Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys

Rationale: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent DA uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine . In a previous study using a fixed-ratio 10 schedule, two chloro-analogs ( 3'-C1-BZT and -4'-Cl-BZT) maintained IV self-administration in monkeys but appeared to be weak positive reinforcers. Objectives: The present experimen ts were designed to test the hypothesis that 3'-C1-BZT and 4'-Cl-BZT are re latively weak reinforcers by evaluating reinforcing effects under increased response requirements. To examine further the effect of this halogen subst itution on self-administration, 3',4 " -diCl-BZT was also evaluated for rei nforcing effects. Methods: Four rhesus monkeys self-administered cocaine (0 .03 mg/kg per injection, IV) under a fixed-ratio 25 (FR25) schedule until s table responding was established. Saline, various doses of cocaine (0.003-0 .2 mg/kg per injection), the BZT analogs (0.012-0.2 mg/kg per injection), G BR 12909 (0.012-0.2 mg/kg per injection), and compounds with known reinforc ing effects (d-amphetamine, morphine, pentobarbital, ketamine) were then ma de available for self-administration. Various doses (0.01-0.3 mg/kg per inj ection) of the compounds that maintained self-administration under the FR s chedule were then substituted for cocaine (0:1 mg/kg per injection) under p rogressive-ratio (PR) schedules. Results: Reinforcing effects were evident under the FR schedule for 3'-C1-BZT, 4'-Cl-BZT, GBR 12909, and the control compounds, but not by 3',4 " -diCl-BZT. Results with the PR suggested that the rank order of these compounds for their effectiveness as reinforcers wa s cocaine>GBR 12909>3'-C1-BZT=4'-Cl-BZT>>3',4 " -diCl-BZT. Conclusions: Thi s study confirms and extends previous results suggesting that compounds wit h high DAT affinity can have strong, moderate, weak, or no effectiveness as reinforcers. The mechanisms that may underlie this variation in reinforcin g effectiveness of these DAT ligands remain to be established.