Defense Date

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

S. Stevens Negus

Abstract

Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation of many of these compounds (i.e. amphetamine, methamphetamine, phenmetrazine) is their propensity for abuse; however, not all monoamine releasers are abused (i.e. fenfluramine). The goal of this dissertation was to examine pharmacological determinants of abuse-related effects produced by monoamine releasers in two preclinical assays in rats: intracranial self-stimulation (ICSS) and drug discrimination. First, this work confirmed and expanded upon previous findings that selectivity for promoting release of dopamine versus serotonin is one determinant of abuse-related effects produced by monoamine releasers. This was accomplished by determining the behavioral effects of 11 different compounds that ranged in their selectivity for dopamine versus serotonin, and a correlation was found between the ability of a compound to facilitate ICSS and the selectivity of that compound for releasing dopamine versus serotonin. These data were then submitted to a rate-dependency analysis. Here, we found that all compounds produced rate-dependent effects, but that the profile of these effects varied with a compound’s selectivity for dopamine versus serotonin. Next, the mechanism by which serotonin exerts it response rate-decreasing effects was investigated - specifically, the hypothesis that the 5HT2C receptor mediates serotonin’s abuse-limiting effects of monoamine releasers was tested. The data collected suggest that the 5HT2C receptor contributes to, but is not exclusively responsible for, the abuse-limiting effects produced by serotonin release. Finally, selectivity for norepinephrine versus dopamine was examined as a potential determinant of monoamine releaser abuse liability; results from these studies suggest that release of both dopamine and norepinephrine are required for expression of abuse-related effects in assays of ICSS and drug discrimination. These data provide a systematic examination of the determinants of the abuse-related effects produced by monoamine releasers and may contribute to development of medications with reduced abuse potentials.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

July 2013

Available for download on Wednesday, July 18, 2018

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