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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 13, 2005; DOI: 10.1124/jpet.105.091231

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Received for publication June 20, 2005.
Revised July 9, 2005.
Accepted for publication July 11, 2005.

RELATIONSHIP BETWEEN IN VIVO OCCUPANCY AT THE DOPAMINE TRANSPORTER AND BEHAVIORAL EFFECTS OF COCAINE, GBR 12909 AND BENZTROPINE ANALOGUES

Rajeev I Desai 1, Theresa A. Kopajtic 1, Dawn French 1, Amy H. Newman 1, Jonathan L. Katz 1*

1 NIDA Intramural Research Program

* Address correspondence to: E-mail: jkatz{at}intra.nida.nih.gov

Abstract

Analogues of benztropine (BZT) bind to the dopamine (DA) transporter and inhibit DA uptake, but often have behavioral effects that differ from those of cocaine and other DA-uptake inhibitors. To better understand these differences, we examined the relationship between locomotor-stimulant effects of cocaine, GBR 12909 and BZT analogues (AHN 1-055 and AHN 2-005) and their in vivo displacement of the DA transporter ligand [125I]RTI-121, in striatum. Cocaine, GBR 12909 and BZT analogues each displaced [125I]RTI-121 and stimulated locomotor activity in a dose- and time-dependent manner. The time course revealed a slower onset of both effects for AHN 1-055 and AHN 2-005, compared to cocaine and GBR 12909. The BZT analogues were less effective than cocaine and GBR 12909 in stimulating locomotor activity. Locomotor stimulant effects of cocaine were generally greater than predicted by the regression of displacement of [125I]RTI-121 and effect at short times after injection, and less than predicted at longer times after injection, suggesting that the apparent rate of occupancy of the DA transporter, in addition to percentage of sites occupied, contributes to the behavioral effects of cocaine. The present results suggest that among drugs that act at the DA transporter, the slower apparent rates of occupancy with the DA transporter by the BZT analogs may contribute in an important way to differences in their effectiveness.


Key words: Benztropine analogues, Cocaine, Dopamine transporter, GBR 12909, in vivo binding, locomotor behavior


This article has been cited by other articles:


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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., August 1, 2007; 322(2): 760 - 769.
[Abstract] [Full Text] [PDF]


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