Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release.

Autor: Keighron JD; Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.; Department of Biological and Chemical Science, New York Institute of Technology, Old Westbury, NY, USA., Bonaventura J; Biobehavioral Imaging & Molecular Neuropsychopharmacology Unit, Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.; Department of Pathology and Experimental Therapeutics, Institut de Neurociències, Universitat de Barcelona, L'Hospitalet de Llobregat, Catalonia, Spain., Li Y; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., Yang JW; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., DeMarco EM; Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA., Hersey M; Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA., Cao J; Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA., Sandtner W; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., Michaelides M; Biobehavioral Imaging & Molecular Neuropsychopharmacology Unit, Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA., Sitte HH; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., Newman AH; Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.; Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA., Tanda G; Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA. gtanda@intra.nida.nih.gov.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2023 Jun 13; Vol. 13 (1), pp. 202. Date of Electronic Publication: 2023 Jun 13.
DOI: 10.1038/s41398-023-02493-4
Abstrakt: Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKIIα in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine's neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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