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Neuropsychopharmacology. 2014 Oct;39(11):2681-93. doi: 10.1038/npp.2014.124. Epub 2014 May 29.

In vivo amphetamine action is contingent on αCaMKII.

Author information

1
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
2
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Via Morego, Genova, Italy [2] Department of Psychopharmacology, Institute of Pharmacology, Pavlov Medical University, St Petersburg, Russia.
3
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Via Morego, Genova, Italy.
4
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
5
Skolkovo Institute of Science and Technology (Skoltech), Skolkovo, Moscow, Russia.
6
Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
7
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel, Vienna, Austria.
8
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Via Morego, Genova, Italy [2] Skolkovo Institute of Science and Technology (Skoltech), Skolkovo, Moscow, Russia [3] Faculty of Biology and Soil Science, St Petersburg State University, St Petersburg, Russia.

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.

PMID:
24871545
PMCID:
PMC4207348
DOI:
10.1038/npp.2014.124
[Indexed for MEDLINE]
Free PMC Article
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