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

  • Neuropsychopharmacology. 2019 Jul;44(8):1435-1444. doi: 10.1038/s41386-019-0366-z.
Amy Hauck Newman  1 ,  Jianjing Cao  2 ,  Jacqueline D Keighron  2 ,  Chloe J Jordan  2 ,  Guo-Hua Bi  2 ,  Ying Liang  2 ,  Ara M Abramyan  2 ,  Alicia J Avelar  3 ,  Christopher W Tschumi  3  4 ,  Michael J Beckstead  3  4 ,  Lei Shi  2 ,  Gianluigi Tanda  2 ,  Zheng-Xiong Xi  2
Affiliations
  • 1. Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, USA. [email protected].
  • 2. Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, USA.
  • 3. Department of Cellular and Integrative Physiology, UT Health Science Center, San Antonio, TX, USA.
  • 4. Aging & Metabolism Research Group, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
PMID: 30858517 DOI: 10.1038/s41386-019-0366-z
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.

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