Cocaine, nomifensine, mazindol, dita and desmethylimipramine (DMI) inhibit the K+-stimulated release of (3H-DA) from nerve terminals in the striatum.d The extent of inhibition is 40 -50%. Although all five drugs are inhibitors of catecholamine uptake, this action could be dissociated from the effect on DA release therefore, catecholamine uptake inhibitors possess a second, separate and distinct action on the release process for DA. Only DMI exhibits a similar action on the release of 3H-norepinephrine from terminals in the occipital cortex. These observations were extended through funding from an NIMH Small Grant. The strength of the depolarizing stimulus was studied and the release of endogenous DA and 3H-DA was compared for mazindol, nomifensine and DMI. The degree of inhibition of release was similar for 3H-DA and endogenous DA. Diminished release of DA in the presence of mazindol or nomifensine was overcome by raising the concentration of K+ from 15 mM to 40-60mM. In contrast, the diminished release of DA in the presence of DMi persisted up to 60 mM K+. These results indicate that suppression of evoke release of DA by mazindol and nomifensine is probably via a mechanism different from DMI. In new experiments, the release of endogenous DA will be studied. Complete K+ dose-response curves will be obtained for cocaine, and studies of the other uptake inhibitors will be extended. Calcium dependency for K+- stimulated release of DA, as well as other types of release, such as that evoked by chemical agents (d-amphetamine, veratridine, p-hydroxyamphetamine), or by hypoxia, will be assessed. Other DA-rich areas of brain will also be studied. The effect of DA receptor agonists and antagonists will be assessed. In vivo/in vitro experiments will be performed in which the drug will be administered to rats and, experiments will be performed in which the drug will be administered to rats and, subsequently, K+-stimulated release of DA from strialtal slices will be studied in vitro. The data obtained from these studies will clarify aspects of the action of these drugs and, hopefully, identify the mechanism(s) involved. Although all the drugs suppress DA release, there is reason to speculate that the inhibition of release by cocaine may have relevance to an aspect of cocaine addiction.
