Reinforcing and discriminative stimulus effects of RTI 111, a 3-phenyltropane analog, in rhesus monkeys: interaction with methamphetamine

Rationale: The neuronal actions of methamphetamine (MA) include an increase in extracellular levels of monoamines, presumably via reverse transport in volving the monoamine transporters. This action is thought to play an impor tant role in the effects of MA. Therefore, in the present experiment, it wa s hypothesized that a monoamine uptake blocker would block behavioral effec ts of MA related to its abuse. Objective: RTI 111, a newly synthesized 3-ph enyltropane analog with high affinity for the dopamine, norepinephrine, and serotonin transporters, was evaluated alone and in combination with MA for its ability to block the reinforcing and discriminative stimulus effects o f MA in rhesus monkeys. Methods: RTI 111 (0.0003-0.03 mg/kg, i.v.) was made available to four rhesus monkeys for self-administration under a fixed-rat io 25 (FR 25) schedule of reinforcement. RTI 111 (0.01-0.1 mg/kg, i.m.) was also administered as a pretreatment (15 min prior) to four monkeys self-ad ministering MA (0.0-0.3 mg/kg per injection, i.v.) on a progressive-ratio s chedule of reinforcement. MA (0.01-1.0 mg/kg, i.m.), RTI 111 (0.001-0.1 mg/ kg, i.m.), or the combination of MA and RTI 111 were administered to four m onkeys trained to discriminate (+)-amphetamine (AMPH; 1.0 or 1.7 mg/kg, int ragastric) from saline. Results: When RTI 111 was made available for self-a dministration under an FR 25 schedule it functioned as a positive reinforce r in all four monkeys tested. When RTI 111 was given as a pretreatment to m onkeys self-administering MA under a progressive-ratio schedule, the MA dos e-response function shifted to the left and down. When RTI 111 or MA were g iven to monkeys trained to discriminate AMPH from saline, full AMPH-like re sponding was observed for both drugs. Given in combination, RTI 111 shifted the MA dose-response function to the left. Conclusions: These data suggest that RTI 111 is behaviorally similar to traditional psychomotor stimulants that act at the DA transporter and that it increases, rather than blocks, the behavioral potency of MA.