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Evaluation of N‐Substituted Benztropine (BZT) Analogs for Cocaine Antagonist Effects in Rats Trained to Self‐Administer Cocaine
Author(s) -
Hiranita Takato,
Kopajtic Theresa,
Cao Jianjing,
Newman Amy H.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.765.6
Subject(s) - nomifensine , dopamine uptake inhibitors , pharmacology , chemistry , dopamine transporter , benztropine , self administration , antagonist , dopamine , medicine , dopaminergic , biochemistry , receptor
N ‐substituted BZT analogs with high dopamine transporter (DAT) affinity and slow onsets of effect decreased cocaine self administration (SA) in rats (JPET 329:677). The present study examined additional N ‐substituted 4′,4″‐diF‐BZT selective DAT inhibitors, with DAT affinities of 5.59 to 29.2 nM, and relatively faster onsets of action [JHW 013 ( N ‐methyl‐cyclopropyl‐diF‐BZT), GA 1–69 ( N ‐ethyl‐3‐indole‐diF‐BZT), GA 2–50 ( N ‐(R)‐2″‐amino‐3″‐methyl‐n‐butyl‐diF‐BZT) and GA 2–99 ( N ‐2″‐aminoethyl‐diF‐BZT)]. Rats were trained with cocaine SA (0.032–1.0 mg/kg/injection, IV) under fixed‐ratio 5‐response schedules of reinforcement. Maximal response rates were maintained by 0.32 mg/kg/inj of cocaine or by a standard DAT inhibitor, nomifensine (0.1 mg/kg/inj) when substituted for cocaine. Lower response rates were maintained at higher and lower doses. Responding was virtually eliminated when responses did not produce injections, and none of the BZT analogs maintained responding above those levels. Pretreatment (IP) with nomifensine dose‐dependently shifted the cocaine SA dose‐effect curve leftward. In contrast, the BZT analogs (IP) dose‐dependently decreased cocaine SA at lower doses than those that decreased response rates maintained by food reinforcement. The present study further supports the development of N ‐substituted BZT analogs as medications to treat cocaine abuse. Supported by NIDA IRP.