Ritalin (methylphenidate; MPH) is one of the most commonly prescribed drugs for children with attention deficit hyperactivity disorder (ADHD). Over the past decade, ritalin usage has increased in the United States such that children diagnosed with ADHD often are maintained on the drug throughout late childhood and adolescence. Little is known however, regarding the long term consequences of therapeutic doses of MPH on brain development. Developmental MPH exposure may profoundly affect synaptogenesis, myelination and gliogenesis in several brain regions. Of particular note is the process of synaptogenesis, which occurs postnatally in several regions of the brain that are associated with learning and memory (e.g., hippocampus and cerebral cortex). Thus, the present proposal seeks to generate data to aid in evaluating the safety of therapeutic maintenance of MPH in children and adolescents. To achieve this goal, two aims are proposed: (1 ) to develop an animal model that reflects the clinical maintenance of MPH in children and (2) to assess the effects of long-term developmental exposure to therapeutic doses of MPH in this model on the adult brain. Initially, this model will utilize the maximum therapeutic dosage and duration of MPH that is used to treat ADHD in children. Long-term exposure to therapeutic doses of MPH then will be assessed in the forebrain of young adult rats at two time-points using sensitive, quantitative immunocytochemical methods. Focus will be on the: (a) dopaminergic system; (b) ascending noradrenergic system; and (c) ascending serotonergic system (especially their innervation of the cerebral cortex and hippocampus), since current experimental evidence indicates that these monoamines are either directly or indirectly affected following MPH administration. Additionally, the basal forebrain cholinergic and cortical glutamatergic systems will be analyzed since both are targeted by monoaminergic afferent systems, play a prominent role in attention and undergo synaptogenesis postnatally. Monoaminergic and cholinergic neurons and their efferent processes will be identified using antibodies to either their synthetic enzymes or transporters (i.e., to label subpopulations that are important in uptake and release), whereas cortical glutamatergic synapses will be identified by antibodies to NMDA receptors. If changes in any of the immunocytochemical markers are seen using these parameters in this model, future experiments would focus on: (1) dosage (e.g., to determine the maximum dose necessary to see these changes); (2) duration (e.g., to determine if the changes diminish with smaller periods of exposure or to identify developmental stages that may be uniquely sensitive to the drug effects); and (3) the age of assessment (e.g., to determine if the changes persist as the brain ages). Determining how therapeutic dosage regimens effect these transmitter systems is critical in understanding the safety of long-term therapeutic doses of MPH administered to children and adolescents with ADHD and other related disorders.
|Torres-Reveron, Annelyn; Gray, Jason D; Melton, Jay T et al. (2009) Early postnatal exposure to methylphenidate alters stress reactivity and increases hippocampal ectopic granule cells in adult rats. Brain Res Bull 78:175-81|
|Gray, Jason D; Punsoni, Michael; Tabori, Nora E et al. (2007) Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress. J Neurosci 27:7196-207|