title: The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats.
abstract: Accumulating evidence indicates that dopamine (DA) D(3) receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D(3)-selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long-Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1-10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D(3)-selective antagonist NGB 2904 attenuates cocaine's rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.
authors.affiliation: Neuropsychopharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, MD 21224, USA. zxi@intra.nida.nih.gov
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Gilbert
authors.forename: Arlene C
authors.initials: AC
authors.lastname: Pak
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Peng
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Leah
authors.initials: L
authors.lastname: Gitajn
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000503:physiopathology / Q000528:radiation effects; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D018492:Dopamine Antagonists / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005108:Extinction, Psychological / Q000187:drug effects; D005449:Fluorenes / Q000008:administration & dosage*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration
chemical_list: D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D005449:Fluorenes; C116818:NGB 2904; D010879:Piperazines; D003042:Cocaine