title: CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction.
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.
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
authors.forename: Zheng-Xiong
authors.identifier: 0000-0001-6482-8104
authors.initials: ZX
authors.lastname: Xi
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures and Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures and Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Guan-Yi
authors.initials: GY
authors.lastname: Lu
authors.affiliation: Department of Behavioral Health, Saint Elizabeth's Hospital, Washington, DC, USA.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Peng
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Bi
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
authors.forename: Siyuan Peter
authors.initials: SP
authors.lastname: Sheng
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
authors.forename: Hong-Ju
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures and Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Froimowitz
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008774:Methylphenidate / Q000032:analysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D012201:Reward
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008774:Methylphenidate