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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.
J Pharmacol Exp Ther. 2007 Aug; 322(2):760-9.JP

Abstract

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+Show Affiliations

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Baltimore, MD 21201, USA. neddingt@rx.umaryland.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

17519385

Citation

Othman, Ahmed A., et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 322, no. 2, 2007, pp. 760-9.
Othman AA, Newman AH, Eddington ND. 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. J Pharmacol Exp Ther. 2007;322(2):760-9.
Othman, A. A., Newman, A. H., & Eddington, N. D. (2007). 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. The Journal of Pharmacology and Experimental Therapeutics, 322(2), 760-9.
Othman AA, Newman AH, Eddington ND. 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. J Pharmacol Exp Ther. 2007;322(2):760-9. PubMed PMID: 17519385.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Othman,Ahmed A, AU - Newman,Amy Hauck, AU - Eddington,Natalie D, Y1 - 2007/05/22/ PY - 2007/5/24/pubmed PY - 2007/9/21/medline PY - 2007/5/24/entrez SP - 760 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 322 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17519385/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_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17519385 DB - PRIME DP - Unbound Medicine ER -