title: 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.
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steinkellner
authors.affiliation: 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.
authors.forename: Liudmilla
authors.identifier: 0000000275887617
authors.initials: L
authors.lastname: Mus
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Eisenrauch
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Andreea
authors.initials: A
authors.lastname: Constantinescu
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Via Morego, Genova, Italy.
authors.forename: Damiana
authors.initials: D
authors.lastname: Leo
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Lisa
authors.identifier: 0000000187253139
authors.initials: L
authors.lastname: Konrad
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mattias
authors.initials: M
authors.lastname: Rickhag
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sørensen
authors.affiliation: Skolkovo Institute of Science and Technology (Skoltech), Skolkovo, Moscow, Russia.
authors.forename: Evgenia V
authors.initials: EV
authors.lastname: Efimova
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Eryan
authors.initials: E
authors.lastname: Kong
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel, Vienna, Austria.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Willeit
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Via Morego, Genova, Italy.
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kudlacek
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gether
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Pollak
authors.affiliation: 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.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringer Strasse, Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology*; D000076122:Disks Large Homolog 4 Protein; D004298:Dopamine / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011954:Receptors, Dopamine / Q000378:metabolism; D012201:Reward; D013028:Space Perception / Q000187:drug effects / Q000502:physiology
chemical_list: D000697:Central Nervous System Stimulants; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D011954:Receptors, Dopamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; D051528:Guanylate Kinases; D003913:Dextroamphetamine; D004298:Dopamine