Recent studies demonstrated that vesicular dopamine (DA) uptake can be rapidly altered in synaptic vesicles purified from the striata of stimulant-treated rats. Specifically, a single administration of the plasmalemmal DA transporter inhibitor, cocaine, or the DA D 2 agonist, quinpirole, increases vesicular DA uptake in vesicles purified from the striata of treated rats. These effects of cocaine are prevented by pretreatment with a D 2 , but not D 1 , DA receptor antagonist. The purpose of the present study was to characterize the effect of a mechanistically different psychostimulant, methamphetamine (METH), on vesicular DA uptake. Results demonstrated that a single administration of this DA-releasing agent rapidly and reversibly decreased vesicular DA uptake. The METH-related decrease in vesicular DA uptake was attenuated by pretreatment with the D 2 antagonist, eticlopride, but not the D 1 antagonist, SCH23390 (R-[ϩ]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). Core body temperature did not contribute to the effects of METH on vesicular DA uptake. Neither quinpirole nor cocaine increased vesicular DA uptake when rats were concurrently treated with METH. These studies provide further evidence that psychostimulants rapidly and differentially modify vesicular DA uptake. In addition, these studies demonstrate a complex role for D 2 DA receptors in altering vesicular DA transport.Sequestration of monoamines, such as dopamine (DA), into synaptic vesicles for storage and subsequent release, is mediated by the vesicular monoamine transporter-2 (VMAT-2). Recent studies demonstrate a novel mechanism whereby this sequestration is rapidly regulated by both psychostimulant and D 2 DA receptor agonist treatment. Specifically, Brown et al. (2001b) demonstrated that a single injection of cocaine or quinpirole increases vesicular [ 3 H]DA uptake, as assessed in synaptic vesicles purified from the striata of treated rats sacrificed 1 h after treatment. The cocaine-induced effect was not attributable to residual drug in the vesicular preparation, and was associated with an increase in B max of binding of the VMAT-2 ligand, Brown et al., 2001a). In addition, this increase was: 1) reversed within 6 h after drug treatment; 2) mimicked by administration of other DA transporter inhibitors (GBR-12935 and amfonelic acid); and 3) dependent on D 2 , but not D 1 , receptor activation (Brown et al., 2001a,b).Recent evidence suggests that not only do cocaine or D 2 receptor agonists rapidly alter vesicular DA uptake, but methamphetamine (METH) administration does as well.Specifically, multiple high-dose administrations of METH produce a rapid (within 1 h; Brown et al., 2000Brown et al., , 2001a and prolonged (persisting at least 24 h; Brown et al., 2000;Hogan et al., 2000) (Brown et al., 2001a). The purpose of the present study was to characterize and determine the role, if any, of DA receptors in this latter effect. Results demonstrated that a single METH administration rapidly and reversibly decreased...

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Repeated high-dose methamphetamine administrations can cause persistent dopaminergic deficits. As individuals abusing methamphetamine are often exposed to recurrent high-dose administration, the impact of its repeated exposure merits investigation. Accordingly, rats were pretreated with repeated high-dose injections of methamphetamine, and subsequently "challenged" with the same neurotoxic regimen 7 or 30 days later. Results revealed that the initial methamphetamine treatment caused persistent deficits in striatal dopamine levels, dopamine transporter function, and vesicular monoamine transporter-2 function. The subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, as assessed 7 days after the challenge, regardless of the interval (7 or 30 days) between the initial and challenge drug exposures. Similarly, a methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effect on dopamine transporter or VMAT-2 function, as assessed 1 hour later. Thus, this study describes a model of resistance, possibly explained by: 1) the existence of dopaminergic neurons that are a priori refractory to deficits caused by methamphetamine; 2) the existence of dopaminergic neurons made persistently resistant consequent to a neurotoxic methamphetamine exposure; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced dopamine neurotoxicity.