Locus Coeruleus Function and Methylphenidate Action

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DESCRIPTION (provided by applicant): The goal of the proposed project is to investigate interactions between the central noradrenergic system and systemically administered methylphenidate (MPH) - RitalinR in juvenile, adult and aged rats. This amphetamine-like psychostimulant has been the drug of choice for treating the core symptoms (inattention, distractibility, impulsivity, hyperactivity) of attention deficit hyperactivity disorder (ADHD) for more than 20 years and is now gaining notoriety for its off-label use as a cognitive enhancer in healthy subjects. Despite a long history of prescription use and more recent illicit appeal, the neural circuit mechanisms responsible for methylphenidate's effects on sensory signal processing and cognition have not been elucidated. For example, it is well known that MPH blocks reuptake of synaptically released norepinephrine (NE) and dopamine in the brain but these biochemical actions do not provide a clear physiological explanation for the drug's efficacy in either normal individuals or ADHD patients. In this context there have been major advances in our understanding of the cellular/membrane actions of NE and dopamine on target neurons in the brain, yet we still do not fully comprehend how systemically administered agents interact with noradrenergic and dopaminergic systems to bring about changes in neuronal function, signal transfer, and behavior in intact animals. Previously funded and current work focuses on the endogenous NE system. The theme is to better understand specific dimensions of central noradrenergic function in the context of low dose psychostimulant drug action. The project employs a variety of experimental approaches including: 1) measurement of drug levels in blood plasma following systemic MPH administration, 2) stereological analysis of the distribution and density of noradrenergic profiles across various brain regions, 3) microdialysis and high pressure liquid chromatography with electrochemical detection (HPLC-EC) of NE release in sensory and cognitive brain areas before and after drug administration, 4) multi-channel, multi-neuron recording at relay sites along the somatosensory pathway in waking or anesthetized rats before and after drug, and 5) activation of the locus coeruleus-noradrenergic efferent pathway in waking or anesthetized animals. Protocols will be carried out primarily in adult animals but also in prepubertal juvenile and aged rats. The overall goal is to establish a link between the actions of low dose MPH and operation of the endogenous central noradrenergic transmitter system within sensory and cognitive brain circuits of juvenile, adult, and aged rats. Completion of this work will not only further our understanding of LC noradrenergic system function and psychostimulant drug action but will also provide insight regarding the pathology of ADHD and the motivation for off-label use of this class of drugs to promote wakefulness and enhance cognition in healthy subjects.