Cocaine, a psychomotor stimulant and local anesthetic (LA), is a significan drug of abuse. Dopaminergic mechanisms are thought to play a central role in the reinforcing and discriminative stimulus effects of cocaine. Specifically, cocaine binds to the dopamine transporter (DAT) and blocks the uptake of dopamine (DA). Other LAs also bind to the DAT and inhibit DA uptake. However, these compounds may differ from cocaine in their potency and intrinsic efficacy (maximum DA uptake blockade produced) as DA uptake blockers. The purpose of the research in this proposal is to correlate the reinforcing and discriminative potency and efficacy of cocaine, dimethocaine, chloroprocaine, procaine (Las that block DA uptake), and lidocaine (LA that does not block DA uptake) with their affinity and efficacy at the DAT. The reinforcing potency and efficacy (maximum reinforcing effect) of cocaine, dimethocaine, chloroprocaine, and procaine will be studied using a progressive-ratio (PR) paradigm in rhesus monkeys. In addition, low efficacy drugs in our PR procedure will be given as pre- treatments prior to cocaine PR sessions. The discriminative potency and efficacy of cocaine, dimethocaine, chloroprocaine, procaine, and lidocaine will be studied using a drug discrimination procedure. Rts will be trained to discriminate either a high or a low doe of cocaine from saline, and cocaine and the various Las will be tested in both groups. We will also study combinations of low efficacy DA uptake blockers (i.e., lidocaine) and cocaine in our drug discrimination procedure. Finally, these compounds will be studied using radioligand binding and DA uptake assays in rat and rhesus monkey brain tissue, to determine their affinity at the DAT and their degree of DA uptake blockade.
