Document Detail


Applicability of the dopamine and rate hypotheses in explaining the differences in behavioral pharmacology of the chloro-benztropine analogs: studies conducted using intracerebral microdialysis and population pharmacodynamic modeling.
MedLine Citation:
PMID:  17519385     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Previous studies indicated that the chloro-benztropine analogs differed significantly in their cocaine-like activity, which was not expected based on the similarity in their in vitro binding affinity and functional potency at the dopamine transporter (DAT). The present study was designed to extend the understanding of the involvement of both pharmacokinetic and pharmacodynamic factors in mediating the behavioral differences among these analogs. The pharmacokinetics of 3'-chloro-3alpha-(diphenylmethoxy)tropane (3'-Cl BZT), the analog showing a cocaine-like behavioral profile in rodents, was compared with previously reported pharmacokinetic characteristics of cocaine and 4',4''-dichloro-3alpha-(diphenylmethoxy)tropane (4',4''-diCl BZT), an analog totally devoid of cocaine-like actions. Microdialysis studies in rats were conducted to determine whether 3'-Cl and 4',4''-diCl BZT differed significantly in their effect on nucleus accumbens extracellular dopamine levels, with cocaine serving as a reference. A mechanistic model based on DAT association/dissociation kinetics was used to describe the time delay between the plasma concentrations of the chloro-analogs and their dopaminergic effects. 3'-Cl BZT had plasma elimination half-life of 1.9 h versus 0.5 and 21.1 h for cocaine and 4',4''-diCl BZT, respectively. 4',4''-diCl BZT increased the DA levels at a slower rate and to a significantly lower extent relative to 3'-Cl BZT that were, in turn, lower than cocaine. The duration of dopamine elevation was as follows: 4',4''-diCl BZT > 3'-Cl BZT > cocaine. The model indicated faster association and dissociation with DAT for 3'-Cl BZT relative to 4',4''-diCl BZT. The present results indicate that behavioral differences among the chloro-analogs may be explainable based on both the dopamine and rate hypotheses of drug abuse.
Authors:
Ahmed A Othman; Amy Hauck Newman; Natalie D Eddington
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2007-05-22
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  322     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-07-20     Completed Date:  2007-09-20     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  760-9     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Baltimore, MD 21201, USA. neddingt@rx.umaryland.edu
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MeSH Terms
Descriptor/Qualifier:
Algorithms
Animals
Area Under Curve
Benztropine / analogs & derivatives*,  metabolism,  pharmacokinetics,  pharmacology
Brain Chemistry
Cocaine / metabolism,  pharmacokinetics,  pharmacology
Dopamine / metabolism*
Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors,  metabolism
Dopamine Uptake Inhibitors / metabolism,  pharmacokinetics*,  pharmacology
Dose-Response Relationship, Drug
Male
Microdialysis
Models, Biological*
Molecular Structure
Nucleus Accumbens / drug effects,  metabolism
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
R01 DA16715-03/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/3'-chloro-3-(diphenylmethoxy)tropane; 0/4',4''-dichloro-3-(diphenylmethoxy)tropane; 0/Dopamine Plasma Membrane Transport Proteins; 0/Dopamine Uptake Inhibitors; 50-36-2/Cocaine; 86-13-5/Benztropine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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