On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns

Rationale: Drugs that are self-administered appear to vary in their potency and effectiveness as positive reinforcers. Understanding mechanisms that d etermine relative effectiveness of drugs as reinforcers will enhance our un derstanding of drug abuse. Objectives: The hypothesis of the present study was that differences among dopamine transporter (DAT) ligands in potency an d effectiveness as a positive reinforcers were related to potency and effec tiveness as DA uptake inhibitors. Accordingly, self-administration of a gro up of local anesthetics that are DAT ligands was compared to their effects as DA uptake blockers in vitro in brain tissue. Methods: Rhesus monkeys wer e allowed to self-administer cocaine and other local anesthetics IV under a progressive-ratio schedule. The same compounds were compared in standard i n vitro DA uptake assays using monkey caudate tissue. Results: The rank ord er of both potency and effectiveness as reinforcers was cocaine>dimethocain e>procaine>chloroprocaine. Tetracaine did not maintain self-administration. For inhibiting DA uptake, the potency order was cocaine>dimethocaine>tetra caine>procaine chloro-procaine. At maximum, these compounds were equally ef fective in blocking DA uptake. Lidocaine did not inhibit DA uptake. Conclus ions: The potency of local anesthetics as positive reinforcers is likely re lated to their potency as DA uptake inhibitors. Variation in their effectiv eness as positive reinforcers was not a function of differences in effectiv eness as DA uptake blockers, but may be related to relative potency over th e concentrations that are achieved in vivo. Effects at sodium channels may limit the reinforcing effects of local anesthetics.