In Vivo Amphetamine Action is Contingent on αCaMKII
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 dop...
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| Format: | Online |
| Language: | English |
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Nature Publishing Group
2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207348/ |
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pubmed-42073482014-10-27 In Vivo Amphetamine Action is Contingent on αCaMKII Steinkellner, Thomas Mus, Liudmilla Eisenrauch, Birgit Constantinescu, Andreea Leo, Damiana Konrad, Lisa Rickhag, Mattias Sørensen, Gunnar Efimova, Evgenia V Kong, Eryan Willeit, Matthäus Sotnikova, Tatyana D Kudlacek, Oliver Gether, Ulrik Freissmuth, Michael Pollak, Daniela D Gainetdinov, Raul R Sitte, Harald H Original Article 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. Nature Publishing Group 2014-10 2014-06-25 /pmc/articles/PMC4207348/ /pubmed/24871545 http://dx.doi.org/10.1038/npp.2014.124 Text en Copyright © 2014 American College of Neuropsychopharmacology http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Steinkellner, Thomas Mus, Liudmilla Eisenrauch, Birgit Constantinescu, Andreea Leo, Damiana Konrad, Lisa Rickhag, Mattias Sørensen, Gunnar Efimova, Evgenia V Kong, Eryan Willeit, Matthäus Sotnikova, Tatyana D Kudlacek, Oliver Gether, Ulrik Freissmuth, Michael Pollak, Daniela D Gainetdinov, Raul R Sitte, Harald H |
| spellingShingle |
Steinkellner, Thomas Mus, Liudmilla Eisenrauch, Birgit Constantinescu, Andreea Leo, Damiana Konrad, Lisa Rickhag, Mattias Sørensen, Gunnar Efimova, Evgenia V Kong, Eryan Willeit, Matthäus Sotnikova, Tatyana D Kudlacek, Oliver Gether, Ulrik Freissmuth, Michael Pollak, Daniela D Gainetdinov, Raul R Sitte, Harald H In Vivo Amphetamine Action is Contingent on αCaMKII |
| author_facet |
Steinkellner, Thomas Mus, Liudmilla Eisenrauch, Birgit Constantinescu, Andreea Leo, Damiana Konrad, Lisa Rickhag, Mattias Sørensen, Gunnar Efimova, Evgenia V Kong, Eryan Willeit, Matthäus Sotnikova, Tatyana D Kudlacek, Oliver Gether, Ulrik Freissmuth, Michael Pollak, Daniela D Gainetdinov, Raul R Sitte, Harald H |
| author_sort |
Steinkellner, Thomas |
| title |
In Vivo Amphetamine Action is Contingent on αCaMKII |
| title_short |
In Vivo Amphetamine Action is Contingent on αCaMKII |
| title_full |
In Vivo Amphetamine Action is Contingent on αCaMKII |
| title_fullStr |
In Vivo Amphetamine Action is Contingent on αCaMKII |
| title_full_unstemmed |
In Vivo Amphetamine Action is Contingent on αCaMKII |
| title_sort |
in vivo amphetamine action is contingent on αcamkii |
| description |
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. |
| publisher |
Nature Publishing Group |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207348/ |
| _version_ |
1613148052096286720 |