Mechanisms underlying methamphetamine-induced dopamine transporter complex formation.

Hadlock GC, Baucum AJ, King JL, Horner KA, Cook GA, Gibb JW, Wilkins DG, Hanson GR, Fleckenstein AE
J Pharmacol Exp Ther. 2009 329 (1): 169-74

PMID: 19141713 · PMCID: PMC2670587 · DOI:10.1124/jpet.108.145631

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-(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride], but not the D1 receptor antagonist, SCH23390 [R(+)-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.

MeSH Terms (22)

Animals Benzazepines Blotting, Western Data Interpretation, Statistical Dopamine Dopamine Antagonists Dopamine D2 Receptor Antagonists Dopamine Plasma Membrane Transport Proteins Dopamine Uptake Inhibitors In Vitro Techniques Male Methamphetamine Neostriatum Nucleus Accumbens Oxidopamine Rats Rats, Sprague-Dawley Receptors, Dopamine D1 Receptors, Dopamine D2 Salicylamides Sympathectomy, Chemical Synaptosomes

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