Widespread administration of psychoactive drugs to children, often without documented pathology, occurs in most of the United States today. New trends toward prescribing medications for Attention Deficit Hyperactivity Disorder (ADHD) to children without parental/family physician approval will surely increase the exposure of our population to drugs containing methylphenidate. Adequate knowledge about the long-term effects of chronic exposure of healthy children does not exist. These studies will utilize a rat model to address the following:
Specific Aim 1 will determine the behavioral consequences of repeated methylphenidate (MPD) administration during periadolescence. Methylphenidate will be administered orally throughout the periadolescent period. A. Behavioral activation: Behavioral responses to MPD will be determined in photobeam boxes initially and after every thirteen days of dosing. The goal will be to find doses that activate behavior without producing sensitization. B. Spatial Learning: Effects of methylphenidate on performance in the radial arm maze (RAM) will be used as a measure of spatial learning. Rats will be trained on the 8-arm RAM daily following MPD dosing to determine whether MPD at doses which activate behavior facilitates learning. It is expected that MPD will enhance acquisition of spatial learning in the radial arm maze task.
Specific Aim 2 will determine the neurofunctional consequences of periadolescent methylphenidate exposure. Brain metabolism using the deoxyglucose method will be determined in rats trained on RAM (Aim 1B) after the last dose on day 60 and shifted to the 12-arm RAM. Brain sections will be analyzed for molecular markers of dopamine function using in situ hybridization histochemistry (ISHH). Correlations of brain function and behavior on the 12-arm RAM (assessed simultaneously) and between brain function within specific neuronal circuits will be determined. It is expected that repeated exposure to MPD will alter brain metabolism in two ways: increasing metabolism in components of the mesolimbic and nigrostriatal dopamine circuits and by increasing functional coupling (correlations) among components of the hippocampus.
Specific Aim 3 will determine the long-term behavioral and neurofunctional consequences of periadolescent methylphenidate exposure. It is expected that basal levels of brain metabolic function will also be altered 1 month after periadolescent exposure to MPD. Correlations between spontaneous behavior and metabolism as well as among metabolic rates in structures within identified neuronal circuits will be determined. Animals generated in Aim 1A will be used.
Specific Aim 4 will determine the plasma levels of methylphenidate which produce behavioral activation. Plasma drug levels will be determined at those doses which were found to produce behavioral alterations. This will facilitate comparison with human studies reporting therapeutic plasma drug levels. These studies will determine the immediate and long-term consequences of administration of methylphenidate in rats during childhood and adolescence. The overall hypothesis to be tested is that chronic administration of methylphenidate to periadolescent rats will alter learning as assessed in the radial arm maze, activate behavior, and produce immediate and long-term alterations in function of critical neural circuits. The functional relationships between components of the hippocampus and spatial cognition will be established and the effects of MPD on these relationships explored. Through these studies, a comprehensive pre-clinical evaluation of the effects of chronic methylphenidate on learning, behavior, brain function and molecular patterns will be completed.
