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.