IN-VITRO AND IN-VIVO EFFECTS OF COCAINE AND SELECTED LOCAL-ANESTHETICS ON THE DOPAMINE TRANSPORTER

The effects of selected local anesthetics on in vitro and in vivo measurements of dopamine transporter activity were determined to investigate the role of local anesthetic activity in the neuronal actions of cocaine. Cocaine inhibited [H-3]2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate (CFT) binding and [H-3]dopamine uptake with estimated K-i and IC50 values of 0.6 mu M and 0.7 mu M, respectively. Of the local anesthetics tested, only dimethocaine showed full displacement of CFT binding (0-30 mu M tested) and full inhibition of dopamine uptake (0-100 mu M tested). Dimethocaine was only slightly less potent than cocaine with an estimated K-i of 1.4 mu M and an IC50 value of 1.2 mu M for [H-3]CFT binding and dopamine uptake. At a maximum concentration of 100 mu M, the ester containing local anesthetics procaine, tetracaine, piperocaine and the amide containing local anesthetic dibucaine and bupivacaine partially inhibited dopamine uptake by 47-70%. The ester containing local anesthetic propoxycaine and the amide containing local anesthetics prilocaine, etidocaine, procainamide, and lidocaine inhibited dopamine uptake by 8-30% at 100 mu M. A 10 min administration of cocaine, dimethocaine, or procaine in the dialysis solution produced dose-dependent, reversible increases in endogenous dopamine efflux from the striata of awake rats. Cocaine and dimethocaine produced similar 12-fold increases in dialysate dopamine at concentrations of 0.1 mM and 1 mM respectively. Procaine (10 mM) produced a 6-fold increase in dialysate dopamine while lidocaine (1 mM) produced a reproducible and reversible decrease (30%). These results show that the cocaine-like actions of certain local anesthetics such as dimethocaine and procaine result from their direct actions of dopamine uptake inhibitors.