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

Abstract

After cessation of repeated, intermittent amphetamine, we detected an emergent Ca 2ϩ -dependent component of amphetamine-induced dopamine release and an increase in calmodulin and Ca 2ϩ -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 Ca 2ϩ -dependent dopamine release in response to amphetamine or K ϩ 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 Rats were pretreated for 5 d with 2.5 mg/kg amphetamine or saline and withdrawn from drug for 10 d. The selective CaM kinase II inhibitor KN-93 (1 M), but not the inactive analog KN-92, attenuated the Ca 2ϩ -dependent amphetaminemediated dopamine release from amphetamine-pretreated rats but had no effect in saline-pretreated controls.[ 3 H]Dopamine uptake was unaltered by repeated amphetamine or KN-93 and was Ca 2ϩ 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 Ca 2ϩ -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 ϩ -mediated dopamine release. Reserpine did not disrupt the ability of 1 M KN-93 to block the Ca 2ϩ -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 Ca 2ϩ -and calmodulin-dependent phosphorylation and is independent of vesicular dopamine storage. On the contrary, the enhanced depolarization-mediated vesicular dopamine release is independent of Ca 2ϩ -and calmodulin-dependent phosphorylation.

Membrane-permeable C-terminal Dopamine Transporter Peptides Attenuate Amphetamine-evoked Dopamine Release*

“…Hence, we obtained evidence for a model in which CaMKII␣ binding to a domain corresponding to the last 24 C-terminal residues facilitates N-terminal phosphorylation and thereby AMPH-induced DA efflux (17). The model concurs with data suggesting that CaMKII␣ is activated upon AMPH administration (23,24) possibly as a consequence of elevated intracellular calcium levels through still poorly understood mechanisms (25). Impaired AMPH-induced efflux in synaptosomes from mice with ablated CaMKII␣ activity has provided further indirect support for the model (26).…”

“…Notably, such a function of PICK1 has been proposed in relation to its binding to ASIC1/2 (acid-sensing ion channels 1/2) and the GluR2 subunit of the AMPA receptor (40,41). It has also previously been suggested that PKC isoforms, including PKC␣ and PKC␤, might play a role in AMPH-mediated DA efflux (17,23,(42)(43)(44). Furthermore, the dominant-negative TAT-C24WT peptide would be predicted to abolish not only the association of CaMKII␣ to endogenous DAT but also the association of the PDZ domain protein PICK1 (17).…”

“…Altogether, it is becoming increasingly clear that DAT is subject to complex and delicate regulatory mechanisms that govern trafficking and catalytic activity of the protein via complex protein-protein interactions and post-translational modifications. Some interactions and pathways might even serve dual roles such as CaMKII␣ and protein kinase C, for example, that have both been suggested to be involved in controlling trafficking and DA efflux (13,17,23,(42)(43)(44). Further studies are required to dissect this complicated interplay.…”

Chronic Blockade of Neurotensin Receptors Strongly Reduces Sensitized, but Not Acute, Behavioral Response to D-amphetamine

“…Microinjection of calcium channel antagonists into the NAC dose-dependently impaired behavioral sensitization to cocaine without altering the acute locomotor response to this psychostimulant (Pierce et al 1998). Similarly, other experiments revealed that the sensitized DA release in the NAC induced by amphetamine is calcium-dependent and can be attenuated by a selective calmodulin-dependent protein kinase II inhibitor, whereas DA release induced by a single dose of amphetamine is calcium-independent (Carboni et al 1989;Warburton et al 1996;Pierce and Kalivas 1997b;Kantor et al 1999). Thus, one may hypothesize that blockade of NT receptors alters the behavioral sensitized response to amphetamine by acting on the calcium-dependent portion of the DA response to amphetamine.…”

The Immunobiology of Tourette's Disorder, Pediatric Autoimmune Neuropsychiatric Disorders Associated withStreptococcus, and Related Disorders: A Way Forward

“…In vitro, these antibodies can induce increases in the activity of calcium/calmodulin-dependent protein kinase II (CaM kinase II), which in turn can lead to increases in dopamine production and release. CaM kinase II activation is a potential mechanism by which clinical symptoms ensue (Roberts-Lewis et al 1986;Kantor et al 1999). The anti-carbohydrate A antibody measures the immune response to N-acetyl-beta-dglucosamine (Bloem et al 1988).…”