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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA027222-05
Application #
8425106
Study Section
Special Emphasis Panel (ZRG1-PMDA-A (01))
Program Officer
Sorensen, Roger
Project Start
2009-04-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$282,752
Indirect Cost
$75,327
Name
University of Texas Health Science Center Houston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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; Dafny, Nachum (2014) Acute administration of methylphenidate alters the prefrontal cortex neuronal activity in a dose-response characteristic. J Exp Pharmacol 6:1-9
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
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
Tang, Bin; Dafny, Nachum (2013) Dorsal raphe neuronal activities are modulated by methylphenidate. J Neural Transm (Vienna) 120:721-31
Jones, Zachary; Dafny, Nachum (2013) Dose response effect of methylphenidate on ventral tegmental area neurons and animal behavior. Brain Res Bull 96:86-92
Lee, Min J; Burau, Keith D; Dafny, Nachum (2013) Behavioral daily rhythmic activity pattern of adolescent female rat is modulated by acute and chronic cocaine. J Neural Transm (Vienna) 120:733-44
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
Claussen, Catherine M; Chong, Samuel L; Dafny, Nachum (2012) Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects. Pharmacol Biochem Behav 101:208-16
Chelaru, Mircea I; Yang, Pamela B; Dafny, Nachum (2012) Sex differences in the behavioral response to methylphenidate in three adolescent rat strains (WKY, SHR, SD). Behav Brain Res 226:8-17

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