In Vivo Binding of N‐Substituted Benztropine Analogs and Antagonism of Cocaine Self‐Administration

Abstract

Previous studies indicate that benztropine (BZT) analogs bind to the dopamine transporter (DAT), inhibit DA uptake, are less effective than cocaine in a variety of procedures, and block cocaine self administration. Previously studied BZT analogs have a low apparent rate of association, which has been hypothesized to contribute to their lower cocaine‐like effectiveness. Recent studies have revealed BZT analogs with a relatively fast onset of action, but it is unclear if these actions were related to DAT binding. Therefore, the present study assessed the in vivo displacement of [125I]RTI‐121 binding to the DAT by the N‐substituted BZT analog JHW 013, its self administration, effects on cocaine self administration and effectiveness in stimulating DA levels in the nucleus accumbens shell. Maximal in vivo binding of JHW 013 was achieved at 30 min, compared to 45 min with cocaine, indicating a relatively fast rate of association. In addition, JHW 013 dose‐dependently increased DA in the nucleus accumbens shell. JHW 013 failed to maintain self‐administration at levels greater than saline and its pretreatment blocked cocaine self administration. The relatively fast onset of action of JHW 013 at the DAT indicates that a low rate of association is not necessary for the reduced cocaine‐like effects of BZT analogs and their potential as therapeutics for stimulant abuse. Supported by NIDA IRP