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.

Public Health Relevance

The goal of the proposed project is to investigate interactions between the endogenous norepinephrine transmitter system in the brain and systemically administered methylphenidate (Ritalin), an amphetamine-like psychostimulant that is the drug of choice for treating ADHD and is gaining popularity among otherwise healthy individuals across the aging spectrum for its wake promoting and cognitive enhancing effects. Methylphenidate elevates norepinephrine and dopamine transmitter levels in cognitive and sensory regions of the brain, yet the basic physiological mechanisms through which it brings about its therapeutic and cognitive enhancing effects are unknown. A series of anatomical, neurochemical, and electrophysiological experiments will be used to establish a link between methylphenidate's actions and operation of the endogenous norepinephrine transmitter system within sensory and cognitive brain circuits of juvenile, adult, and aged rats.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017960-10
Application #
8512679
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2004-05-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$318,806
Indirect Cost
$111,381
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bhattacharya, Shevon E; Shumsky, Jed S; Waterhouse, Barry D (2015) Attention enhancing effects of methylphenidate are age-dependent. Exp Gerontol 61:7-Jan
Zitnik, Gerard A; Clark, Brian D; Waterhouse, Barry D (2014) Effects of intracerebroventricular corticotropin releasing factor on sensory-evoked responses in the rat visual thalamus. Brain Res 1561:35-47
Chandler, Daniel J; Waterhouse, Barry D; Gao, Wen-Jun (2014) New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons. Front Neural Circuits 8:53
Agster, Kara L; Mejias-Aponte, Carlos A; Clark, Brian D et al. (2013) Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex. J Comp Neurol 521:2195-207
Navarra, Rachel L; Clark, Brian D; Zitnik, Gerard A et al. (2013) Methylphenidate and atomoxetine enhance sensory-evoked neuronal activity in the visual thalamus of male rats. Exp Clin Psychopharmacol 21:363-74
Chandler, Daniel J; Lamperski, Carolyn S; Waterhouse, Barry D (2013) Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex. Brain Res 1522:38-58
Zitnik, Gerard A; Clark, Brain D; Waterhouse, Barry D (2013) The impact of hemodynamic stress on sensory signal processing in the rodent lateral geniculate nucleus. Brain Res 1518:36-47
Berridge, Craig W; Shumsky, Jed S; Andrzejewski, Matt E et al. (2012) Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic ýýýýý - and ýýýýý-receptors. Biol Psychiatry 71:467-73
Devilbiss, David M; Waterhouse, Barry D (2011) Phasic and tonic patterns of locus coeruleus output differentially modulate sensory network function in the awake rat. J Neurophysiol 105:69-87
Drouin, Candice; Wang, Dorothy; Waterhouse, Barry D (2007) Neurophysiological actions of methylphenidate in the primary somatosensory cortex. Synapse 61:985-90

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