3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys.
BACKGROUND
The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission. Drugs that block dopamine (DA) uptake have generally been found to function as positive reinforcers. Benztropine (BZT) and several of its halogenated analogs have previously been characterized as potent DA-uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine.


OBJECTIVE
The present experiments were designed to examine, in rhesus monkeys, the reinforcing effects of the DA-uptake inhibitor BZT and two chloro-analogs 3'-Cl-BZT and 4'-Cl-BZT, and to compare self-administration and binding profiles.


METHODS
Four rhesus monkeys self-administered cocaine i.v. under a fixed-ratio 10 (FR10) schedule until stable responding was established. Saline, and various doses of cocaine, BZT, and the BZT analogs were then made available for self-administration. Binding of these compounds to monoaminergic and cholinergic sites in monkey brain were determined using standard radioligand binding techniques.


RESULTS
Self-administration was maintained by both 3'-Cl-BZT and 4'-Cl-BZT, but not by BZT. Results suggested that 3'-Cl-BZT and 4'-Cl-BZT were weak positive reinforcers. BZT and analogs bound DA transporters (DAT) with affinities higher than that of cocaine and had affinity for muscarinic binding sites.


CONCLUSIONS
Surprisingly, high affinity at DATs was associated with weak or no reinforcing effects. The mechanism(s) that may underlie this dissociation between DAT actions and reinforcing effects remains to be established. These data support the proposal that a lead for the discovery of a pharmacotherapeutic agent for cocaine abuse may come from this group of compounds.
Woolverton
W L
WL
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216-4505, USA. WWoolverton@psychiatry.umsmed.edu
Rowlett
J K
JK
Wilcox
K M
KM
Paul
I A
IA
Kline
R H
RH
Newman
A H
AH
Katz
J L
JL
D000818:Animals; D001590:Benztropine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003216:Conditioning, Operant; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D019966:Substance-Related Disorders / Q000523:psychology
C405623:3'-chlorobenztropine; C105321:4'-chloro-3-(diphenylmethoxy)tropane; D018765:Dopamine Uptake Inhibitors; D001590:Benztropine