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

Study authors Jacqueline Keighron, Melinda Hersey, Amy Hauck Newman and Gianluigi Tanda

Featured Paper of the Month – November 2023

Published in Translational Psychiatry by Jacqueline Keighron and Gianluigi Tanda, et al. of the NIDA IRP Medication Development Program.

Summary

Typical (cocaine-like) and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, which may result in DAT interactions with other proteins and in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted 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. In addition, 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.

Publication Information

Keighron, Jacqueline D; Bonaventura, Jordi; Li, Yang; Yang, Jae-Won; DeMarco, Emily M; Hersey, Melinda; Cao, Jianjing; Sandtner, Walter; Michaelides, Michael; Sitte, Harald H; Newman, Amy Hauck; Tanda, Gianluigi

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

In: Transl Psychiatry, vol. 13, no. 1, pp. 202, 2023, ISSN: 2158-3188.

Abstract | Links

@article{pmid37311803b,

title = {Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release},

author = {Jacqueline D Keighron and Jordi Bonaventura and Yang Li and Jae-Won Yang and Emily M DeMarco and Melinda Hersey and Jianjing Cao and Walter Sandtner and Michael Michaelides and Harald H Sitte and Amy Hauck Newman and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/37311803/},

doi = {10.1038/s41398-023-02493-4},

issn = {2158-3188},

year  = {2023},

date = {2023-06-01},

urldate = {2023-06-01},

journal = {Transl Psychiatry},

volume = {13},

number = {1},

pages = {202},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}