Recent publication in the November 2006 edition of the Journal of the American Academy of child and adolescent Psychiatry report the risks and benefits of methylphenidate (MPD) use in the treatment of attention deficit hyperactive disorder (ADHD) and strongly indicate the need of basic science research of MPD. The majority of the MPD investigations studied the drug effects on animal behavior using behavioral assays before and after different means of drug administration and lesioning as well as neurochemical and molecular approaches. MPD exerts its effect on the brain, therefore one of the best approaches to study the physiology and the MPD mechanism of action is to record the neurophysiological events from the brain itself. There are limited in vivo or in vitro neurophysiological reports that study the effect of MPD on one selective brain area. At the present, there is not one report to our knowledge that records the neuronal activity from several brain sites simultaneously in adolescent and adult freely behaving animals previously implanted stereotaxical with permanent electrodes as well as recording from the same animals their behavior using dose response protocol. The objective of this proposal is: 1) to obtain the functional neuronal circuit of MPD action;2) to obtain the window (latency and duration) of MPD action in each of the 5 structures proposed for each dose;3) to obtain the neurophysiological activity underlying MPD administration using dose response protocol;and 4) to determine behaviorally and neurophysiologically the dose response characteristics of MPD in MPD naive adolescent and adult animals and in animals treated chronically with the drug . The general hypothesis of this study is that MPD elicited down regulation in 4 brain site(s), and up-regulation in one brain site(s).
The aim of this study is to verify this hypothesis. The result from this proposal will provide the functional circuit and the property of MPD action, and the vital mechanism underlying MPD therapy.

Public Health Relevance

Attention deficit disorder (ADHD) is treated by psychostimulant such as Ritalin for prolonged period of time, and its long term effect is unknown. Most studies of Ritalin using animals under anesthesia or brain slices, anesthesia is known to affect brain activity and interact with the drug under investigation. The objective of this proposal is to provide essential neurophysiological data where and how Ritalin affect different brain areas known to be the site of psychostimulant action and to understand the mechanism of methylphenidate (Ritalin) action in the brain using freely behaving adolescent, young adult and older rats previously implanted with a permanent electrode, i.e. animals without the anesthetic interfering in 5 brain areas suggested to be the brain sites where psychostimulant acts. These data are essential to understand how Ritalin affect the brain and will be beneficial to the ADHD patient and psychostimulant drug abusers in general.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZRG1-PMDA-A (01))
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Sorensen, Roger
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University of Texas Health Science Center Houston
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Kharas, Natasha; Reyes-Vazquez, Cruz; Dafny, Nachum (2017) Locus coeruleus neuronal activity correlates with behavioral response to acute and chronic doses of methylphenidate (Ritalin) in adolescent rats. J Neural Transm (Vienna) 124:1239-1250
Kharas, Natasha; Whitt, Holly; Reyes-Vasquez, Cruz et al. (2017) Methylphenidate modulates dorsal raphe neuronal activity: Behavioral and neuronal recordings from adolescent rats. Brain Res Bull 128:48-57
Claussen, Catherine M; Dafny, Nachum (2015) Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure. Pharmacol Biochem Behav 136:21-30
Frolov, Alexander; Reyes-Vasquez, Cruz; Dafny, Nachum (2015) Behavioral and neuronal recording of the nucleus accumbens in adolescent rats following acute and repetitive exposure to methylphenidate. J Neurophysiol 113:369-79
Jones, Cathleen G; Yang, Pamela B; Wilcox, Victor T et al. (2014) Acute and chronic psychostimulant treatment modulates the diurnal rhythm activity pattern of WKY female adolescent rats. J Neural Transm (Vienna) 121:457-68
Claussen, Catherine M; Dafny, Nachum (2014) Acute administration of methylphenidate alters the prefrontal cortex neuronal activity in a dose-response characteristic. J Exp Pharmacol 6:1-9
Jones, Zachary; Dafny, Nachum (2014) Acute and chronic dose-response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior. J Neural Transm (Vienna) 121:327-45
Claussen, Catherine M; Chong, Samuel L; Dafny, Nachum (2014) Nucleus accumbens neuronal activity correlates to the animal's behavioral response to acute and chronic methylphenidate. Physiol Behav 129:85-94
Tang, Bin; Dafny, Nachum (2013) Behavioral and dorsal raphe neuronal activity following acute and chronic methylphenidate in freely behaving rats. Brain Res Bull 98:53-63
Jones, Zachary; Dafny, Nachum (2013) Dose response effect of methylphenidate on ventral tegmental area neurons and animal behavior. Brain Res Bull 96:86-92

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