The effects of stimulants on dopaminergic terminal function. (A–C) Exposure of dopaminergic terminals (A) to releasers (B) and reuptake inhibitors (C) alters the distribution and function of DAT and VMAT2. (B) Releasers function as DAT substrates and diffuse through the cytoplasmic membrane, leading to reversal of DA transport through the DAT. PKC-mediated DAT internalization may occur but has not been demonstrated in vivo. Releasers also reduce DA uptake into VMAT2 synaptic vesicles, by potentially functioning as a weak base to decrease vesicular pH or by binding VMAT2 directly, presumably increasing cytoplasmic DA. Finally, releasers reduce VMAT2 synaptic vesicles within the cytoplasmic fraction. (C) Reuptake inhibitors prevent DA transport via the DAT while also increasing DAT expression at the plasma membrane, increasing extracellular DA. In addition, reuptake inhibitors increase VMAT2 synaptic vesicles within the cytoplasmic fraction while reducing the number of vesicles in the membrane fraction, increasing DA content within striatal dopaminergic terminals. DAT, VMAT2, and DA are depicted as in Fig. 1. CCV, clathrin-coated vesicle; EE, early endosome; RE, recycling endosome.