Most current evidence supports the use of stimulants such as methylphenidate as the most effective treatment for Attention Deficit Hyperactivity Disorder. Unfortunately, an accurate appraisal of the therapeutic actions of stimulants, as well as the development of alternative treatment strategies, are hampered by limited understanding of the neuronal mechanisms that are affected by exposure to clinically relevant doses of these drugs. One major problem in assessing the relevancy of animal models to study the effects of these drugs is the difficulty in equating drug exposure conditions in humans and experimental animals. The profound effect of treatment conditions on the neurobiological responses to drugs has been extensively documented, and thus the translational utility of an animal model of drug usage critically depends on the degree to which the exposure profile simulates the human conditions. To enhance the potential translational value of animal models, we are developing an intravenous drug delivery methodology which enables an approximation in rats of the temporal profile of human plasma drug concentrations. The focus of the present proposal is to refine this methodology to simulate the temporal profile of plasma methylphenidate concentrations following oral administration that has been associated with the pharmacotherapy of Attention Deficit Hyperactivity Disorder. The exposure profile will include: a gradual increase in plasma methylphenidate to approximate the rise in drug associated with oral administration; day-long, constant or ascending plasma levels that have been associated with therapeutic efficacy; and the gradual decline in plasma drug corresponding to the human plasma half-life of about three hours. We will then apply this approach in rats in multidisciplinary studies using in vivo microdialysis and the 5-choice serial reaction time task to test the hypothesis that within-day-tolerance in efficacy that appears to occur when constant plasma levels of methylphenidate are maintained will be reflected in a decrease in the frontal cortex extracellular norepinephrine response and a corresponding decrease in attentional performance. The results of these studies will have important implications for understanding the mechanisms by which methylphenidate exerts its therapeutic effects and will provide a foundation and context for subsequent studies directed at the mechanisms by which this drug exerts its therapeutic effects. ? ? ?
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