CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

Zheng Xiong Xi, Rui Song, Xia Li, Guan Yi Lu, Xiao Qing Peng, Yi He, Guo Hua Bi, Siyuan Peter Sheng, Hong Ju Yang, Haiying Zhang, Jin Li, Mark Froimowitz, Eliot L. Gardner

Research output: Contribution to journalArticle

Abstract

Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-Administer CTDP-32476. In a substitution test, cocaine self-Administration rats displayed a progressive reduction in CTDP-32476 self-Administration with an extinction pattern of drug-Taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-Administration, cocaine-Associated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy 'drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual-thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction.

Original languageEnglish (US)
Pages (from-to)682-694
Number of pages13
JournalNeuropsychopharmacology
Volume42
Issue number3
DOIs
StatePublished - Feb 1 2017

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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  • Cite this

    Xi, Z. X., Song, R., Li, X., Lu, G. Y., Peng, X. Q., He, Y., Bi, G. H., Sheng, S. P., Yang, H. J., Zhang, H., Li, J., Froimowitz, M., & Gardner, E. L. (2017). CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction. Neuropsychopharmacology, 42(3), 682-694. https://doi.org/10.1038/npp.2016.155