3 '- and 4 '-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys

Rationale: The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission. Drugs that block dopa mine (DA) uptake have generally been found to function as positive reinforc ers. Benztropine (BZT) and several of its halogenated analogs have previous ly been characterized as potent DA-uptake inhibitors with behavioral profil es that indicate diminished psychomotor stimulant effects relative to cocai ne. Objectives: The present experiments were designed to examine, in rhesus monkeys, the reinforcing effects of the DA-uptake inhibitor BZT and two ch loro-analogs 3'-C1-BZT and 4'-Cl-BZT, and to compare self-administration an d binding profiles. Methods: Four rhesus monkeys self-administered cocaine i.v. under a fixed-ratio 10 (FRIO) schedule until stable responding was est ablished. Saline, and various doses of cocaine, BZT, and the BZT analogs we re then made available for self-administration. Binding of these compounds to monoaminergic and cholinergic sites in monkey brain were determined usin g standard radioligand binding techniques. Results: Self-administration was maintained by both 3'-C1-BZT and 4'-Cl-BZT, but not by BZT. Results sugges ted that 3'-Cl-BZT and 4'-Cl-BZT were weak positive reinforcers. BZT and an alogs bound DA transporters (DAT) with affinities higher than that of cocai ne 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 a nd reinfurcino effects remains to be established. These data support the pr oposal that a lead for the discovery of a pharmacotherapeutic agent for coc aine abuse may come from this group of compounds.