Vol. 292, Issue 2, 521-529, February 2000

Comparative Behavioral Pharmacology of Cocaine and the Selective Dopamine Uptake Inhibitor RTI-113 in the Squirrel Monkey¹

Leonard L. Howell , Paul W. Czoty, Michael J. Kuhar and F. Ivy Carrol

Yerkes Regional Primate Research Center (L.L.H., P.W.C., M.J.K.), and Departments of Psychiatry and Behavioral Sciences (L.L.H.) and of Pharmacology (L.L.H., M.J.K.), Emory University, Atlanta, Georgia; and Research Triangle Institute, Research Triangle Park, North Carolina (F.I.C.).

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.