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NEUROPHARMACOLOGY

Repeated Amphetamine Couples Norepinephrine Transporter and Calcium Channel Activities in PC12 Cells

Department of Pharmacology, University of Michigan, Ann Arbor, Michigan

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 Ca²⁺ is required for the detection of this enhancement in the rat. In this study, we examined the role of Ca²⁺ and Ca²⁺ channels in the enhanced amphetamine-induced dopamine efflux that develops in PC12 cells following repeated intermittent amphetamine. Repeated pretreatment of PC12 cells with 1 µM 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 Ca²⁺ and was inhibited by the blockade of N-type and L-type Ca²⁺ 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 Ca²⁺ concentrations using fura-2/acetoxymethyl ester revealed that amphetamine increased intracellular Ca²⁺ by a transporter-dependent mechanism. In amphetamine-pretreated cells, amphetamine elicited a greater increase in intracellular Ca²⁺; this increase depended upon the presence of extracellular Ca²⁺ and N- and L-type Ca²⁺ channel activity. The enhanced amphetamine-induced dopamine efflux requires Ca²⁺/calmodulin kinase activity. In vehicle-treated cells, 1 µM 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 Ca²⁺ signaling.

Address correspondence to: Margaret E. Gnegy, Department of Pharmacology, 2220E Medical Science Research Building III, University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: pgnegy{at}umich.edu

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