| Description |
The vesicular monoamine transporter-2 (VMAT-2) is responsible for the sequestration of dopamine (DA) into synaptic vesicles and therefore may influence quantal release. Studies assessing whether pharmacological agents can regulate VMAT-2 acutely have yielded conflicting results. Hence, the purpose of the present studies was to determine if psychostimulant administration alters vesicular DA uptake. Results presented demonstrate that multiple methamphetamine (METH) administrations produced rapid (within 1 h) and prolonged (i.e., up to 24 h) decreases in vesicular DA uptake and binding of the VMAT-2 ligand dihydrotetrabenazine (DHTBZ), as assessed in purified vesicles prepared from drug-treated rats. A single METH administration rapidly (within 1 h) but transiently (recovered by 24 h) decreased vesicular DA uptake an effect dependent on activation of D2 DA receptors. In contrast to METH, administration of DA transporter inhibitors, including cocaine, increased both vesicular DA uptake and DHTBZ binding in purified vesicular preparations. The rapid (within 1 h) and reversible (within 6 h) increase induced by cocaine was dependent on D2 receptor activation. Activation of D2 receptors was also sufficient to increase vesicular DA uptake and DHTBZ binding. These studies also examined a mechanism for these cocaine-induced increases, trafficking of synaptic vesicles that contain the VMAT-2. Results demonstrate that a single administration of cocaine decreased VMAT-2 immunoreactivity associated with membrane-bound vesicles, but increased VMAT-2 immunoreactivity associated with the cytoplasmic pool of vesicles, the latter representing the pool of vesicles purified in the above-mentioned studies. In conclusion, studies presented here suggest that vesicular DA uptake is regulated by drug treatments. Of relevance is the finding that multiple high-dose administrations of METH cause prolonged decreases in vesicular DA uptake and long-term damage to dopaminergic neurons. In contrast, cocaine, which increases vesicular DA uptake, does not cause long-term damage to dopamine neurons. Therefore, prolonged inhibition of VMAT-2 may contribute to drug-induced cell damage. Hence, regulation of VMAT-2 activity may have implications in addition to regulation of quantal DA release. Further studies examining regulation of this transporter are warranted. |
