Development and application of analytical chemical methods for the simultaneous analysis of the behavioral and pharmacokinetic response to amphetamine in rats
by Osterhaus, Gregory L., Ph.D., UNIVERSITY OF KANSAS, 2007, 229 pages; 3273494

Abstract:

Amphetamine is a psychostimulant that is used clinically for the treatment of attention-deficit hyperactivity disorder and narcolepsy. Using a force-plate actometer, amphetamine has been determined to produce a predictable behavioral phenomenon known as 'focused stereotypy' in Sprague-Dawley and Fischer 344 (F344) rats. Chronic administration of amphetamine can result in behavioral sensitization, a phenomenon by which later doses result in a more intense behavioral response than the same, initial dose. In rats, the behavioral response to a determined dose of amphetamine varies between strains and between individual rats within a strain. These variations result in uncertainty as to whether the resulting behavioral differences elicited by the drug are pharmacokinetic or pharmacodynamic in nature. Microdialysis provides a means to collect extracellular fluid from a particular brain region which can then be measured to determine the pharmacokinetic response to amphetamine in this region. A high performance liquid chromatography method using tandem mass spectrometry detection was developed for the analysis of amphetamine, the amphetamine metabolites (p-hydroxyamphetamine, norephedrine and p-hydroxynorephedrine), dopamine and clozapine to attempt to measure these compounds in dialysate obtained from the striatum of rat brains. This method was combined with high resolution behavioral measures obtained from a force plate actometer to determine how closely associated drug pharmacokinetics are to the behaviors they elicit. Results indicate that amphetamine induced behaviors are not clearly linked to amphetamine pharmacokinetics and that the observed behavioral differences are likely pharmacodynamic in nature. The atypical antipsychotic drug clozapine has been shown to lengthen the duration of amphetamine induced focused stereotypy in rats. Amphetamine/clozapine interactions cannot be ruled out as a possible cause of this phenomenon. Because microdialysis was ineffective in determining clozapine levels in rat brain, a liquid/liquid extraction method was used to determine whether amphetamine had an effect on whole brain clozapine concentrations. Using this method, it was determined that clozapine levels were not affected by amphetamine at the time point analyzed.

 
AdviserStephen C. Fowler
SchoolUNIVERSITY OF KANSAS
SourceDAI/B 68-07, p. , Nov 2007
Source TypeDissertation
SubjectsNeurosciences; Analytical chemistry
Publication Number3273494
Adobe PDF Access the complete dissertation:
 

» Find an electronic copy at your library.
  Use the link below to access a full citation record of this graduate work:
  http://gateway.proquest.com/openurl%3furl_ver=Z39.88-2004%26res_dat=xri:pqdiss%26rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation%26rft_dat=xri:pqdiss:3273494
  If your library subscribes to the ProQuest Dissertations & Theses (PQDT) database, you may be entitled to a free electronic version of this graduate work. If not, you will have the option to purchase one, and access a 24 page preview for free (if available).

About ProQuest Dissertations & Theses
With over 2.3 million records, the ProQuest Dissertations & Theses (PQDT) database is the most comprehensive collection of dissertations and theses in the world. It is the database of record for graduate research.

The database includes citations of graduate works ranging from the first U.S. dissertation, accepted in 1861, to those accepted as recently as last semester. Of the 2.3 million graduate works included in the database, ProQuest offers more than 1.9 million in full text formats. Of those, over 860,000 are available in PDF format. More than 60,000 dissertations and theses are added to the database each year.

If you have questions, please feel free to visit the ProQuest Web site - http://www.proquest.com - or call ProQuest Hotline Customer Support at 1-800-521-3042.