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

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.

SUBMITTER: Newman AH

PROVIDER: S-EPMC6785152 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Newman Amy Hauck AH Newman Amy Hauck AH Cao Jianjing J Keighron Jacqueline D JD Jordan Chloe J CJ Bi Guo-Hua GH Liang Ying Y Abramyan Ara M AM Avelar Alicia J AJ Tschumi Christopher W CW Beckstead Michael J MJ Shi Lei L Tanda Gianluigi G Xi Zheng-Xiong ZX

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190311 8

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 similari ...[more]

PMID: 30858517

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Project description:Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. (S)-CE-123 ((S)-5-((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of (S)-CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. (S)-CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that (S)-CE-123 significantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, (S)-CE-123 has the behavioral and neurochemical profile of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that (S)-CE-123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans.

Dataset Information

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

Publications

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

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