D2 Receptor-Mediated Regulation of Vesicular Dopamine Uptake

The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic monoamines, including dopamine (DA), into synaptic vesicles. It has been suggested that VMAT-2 is resistant to regulation by drug treatment. However, recent data indicate that agents which alter DA disposition also rapidly modify VMAT-2 function. For example, our laboratory reported that multiple injections of the DA-releasing agent, methamphetamine (METH), rapidly (within 1 h) decrease vesicular [3H]DA uptake and binding of the VMAT-2 ligand, [3H]dihydrotetrabenazine ([3H]DHTBZ), as assessed in purified striatal vesicles obtained from treated rats; an effect unrelated to residual METH introduced by the original drug injections.1 Similarly, Hogan et al. have demonstrated decreases in [3H]DA uptake and [3H]DHTBZ binding 24 h after high-dose METH treatment.2 Accordingly, our laboratory investigated whether other stimulants, including cocaine and methylenedioxymethamphetamine (MDMA), rapidly affect VMAT-2. Our results indicate that these psychostimulants rapidly and differentially regulate vesicular DA uptake. In addition, D2 receptors mediate the effects of cocaine on vesicular DA uptake. These data may explicate mechanisms contributing to psychostimulant-induced neurotoxicity, and provide insight into the physiological regulation of DA neurons.