In Vivo Amphetamine Action is Contingent on αCaMKII

Abstract

Addiction to psychostimulants (ie, amphetamines and cocaine) imposes a major socioeconomic burden. Prevention and treatment represent unmet medical needs, which may be addressed, if the mechanisms underlying psychostimulant action are understood. Cocaine acts as a blocker at the transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), but amphetamines are substrates that do not only block the uptake of monoamines but also induce substrate efflux by promoting reverse transport. Reverse transport has been a focus of research for decades but its mechanistic basis still remains enigmatic. Recently, transporter-interacting proteins were found to regulate amphetamine-triggered reverse transport: calmodulin kinase IIα (αCaMKII) is a prominent example, because it binds the carboxyl terminus of DAT, phosphorylates its amino terminus, and supports amphetamine-induced substrate efflux in vitro. Here, we investigated whether, in vivo, the action of amphetamine was contingent on the presence of αCaMKII by recording the behavioral and neurochemical effects of amphetamine. Measurement of dopamine efflux in the dorsal striatum by microdialysis revealed that amphetamine induced less dopamine efflux in mice lacking αCaMKII. Consistent with this observation, the acute locomotor responses to amphetamine were also significantly blunted in αCaMKII-deficient mice. In addition, while the rewarding properties of amphetamine were preserved in αCaMKII-deficient mice, their behavioral sensitization to amphetamine was markedly reduced. Our findings demonstrate that amphetamine requires the presence of αCaMKII to elicit a full-fledged effect on DAT in vivo: αCaMKII does not only support acute amphetamine-induced dopamine efflux but is also important in shaping the chronic response to amphetamine.

Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine

“…Deletion of Maged1 in the striatum did not induce any alteration in the behaviours examined. Such a decoupling between locomotor sensitization and CPP has been reported for other knockout models, such as mice lacking calcium/ calmodulin protein kinase IIa, a protein involved in synaptic plasticity [48], suggesting that these behavioural responses to cocaine are driven by different mechanisms. Interestingly, the complete lack of Maged1 impaired motor coordination but did not affect motor learning, whereas deletion of Maged1 only in the PFC resulted in no alteration of motor coordination, but in a severe deficit in motor learning.…”

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

“…It is possible that although cocaine binding to DAT may be necessary to initiate cocaine reward subsequent alterations in DA signals may lead to modulation of other neuronal substrates including NET regulation, which in collaboration may evoke cocaine-associated behaviors. In addition, it is now clear that multiple DA brain regions are implicated in producing different aspects of cocaine reward, which may be attributed by the differences in DAT expression levels in different brain regions (78,79). NET expression is localized to noradrenergic terminals where it facilitates transport of NE and DA (80,81).…”

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…Fog et al (2006) also found that intracellular perfusion of activated CaMKIIa enhanced AMPH-induced DA efflux. Most recently, Steinkellner et al (2014) reported a reduction in AMPH-evoked DA release in vivo via microdialysis in CaMKIIa knockout mice as well as a blunting of AMPHinduced locomotor activation. Consistent with these findings, transgenic expression of a CaMKII inhibitory peptide blocks the locomotor stimulating actions of AMPH in Drosophila melanogaster (Pizzo et al, 2014).…”