute (one injection) or chronic (28 days) administration of MPH., Main Methods: MPH was acutely or chronically administered to young and adult rats. For acute administration, a single injection of MPH was given to rats on postnatal day (PD) 25 or PD 60, in the young and adult groups, respectively. For chronic administration, MPH injections were given to young rats starting at PD 25 once daily for 28 days (last injection at PD 53). In adult rats, the same regimen was performed starting at PD 60 (last injection at PD 88). CK activity was measured in brain homogenates., Key Findings: Our results showed that MPH acute administration increased the enzyme in prefrontal cortex, hippocampus, striatum and cerebral cortex, but not cerebellum of young and adult rats. Chronic administration of MPH also increased CK activity in these brain regions, as well as the cerebellum, in young and adult rats. The highest dose (10.0 mg/kg) presented more pronouncing effects., Significance: The present findings suggest that acute or chronic exposure to MPH increased CK activity, an enzyme involved in energy homeostasis, in the brain of young and adult rats.

Methylphenidate has been used as an effective treatment for attention deficit hyperactivity disorder (ADHD). Methylphenidate (MPH) blocks dopamine and norepinephrine transporters causing an increase in extracellular levels. The use of psychomotor stimulants continues to rise due to both the treatment of ADHD and illicit abuse. Methylphenidate sensitization mechanism has still poor knowledge. Neuronal calcium sensor 1 was identified as a dopaminergic receptor interacting protein. When expressed in mammalian cells, neuronal calcium sensor 1 attenuates dopamine-induced D2 receptor internalization by a mechanism that involves a reduction in D2 receptor phosphorylation. Neuronal calcium sensor 1 appears to play a pivotal role in regulating D2 receptor function, it will be important to determine if there are alterations in neuronal calcium sensor 1 in neuropathologies associated with deregulation in dopaminergic signaling. Then, we investigated if methylphenidate could alter neuronal calcium sensor 1 expression in five brain regions (striatum, hippocampus, prefrontal cortex, cortex and cerebellum) in young and adult rats. These regions were chosen because some are located in brain circuits related with attention deficit hyperactivity disorder. Our results showed changes in neuronal calcium sensor 1 expression in hippocampus, prefrontal cortex and cerebellum mainly in adult rats. The demonstration that methylphenidate induces changes in neuronal calcium sensor 1 levels in rat brain may help to understand sensitization mechanisms as well as methylphenidate therapeutic effects to improve attention deficit hyperactivity disorder symptoms.

Methylphenidate (MPH) is psychostimulants used to treat Attention-Deficit/Hyperactivity Disorder and can lead to a long-lasting neurochemical and behavioral adaptations in experimental animals. In the present study, the cerebral antioxidant enzymatic system, superoxide dismutase (SOD) and catalase (CAT) was evaluated at in different age following MPH (1, 2 or 10 mg/kg MPH, i.p.) treatment in young rats. In the acute treatment the SOD activity decreased in the cerebral prefrontal cortex with opposite effect in the cerebral cortex; and the CAT activity decreased in hippocampus. In the chronic treatment the SOD activity increased in the hippocampus and cerebral cortex and decreased in the striatum. The observed changes on the enzyme activities in rat brain were dependent on the structure brain region and duration of treatment with MPH. Probably, the activity of enzymes was not be enough to prevent MPH-induced oxidative damage in specific regions from brain, such as observed for us in another recent study.

Background: Methylphenidate (MPH) is a widely prescribed psychostimulant for the treatment of attention-deficit hyperactivity disorder (ADHD). Recently, some studies have addressed the genotoxic potential of the MPH, but the results have been contradictory. Hence, the present study aimed to investigate the index of cerebral and peripheral DNA damage in young and adult rats after acute and chronic MPH exposure., Methods: We used (1) single cell gel electrophoresis (Comet assay) to measure early DNA damage in hippocampus, striatum and total blood, and (2) micronucleus test in total blood samples., Results: Our results showed that MPH increased the peripheral index of early DNA damage in young and adult rats, which was more pronounced with chronic treatment and in the striatum compared to the hippocampus. Neither acute nor chronic MPH treatment increased micronucleus frequency in young or in adult rats. Peripheral DNA damage was positively correlated with striatal DNA damage., Conclusion: These results suggest that MPH may induce central and peripheral early DNA damage, but this early damage may be repaired.

Methylphenidate (MPH) is frequently prescribed for the treatment of attention deficit/hyperactivity disorder. Psychostimulants can cause long-lasting neurochemical and behavioral adaptations. Here, we evaluated oxidative damage in the rat brain and the differential age-dependent response to MPH after acute and chronic exposure. We investigated the oxidative damage, assessed by the thiobarbituric acid reactive species (TBARS), and the protein carbonyl assays in cerebellum, prefrontal cortex, hippocampus, striatum, and cerebral cortex of young (25 days old) and adult (60 days old) male Wistar rats after acute and chronic exposure to MPH. Chronic MPH-treated young rats presented a dose-dependent increase in TBARS content and protein carbonyls formation in specific rat brain regions. In the acute exposure, only MPH highest dose increased lipid peroxidation in the hippocampus. No difference in protein carbonylation was observed among groups in all structures analyzed. In adult rats, we did not find oxidative damage in both acute and chronic treatment. Chronic exposure to MPH in induces oxidative damage in young rat brain, differentially from chronic exposure during adulthood. These findings highlight the need for further research to improve understanding of MPH effects on developing nervous system and the potential consequences in adulthood resulting from early-life drug exposure.

Objective: Methylphenidate hydrochloride is the most widely used medication for treatment and management of attention-deficit hyperactivity disorder. However, the chronic effects of methylphenidate hydrochloride on anxiety- and depressive-like rat behaviors remain poorly investigated. In this context, the present study evaluated the effects of treatment with methylphenidate hydrochloride on anxiety-and depressive-like behaviors using young and adult rats during the light and the dark cycle. Method: Male Wistar rats (25 or 60 days old) received a once-daily (in either the light or dark cycle) methylphenidate hydrochloride (2mg/kg) or saline intraperitoneal injection for 28 days. We performed elevated plus maze and forced swimming test two hours after the last injection. Results: The light/dark cycle was a significant factor in the anxiety-like behaviors; however, no significant interaction between all three factors (cycle, age and methylphenidate hydrochloride) was found. Nevertheless, we observed a nominally significant interaction between the light/dark cycle and age in the forced swimming test. Conclusion: Our results have shown that age and the light/dark cycle are more significant modulators of anxiety- and depressive-like behaviors than methylphenidate hydrochloride treatment. [ABSTRACT FROM AUTHOR]

Methylphenidate is a central nervous system stimulant used for the treatment of attention-deficit hyperactivity disorder. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that methylphenidate effects on central nervous system metabolism are poorly known and that Na+, K+-ATPase is essential to normal brain function, the purpose of this study was to evaluate the effect of this drug on Na+, K+-ATPase activity in the cerebrum of young and adult rats. For acute administration, a single injection of methylphenidate (1.0, 2.0, or 10.0 mg/Kg) or saline was given to rats on postnatal day 25 or postnatal day 60, in the young and adult groups, respectively. For chronic administration, methylphenidate (1.0, 2.0, or 10.0 mg/Kg) or saline injections were given to young rats starting at postnatal day 25 once daily for 28 days. In adult rats, the same regimen was performed starting at postnatal day 60. Our results showed that acute methylphenidate administration increased Na+, K+-ATPase activity in hippocampus, prefrontal cortex, and striatum of young and adult rats. In young rats, chronic administration of methylphenidate also enhanced Na+, K+-ATPase activity in hippocampus and prefrontal cortex, but not in striatum. When tested in adult rats, Na+, K+-ATPase activity was increased in all cerebral structures studied. The present findings suggest that increased Na+, K+-ATPase activity may be associated with neuronal excitability caused by methylphenidate. [ABSTRACT FROM AUTHOR]