Comparative behavioral pharmacology of cocaine and the selective dopamine uptake inhibitor RTI-113 in the squirrel monkey

Abstract

The behavioral effects of 3?-(4-chlorophenyl)tropane-2?-carboxylic acid phenyl ester hydrochloride (RTI-113; 0.03–1.0 mg/kg), a selective dopamine uptake inhibitor, were compared with those of cocaine (0.03–3.0 mg/kg) and 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909; 0.03–3.0 mg/kg) in squirrel monkeys. Intermediate doses of each drug produced significant increases in response rate maintained by a fixed-interval (FI) 300-s schedule of stimulus termination, but RTI-113 was less effective than cocaine or GBR 12909. The order of potency for increasing response rate was RTI-113 ? cocaine > GBR 12909. In drug time course determinations, RTI-113 and GBR 12909 had longer durations of action than cocaine. RTI-113 substituted completely for cocaine in subjects trained to discriminate cocaine and saline under a two-lever drug-discrimination procedure maintained by food delivery. RTI-113 also reliably maintained self-administration behavior in subjects trained under a second-order FI 900-s schedule of i.v. cocaine delivery. Pretreatment with RTI-113 significantly decreased responding for cocaine at the highest pretreatment dose, but RTI-113 had similar effects on responding maintained by a second-order FI 900-s schedule of stimulus termination. The results indicate that the behavioral pharmacology of RTI-113 is similar to that of cocaine, further implicating a prominent role for dopamine uptake inhibition in the behavioral effects of cocaine. Its longer duration of action in conjunction with less pronounced behavioral-stimulant effects are desirable properties for a substitute pharmacotherapy for cocaine abuse. RTI-113 effectively decreased cocaine self-administration behavior, although its direct rate-altering effects may have contributed to the interactions obtained.