Neurobehavioral pharmacology of dopamine uptake inhibitors: Reinforcing and discriminative stimulus effects

Cocaine is a significant drug of abuse. Cocaine's action at dopamine transporters (DATs) to inhibit dopamine (DA) uptake is thought to play a primary role in its abuse. The purpose of the research in the present dissertation was to use animal models to examine the role of the DAT and DA uptake inhibition in the effects of cocaine that lead to its abuse. Specifically, the goal was to correlate reinforcing and discriminative potencies and efficacies of cocaine and other DA uptake inhibitors (local anesthetics) with their affinities at DATs, and potencies and efficacies as DA uptake inhibitors. Reinforcing potencies and efficacies were determined in rhesus monkeys under a self-administration procedure. Discriminative potencies and efficacies were determined in rats under a drug discrimination procedure using a high and a low training dose of cocaine. In vitro DAT and sodium channel effects were determined in rhesus monkey and rat brain and correlated with reinforcing effects in monkeys and discriminative stimulus effects in rats, respectively.; Reinforcing and discriminative potencies were positively correlated with DAT affinities and potencies for DA uptake inhibition. Sodium channel affinities were not correlated with either reinforcing or discriminative potencies. Cocaine and the local anesthetics did not differ in their efficacies as DA uptake inhibitors. However, concentrations of the drugs which maximally inhibited DA uptake were within the toxic concentration range and probably not relevant in vivo. There was a positive correlation between potency as a DA uptake inhibitor and reinforcing efficacy, and a trend towards a positive relationship between potency as a DA uptake inhibitor and discriminative efficacy. In addition, the ratio of sodium channel binding affinity/DAT binding affinity appeared important in determining reinforcing and discriminative efficacies. As this ratio increased reinforcing and discriminative efficacies decreased. Considered together, these data suggest that the reinforcing and cocaine-like discriminative stimulus effects of local anesthetics were mediated by their affinities at DATs and potencies to inhibit DA uptake. In addition, there may be a mutual influence of DAT and sodium channel effects on the reinforcing and cocaine-like discriminative stimulus effects of local anesthetics.