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UNIQUE PHARMACODYNAMIC PROFILE OF METHYLPHENIDATE: SELF-ADMINISTRATION-INDUCED DOPAMINE SYSTEM ALTERATIONS

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title
UNIQUE PHARMACODYNAMIC PROFILE OF METHYLPHENIDATE: SELF-ADMINISTRATION-INDUCED DOPAMINE SYSTEM ALTERATIONS
author
Calipari, Erin Sue
abstract
Methylphenidate (MPH), the active compound in the medication Ritalin, is commonly diverted for off-label use. It is abused at high rates in both the adolescent and adult population; however, until recently, the neurochemical effects of MPH abuse had not been explored in depth. Pharmacologically MPH is a dopamine transporter (DAT) blocker with the same mechanism of action and equivalent potency at the DAT as cocaine. Although MPH is categorized as a DAT blocker, its pharmacological actions are distinct from both blockers and releasers in regards to both its acute effects and the compensatory alterations associated with self-administration of the compound. This work has elucidated the neurochemical consequences of MPH self-administration, whereby MPH administration by a number of paradigms results in consistent neurochemical adaptations characterized by increased maximal rates of uptake (Vmax), increased DAT levels, increased evoked dopamine (DA) release, and an increased potency to inhibit the DAT for MPH and releasers, but not blockers. These changes are opposite from the documented changes that occur following cocaine self-administration, further suggesting that the neurochemical consequences of MPH are unique, and cannot be predicted based on previous literature of compounds of the same psychostimulant class, such as cocaine. The changes directly at the DAT following MPH self-administration are consistent with microdialysis and behavioral analysis that demonstrate increased MPH and amphetamine (AMPH)-induced DA overflow, but not cocaine, and increased reinforcing efficacy of AMPH and MPH, but not cocaine. The increases in the reinforcing efficacy of MPH and releasers such as AMPH, suggests that these compounds may having significant abuse liability following MPH abuse in the adolescent and adult populations.
subject
amphetamine
cocaine
Dopamine
methylphenidate
Self-administration
Voltammetry
contributor
Jones, Sara R (committee chair)
Martin, Thomas J (committee member)
Chen, Rong (committee member)
McCool, Brian A (committee member)
Childers, Steven (committee member)
date
2014-01-15T09:35:41Z (accessioned)
2015-01-15T09:30:09Z (available)
2013 (issued)
degree
Physiology and Pharmacology (discipline)
embargo
2015-01-15 (terms)
identifier
http://hdl.handle.net/10339/39143 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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