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The Journal of Neuroscience, May 15, 1999, 19(10):3801-3808

Enhanced Amphetamine- and K⁺-Mediated Dopamine Release in Rat Striatum after Repeated Amphetamine: Differential Requirements for Ca²⁺- and Calmodulin-Dependent Phosphorylation and Synaptic Vesicles

Lana Kantor, G. H. Keikilani Hewlett, and Margaret E. Gnegy

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0634

After cessation of repeated, intermittent amphetamine, we detected an emergent Ca²⁺-dependent component of amphetamine-induced dopamine release and an increase in calmodulin and Ca²⁺- and calmodulin-dependent protein kinase activity in rat striatum. This study examined the involvement of calmodulin-dependent protein kinase II (CaM kinase II) and synaptic vesicles in the enhanced Ca²⁺-dependent dopamine release in response to amphetamine or K⁺ in rat striatum. Rats were pretreated for 5 d with 2.5 mg/kg amphetamine or saline and withdrawn from drug for 10 d. The selective CaM kinase II inhibitor KN-93 (1 µM), but not the inactive analog KN-92, attenuated the Ca²⁺-dependent amphetamine-mediated dopamine release from amphetamine-pretreated rats but had no effect in saline-pretreated controls. [³H]Dopamine uptake was unaltered by repeated amphetamine or KN-93 and was Ca²⁺ independent. Striatal dopamine release stimulated by 50 mM KCl was enhanced twofold after repeated amphetamine compared with that in saline controls but was unaffected by KN-93. To examine the requirement for dopaminergic vesicles in the Ca²⁺-dependent dopamine release, we administered reserpine to saline- and amphetamine-pretreated rats 1 d before killing. Reserpine pretreatment did not affect amphetamine-mediated dopamine release from either pretreatment group but completely ablated K⁺-mediated dopamine release. Reserpine did not disrupt the ability of 1 µM KN-93 to block the Ca²⁺-dependent amphetamine-mediated dopamine release from amphetamine-pretreated rats. The results indicate that the enhanced dopamine release elicited by amphetamine from chronically treated rats is dependent on Ca²⁺- and calmodulin-dependent phosphorylation and is independent of vesicular dopamine storage. On the contrary, the enhanced depolarization-mediated vesicular dopamine release is independent of Ca²⁺- and calmodulin-dependent phosphorylation.

Key words: repeated amphetamine; dopamine transport; reserpine; CaM kinase II; depolarization; phosphorylation

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19103801-08$05.00/0

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