Effects of methylphenidate after a long period of discontinuation include changes in exploratory behavior and increases brain activities of Na+,K+-ATPase and acetylcholinesterase.

Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder. Since it is not yet known whether MPH can be administered in childhood without consequences in adulthood, in the present study we proposed to investigate the effects of chronic early treatment with MPH after a long period of discontinuation. Wistar male rats were injected with MPH (2 mg/kg, intraperitoneally) or saline solution once daily from 15th to 44th day of life. Two months after the last MPH administration, we evaluated the animal's performances on a battery of behavior tests. We also tested Na+,K+-ATPase and acetylcholinesterase activities in prefrontal cortex and hippocampus, which may be associated with behavior. Rats treated with MPH during peri-adolescence show changes in exploratory behavior in adulthood in the open field but not in the elevated plus maze and light-dark transition tests. MPH-treated rats showed a lower latency to find the platform in the training phase, as well as a better performance in the test phase in the Morris water maze test. No differences were observed in the object recognition index and working memory. Acetylcholinesterase was increased in prefrontal cortex and hippocampus, while Na+,K+-ATPase was increased only in hippocampus. These findings provide additional evidence that early-life exposure to MPH can have complex effects in adulthood and new basis for understanding the behavioral and neurochemical consequences associated with chronic use of MPH during the development of central nervous system.

Evidence That Methylphenidate Treatment Evokes Anxiety-Like Behavior Through Glucose Hypometabolism and Disruption of the Orbitofrontal Cortex Metabolic Networks.

Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder without a consensus about the consequences. Here, we evaluate the effect of MPH treatment on glucose metabolism and metabolic network in the rat brain, as well as on performance in behavioral tests. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 44th postnatal day. Fluorodeoxyglucose-18 was used to investigate cerebral metabolism, and a cross-correlation matrix was used to examine the brain metabolic network in MPH-treated rats using micro-positron emission tomography imaging. Performance in the light-dark transition box, eating-related depression, and sucrose preference tests was also evaluated. While MPH provoked glucose hypermetabolism in the auditory, parietal, retrosplenial, somatosensory, and visual cortices, hypometabolism was identified in the left orbitofrontal cortex. MPH-treated rats show a brain metabolic network more efficient and connected, but careful analyses reveal that the MPH interrupts the communication of the orbitofrontal cortex with other brain areas. Anxiety-like behavior was also observed in MPH-treated rats. This study shows that glucose metabolism evaluated by micro-positron emission tomography in the brain can be affected by MPH in different ways according to the region of the brain studied. It may be related, at least in part, to a rewiring in the brain the metabolic network and behavioral changes observed, representing an important step in exploring the mechanisms and consequences of MPH treatment.