1. ¹Neuropsychopharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, MD, USA
2. ²Medicinal Chemistry Section, Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, MD, USA
3. ³Department of Pharmaceutical Sciences, Saint John's University, Jamaica, NY, USA

Correspondence: Dr Z-X Xi, Neuropsychopharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, Building C, Room 394, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. Tel: +1 410 550 1749; Fax: +1 410 550 5172; E-mail: zxi@intra.nida.nih.gov

Received 1 April 2005; Revised 15 August 2005; Accepted 25 August 2005; Published online 5 October 2005.

Abstract

Accumulating evidence indicates that dopamine (DA) D₃ 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 D₃-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 D₃-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.