Repeated, high-dose methamphetamine (METH) administrations cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. In rats, this treatment also causes the formation of high-molecular mass (greater than approximately 120 kDa) dopamine transporter (DAT)-associated complexes, the loss of DAT monomer immunoreactivity, and a decrease in DAT function, as assessed in striatal synaptosomes prepared 24 h after METH treatment. The present study extends these findings by demonstrating the regional selectivity of DAT complex formation and monomer loss because these changes in DAT immunoreactivity were not observed in the nucleus accumbens. Furthermore, DAT complex formation was not a consequence limited to METH treatment because it was also caused by intrastriatal administration of 6-hydroxydopamine. Pretreatment with the D2 receptor antagonist, eticlopride [S-(Ϫ)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride], but not the D1 receptor antagonist, SCH23390 [R(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], attenuated METH-induced DAT complex formation. Eticlopride pretreatment also attenuated METH-induced DAT monomer loss and decreases in DAT function; however, the attenuation was much less pronounced than the effect on DAT complex formation. Finally, results also revealed a negative correlation between METH-induced DAT complex formation and DAT activity. Taken together, these data further elucidate the underlying mechanisms and the functional consequences of repeated administrations of METH on the DAT protein. Furthermore, these data suggest a multifaceted role for D2 receptors in mediating METH-induced alterations of the DAT and its function.Repeated, high-dose methamphetamine (METH) administrations cause persistent striatal dopaminergic deficits (for review, see Gibb et al., 1994;Brown and Yamamoto, 2003). Although mechanisms contributing to this phenomenon remain to be elucidated fully, dopamine (DA) (Wagner et al., 1983;, the DA transporter (DAT) Fumagalli et al., 1998), hyperthermia (Bowyer et al., 1992), glutamate (Sonsalla et al., 1989;Mark et al., 2004), microglial activation (LaVoie et al., 2004;Thomas et al., 2004), and reactive species (Giovanni et al., 1995;Yamamoto and Zhu, 1998;Gluck et al., 2001;Imam et al., 2001) are among the contributing factors. Repeated, highdose METH injections also rapidly (within 1 h after the final METH administration) decrease plasmalemmal DA uptake, as assessed in striatal synaptosomes prepared from treated rats. As with METH-induced striatal dopaminergic deficits, DA, reactive species, and hyperthermia contribute to this rapid decrease in DAT function (for review, see Fleckenstein et al., 2000). In addition to effects described above, repeated, high-dose METH administrations also cause the formation of high molecular mass (greater than approximately 120 kDa) DATassociated complexes, as assessed 24 h after treatment. This phenomenon is attenuated by either ...