Low-Dose Methylphenidate and the Prefrontal Cortex

University Of Wisconsin-Madison, Madison WI

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Abstract

Low doses of psychostimulants, including methylphenidate (MPH/Ritalin), are widely used clinically due to their behavioral-calming and cognition-enhancing actions. Less well-recognized is the fact that these drugs exert similar actions in both normal human and animal subjects. Of particular relevance to the proposed studies are the well-documented facilitatory actions of low- doses of MPH and other psychostimulants on prefrontal cortex (PFC)-dependent cognition (i.e. working memory and sustained attention). Despite these cognition-enhancing actions, these drugs possess certain risks, including toxicity and abuse/addiction. For this reason, there is much concern about the widespread use of these drugs, particularly in children. Moreover, these risks preclude use of these drugs in other disorders/conditions associated with relatively modest impairment in PFC- dependent cognition (i.e. normal aging, sleep deprivation). To better develop non-stimulant drugs for the treatment of ADHD and other disorders and conditions associated with impaired PFC- dependent cognition, it is important to understand the neural mechanisms responsible for the cognition-enhancing actions of low-dose psychostimulants. Surprisingly, little is known about the neural substrates underlying the behavioral/cognitive actions of low-dose stimulants. We recently demonstrated that at low doses that improve both working memory and sustained attention in rats, PFC catecholamine efflux displays a greater sensitivity than catecholamine efflux in a number of cortical and subcortical regions outside the PFC. Additional studies indicate that cognition-enhancing doses of MPH increase PFC neuronal responsivity, an effect not observed in the somatosensory cortex. Combined, these observations suggest a prominent role of the PFC in the cognition-enhancing actions of low-dose MPH. The proposed studies are designed to further test this hypothesis and to provide insight into the neural mechanisms that underlie these actions. These studies will use a combination of microdialysis measures of catecholamine release, electrophysiological measurement of PFC neuronal activity, pharmacological manipulations and tests PFC-dependent cognition. These studies will provide novel insight into the neurobiological mechanisms through which low-dose psychostimulants improve cognitive function. Additionally, these studies will provide important information for the development of new pharmacological treatments for ADHD and other disorders/conditions associated with PFC dysfunction.