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PRECLINICAL INVESTIGATION OF IVERMECTIN AS A NOVEL THERAPEUTIC AGENT FOR TREATMENT OF ALCOHOL USE DISORDERS
by
Sheraz Khoja
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(PHARMACEUTICAL SCIENCES)
August 2012
Copyright 2012 Sheraz Khoja
Object Description
| Title | Preclinical investigation of ivermectin as a novel therapeutic agent for treatment of alcohol use disorders |
| Author | Khoja, Sheraz |
| Author email | skhoja@usc.edu;sheraz.khoja@gmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2012-06-22 |
| Date submitted | 2012-07-31 |
| Date approved | 2012-08-01 |
| Restricted until | 2012-08-01 |
| Date published | 2012-08-01 |
| Advisor (committee chair) | Alkana, Ronald L. |
| Advisor (committee member) |
Davies, Daryl L. Rodgers, Kathleen E. |
| Abstract | Alcohol use disorders (AUDs) ranks third in the list of preventable causes of morbidity and mortality in United States having a major national impact affecting over 18 million people and causing over 100,000 deaths annually. The prevalence of AUDs, in combination with limited clinical efficacy of currently approved FDA drugs in the treatment of this disorder signifies the importance for development of novel therapeutic agents. Alcohol is known to modulate a multitude of receptors in the brain to induce its cellular and behavioral effects. Recent electrophysiological findings from our laboratory, coupled with genomic studies, have suggested that the ionotropic receptor, P2X4 receptor (P2X4R) is a critical target that is modulated by ethanol. P2X4R activity has been demonstrated to be inhibited by ethanol at intoxicating and anesthetic concentrations. Recent evidence from our laboratory using electrophysiological strategies has shown that the FDA approved antiparasitic agent, ivermectin (IVM) antagonizes ethanol induced inhibition of P2X4R activity. On the basis of our in vitro data, and suggestion from my advisors I began testing the hypothesis that IVM represents a novel therapy that can be repurposed for treatment of AUDs. ❧ Aim 1 tests the hypothesis by investigating the effect of IVM on alcohol intake and preference in male and female C57BL/6 mice. This was accomplished by testing IVM at doses ranging from 0.65 mg/kg through 10mg/kg versus a 10% ethanol (10E) solution using a 24 hour two bottle choice paradigm. In support of the hypothesis, we found that IVM significantly reduced alcohol intake and preference in male and female mice. In addition, using a similar paradigm, evaluation of IVM’s effect on saccharin intake was undertaken to determine if IVM’s effect was specific for ethanol or if IVM was also active versus a second substance known to have positive reinforcing effects. In agreement with our ethanol studies, IVM significantly decreased saccharin intake and preference. ❧ Aim 2 tests the hypothesis that IVM does not cause behavioral effects that would negatively impact its potential therapeutic application to preventing or treating AUDs. To this end, I tested the effects of IVM on recognized measures of anxiety (open field, marble burying), depression (forced swim test), information processing (prepulse inhibition test). Collaborators from my research team also tested the elevated plus maze, tail suspension, conditioned place preference, hot plate and object exploration. A detailed explanation of these latter studies will be presented elsewhere but the findings will also be summarized in my thesis to present a broad picture of the investigations. The results overall support the hypothesis. IVM did not show rewarding effects in conditioned place preference test, suggesting that it does not have addictive potential and had anxiolytic effects in the marble burying test. However, it does appear to have some negative consequences. ❧ Taken together, the findings from the alcohol drinking and behavioral studies in mice support the hypothesis that IVM represents a novel therapy that can be repurposed for treatment of AUDs. |
| Keyword | behavioral pharmacology; alcohol use disorders; drug development for alcohol use disorders; ethanol |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Khoja, Sheraz |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-KhojaShera-1094.pdf |
Description
| Title | Page 1 |
| Full text | PRECLINICAL INVESTIGATION OF IVERMECTIN AS A NOVEL THERAPEUTIC AGENT FOR TREATMENT OF ALCOHOL USE DISORDERS by Sheraz Khoja A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (PHARMACEUTICAL SCIENCES) August 2012 Copyright 2012 Sheraz Khoja |
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