The long-term objectives of this research are to understand the changes in neuronal structure and function that may be caused by long-term use of ethylphenidate. ADHD/ADD is a common disorder affecting as many as 6% of schoolchildren. The ADHD/ADD population is at risk for school failure, difficulties with interpersonal relationships, and later substance abuse. ADHD/ADD is best treated by a combination of medication and behavior management. The most commonly prescribed drug used to treat ADHD/ADD is methylphenidate, Ritalin. Methylphenidate is a highly effective drug for treating impulsivity, hyperactivity, and inattention, the symptoms of ADHD, and seems to be safe. Abuse, tolerance and sensitivity are not major clinical concerns in its use. At present, we do not understand all of the mechanisms by which methylphenidate exerts its beneficial effects, nor do we know what neuronal changes may result from its use. There is concern about the potential effects on the brain and behavior of its long-term use, and especially over whether its use can affect the likelihood of later substance abuse. One reason for this concern is that Ritalin binds to the dopamine transporter and increases dopamine levels in the brain. Other psychostimulant drugs, amphetamine and cocaine, also increase dopamine levels, and these drugs are major drugs of abuse. A single dose of those drugs cause short-tem changes in expression of the Immediate Early Genes. Chronic use results in a complex pattern of changes in the expression of the IEG's and other genes. These changes in gene expression are thought to mediate the changes in behavior underlying addiction. We have found that a single dose of Ritalin results in expression of the Immediate Early Gene c-fos in the rat brain. We wish now to analyze the effects of chronic Ritalin use on gene expression, using the techniques of immunohistochemistry and DNA Microarray technology. Knowledge of the effects on gene expression will allow a more direct comparison of the effects of Ritalin on the brain with the effects of amphetamine and cocaine, provide more information about its mechanisms of action and allow more informed predictions about the long-term consequences of its use.
