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Home > Amphetamine action at the cocaine- and antidepressant-sensitive serotonin transporter is modulated by αCaMKII.

Steinkellner, Thomas and Montgomery, Therese R and Hofmaier, Tina and Kudlacek, Oliver and Yang, Jae-Won and Rickhag, Mattias and Jung, Gangsoo and Lubec, Gert and Gether, Ulrik and Freissmuth, Michael and Sitte, Harald H (2015) Amphetamine action at the cocaine- and antidepressant-sensitive serotonin transporter is modulated by αCaMKII. The Journal of Neuroscience, 35, (21), pp. 8258-8271.

Serotonergic neurotransmission is terminated by reuptake of extracellular serotonin (5-HT) by the high-affinity serotonin transporter (SERT). Selective 5-HT reuptake inhibitors (SSRIs) such as fluoxetine or escitalopram inhibit SERT and are currently the principal treatment for depression and anxiety disorders. In addition, SERT is a major molecular target for psychostimulants such as cocaine and amphetamines. Amphetamine-induced transport reversal at the closely related dopamine transporter (DAT) has been shown previously to be contingent upon modulation by calmodulin kinase IIα (αCaMKII). Here, we show that not only DAT, but also SERT, is regulated by αCaMKII. Inhibition of αCaMKII activity markedly decreased amphetamine-triggered SERT-mediated substrate efflux in both cells coexpressing SERT and αCaMKII and brain tissue preparations. The interaction between SERT and αCaMKII was verified using biochemical assays and FRET analysis and colocalization of the two molecules was confirmed in primary serotonergic neurons in culture. Moreover, we found that genetic deletion of αCaMKII impaired the locomotor response of mice to 3,4-methylenedioxymethamphetamine (also known as "ecstasy") and blunted d-fenfluramine-induced prolactin release, substantiating the importance of αCaMKII modulation for amphetamine action at SERT in vivo as well. SERT-mediated substrate uptake was neither affected by inhibition of nor genetic deficiency in αCaMKII. This finding supports the concept that uptake and efflux at monoamine transporters are asymmetric processes that can be targeted separately. Ultimately, this may provide a molecular mechanism for putative drug developments to treat amphetamine addiction.


Item Type
Article
Publication Type
Irish-related, Article
Drug Type
CNS depressants / Sedatives, CNS stimulants, Cocaine
Date
2015
Page Range
pp. 8258-8271
Publisher
Baltimore
Volume
35
Number
21
EndNote
Accession Number
HRB (Not in collection)

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