Repeated intermittent amphetamine enhances efflux of dopamine through the dopamine transporter in rat basal ganglia and through the norepinephrine transporter in rat pheochromocytoma PC12 cells. Extracellular Ca 2ϩ is required for the detection of this enhancement in the rat. In this study, we examined the role of Ca 2ϩ and Ca 2ϩ channels in the enhanced amphetamine-induced dopamine efflux that develops in PC12 cells following repeated intermittent amphetamine. Repeated pretreatment of PC12 cells with 1 M amphetamine followed by a drug-free period increased amphetamine-induced efflux of dopamine compared with controls. The enhancement in amphetamine-induced dopamine efflux depended upon the presence of extracellular Ca 2ϩ and was inhibited by the blockade of N-type and L-type Ca 2ϩ channels. The enhanced dopamine efflux was not altered by tetanus toxin or reserpine, treatments that abrogate synaptic vesicle-mediated, exocytotic dopamine efflux. Measurement of intracellular Ca 2ϩ concentrations using fura-2/acetoxymethyl ester revealed that amphetamine increased intracellular Ca 2ϩ by a transporter-dependent mechanism. In amphetamine-pretreated cells, amphetamine elicited a greater increase in intracellular Ca 2ϩ ; this increase depended upon the presence of extracellular Ca 2ϩ and N-and L-type Ca 2ϩ channel activity. The enhanced amphetamine-induced dopamine efflux requires Ca 2ϩ /calmodulin kinase activity. In vehicle-treated cells, 1 M amphetamine inhibited the calmodulin kinase activity although it did not in amphetamine-pretreated cells. This study suggests that repeated intermittent amphetamine couples norepinephrine transporter activity and Ca 2ϩ signaling.
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