Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-03-11

AUTHORS

Amy Hauck Newman, Jianjing Cao, Jacqueline D. Keighron, Chloe J. Jordan, Guo-Hua Bi, Ying Liang, Ara M. Abramyan, Alicia J. Avelar, Christopher W. Tschumi, Michael J. Beckstead, Lei Shi, Gianluigi Tanda, Zheng-Xiong Xi

ABSTRACT

Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development. More... »

PAGES

1-10

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41386-019-0366-z

DOI

http://dx.doi.org/10.1038/s41386-019-0366-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112676588

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30858517


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