In vivo amphetamine action is contingent on αCaMKII

Thomas Steinkellner; Liudmilla Mus; Birgit Eisenrauch; Andreea Constantinescu; Damiana Leo; Lisa Konrad; Karl Mattias Rickhag; Gunnar Sørensen; Evgenia V Efimova; Eryan Kong; Matthäus Willeit; Tatyana D Sotnikova; Oliver Kudlacek; Ulrik Gether; Michael Freissmuth; Daniela D Pollak; Raul R Gainetdinov; Harald H Sitte

doi:10.1038/npp.2014.124

In vivo amphetamine action is contingent on αCaMKII

Thomas Steinkellner, Liudmilla Mus, Birgit Eisenrauch, Andreea Constantinescu, Damiana Leo, Lisa Konrad, Karl Mattias Rickhag, Gunnar Sørensen, Evgenia V Efimova, Eryan Kong, Matthäus Willeit, Tatyana D Sotnikova, Oliver Kudlacek, Ulrik Gether, Michael Freissmuth, Daniela D Pollak, Raul R Gainetdinov, Harald H Sitte

Neuropharm and Genetics

32 Citations (Scopus)

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.

Original language	English
Journal	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Volume	39
Issue number	11
Pages (from-to)	2681-93
Number of pages	13
ISSN	0893-133X
DOIs	https://doi.org/10.1038/npp.2014.124
Publication status	Published - 1 Oct 2014

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Steinkellner, T., Mus, L., Eisenrauch, B., Constantinescu, A., Leo, D., Konrad, L., Rickhag, K. M., Sørensen, G., Efimova, E. V., Kong, E., Willeit, M., Sotnikova, T. D., Kudlacek, O., Gether, U., Freissmuth, M., Pollak, D. D., Gainetdinov, R. R., & Sitte, H. H. (2014). In vivo amphetamine action is contingent on αCaMKII. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 39(11), 2681-93. https://doi.org/10.1038/npp.2014.124

Steinkellner, T, Mus, L, Eisenrauch, B, Constantinescu, A, Leo, D, Konrad, L, Rickhag, KM, Sørensen, G, Efimova, EV, Kong, E, Willeit, M, Sotnikova, TD, Kudlacek, O, Gether, U, Freissmuth, M, Pollak, DD, Gainetdinov, RR & Sitte, HH 2014, 'In vivo amphetamine action is contingent on αCaMKII', Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 39, no. 11, pp. 2681-93. https://doi.org/10.1038/npp.2014.124

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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.",

author = "Thomas Steinkellner and Liudmilla Mus and Birgit Eisenrauch and Andreea Constantinescu and Damiana Leo and Lisa Konrad and Rickhag, {Karl Mattias} and Gunnar S{\o}rensen and Efimova, {Evgenia V} and Eryan Kong and Matth{\"a}us Willeit and Sotnikova, {Tatyana D} and Oliver Kudlacek and Ulrik Gether and Michael Freissmuth and Pollak, {Daniela D} and Gainetdinov, {Raul R} and Sitte, {Harald H}",

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T1 - In vivo amphetamine action is contingent on αCaMKII

AU - Steinkellner, Thomas

AU - Mus, Liudmilla

AU - Eisenrauch, Birgit

AU - Constantinescu, Andreea

AU - Leo, Damiana

AU - Konrad, Lisa

AU - Rickhag, Karl Mattias

AU - Sørensen, Gunnar

AU - Efimova, Evgenia V

AU - Kong, Eryan

AU - Willeit, Matthäus

AU - Sotnikova, Tatyana D

AU - Kudlacek, Oliver

AU - Gether, Ulrik

AU - Freissmuth, Michael

AU - Pollak, Daniela D

AU - Gainetdinov, Raul R

AU - Sitte, Harald H

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

U2 - 10.1038/npp.2014.124

DO - 10.1038/npp.2014.124

M3 - Journal article

C2 - 24871545

SN - 0893-133X

VL - 39

SP - 2681

EP - 2693

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

IS - 11

ER -

In vivo amphetamine action is contingent on αCaMKII

Abstract

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