Low dose psychostimulants, including methylphenidate (MPH), are currently the most effective treatment for attention deficit hyperactivity disorder (ADHD). However, given their abuse potential, there is significant concern about their widespread clinical use. The development of safer treatments for ADHD requires an understanding of the neural mechanisms that underlie the therapeutic actions of psychostimulants. Unfortunately, until recently, our understanding of this issue has been limited. At clinically relevant doses, these drugs improve frontostriatal-dependent cognition in ADHD patients. Similar actions are observed in healthy humans and animals, indicating an animal model of ADHD is not needed to understand the neural mechanisms that underlie the cognition-enhancing effects of psychostimulants. Prior studies in our laboratory identified the prefrontal cortex (PFC), particularly the dorsomedial PFC, as a critical site in the cognition-enhancing actions of MPH, as measured in tests of working memory. The proposed studies will further test the hypothesis that the dose-dependent cognition-enhancing and cognition-impairing actions of psychostimulants involve a facilitation and suppression, respectively, in frontostriatal signaling via drug action in the dorsomedial PFC and will identify the receptor mechanisms involved. These studies will use a combination of behavioral, pharmacological, and electrophysiological approaches, to: 1) test the hypothesis that catecholamine receptors in the dorsomedial PFC contribute to the decreasing procognitive actions of MPH associated with increasing dose;2) test the hypothesis that MPH-induced improvement in attentional processes involves action in the dorsomedial PFC and extended frontostriatal circuitry;and 3) to test the hypothesis that MPH acts in the dorsomedial PFC to facilitate frontostriatal neuronal signaling. Collectively, these studies have strong relevance for the development of new treatments for ADHD and other conditions associated with frontostriatal cognitive dysfunction.

Public Health Relevance

Despite the efficacy of psychostimulants in the treatment of attention deficit hyperactivity disorder (ADHD), their abuse potential raises serious concerns about their widespread clinical use. The development of safer treatments is dependent on a thorough understanding of the neural mechanisms that support the procognitive effects of psychostimulants. This proposal will further test the hypothesis the procognitive actions of psychostimulants involve a facilitation of frontostriatal circuit function via drug action within he prefrontal cortex and subsequent increases in catecholamine receptor signaling. Information gained in these studies may lead to development of novel treatment strategies for frontostriatal dysfunction, including ADHD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-IFCN-C (02))
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Winsky, Lois M
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Foote, Stephen L; Berridge, Craig W (2018) New developments and future directions in understanding locus coeruleus - Norepinephrine (LC-NE) function. Brain Res :
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