Effect of cocaine and 5-HT3 receptor antagonists on 5-HT-induced [3H]dopamine release from rat striatal synaptosomes

The effect of serotonin (5-HT) on the release of tritium from striatal synaptosomes previously loaded with [3H]dopamine ([3H]DA) was studied. 5-HT stimulated both the spontaneous and Ca(2+)-evoked efflux of tritium in a concentration-dependent manner. This effect was not mimicked by the non-selective 5-HT agonist, d-lysergic acid diethylamide. Further, the stimulatory effects of 5 muM 5-HT were unaffected by the selective 5-HT3 receptor antagonists, MDL-72222 and GR-38032F. On the other hand, cocaine and the selective DA uptake inhibitor, nomifensine completely antagonized the effect of 5 muM 5-HT on spontaneous tritium efflux with IC50 values of 0.2 and 0.09 muM, respectively. The effect of 5-HT on Ca(2+)-evoked tritium efflux was also blocked by these DA uptake inhibitors, albeit at somewhat higher concentrations. These data support the hypothesis that 5-HT induces the release of DA from striatal nerve terminals via a mechanism involving the transport of 5-HT into the dopaminergic terminal, rather than by activating 5-HT3 receptors as has been proposed to account for the effect of 5-HT observed in striatal slices.