ngb-2904 and Cocaine-Related-Disorders

Animal research has demonstrated a role of dopamine D1 and D3 receptors in cocaine reward and seeking.. Here, we investigated the potential interaction of these two dopamine receptors in cue-induced reinstatement of cocaine seeking, cocaine conditioned place preference (CPP), and cocaine self-administration in rats.. The co-administration of a D3 receptor antagonist, NGB 2904 and a D1 partial agonist, SKF 77434, of doses which when administered individually produced no significant effects, prior to reinstatement or CPP tests significantly reduced lever pressing and time spent in the cocaine-paired environment, suggesting synergistic effects of the combined compounds on cocaine seeking. When given to rats self-administering cocaine under a progressive ratio schedule of reinforcement doses of NGB 2904 which were ineffective alone significantly enhanced the break point-reducing effects of SKF 77434.. Our results indicate that the combined treatment with a D1 receptor partial agonist and D3 receptor antagonist produces robust decreases in cocaine seeking and reward. This suggests an interaction between dopamine D1 and D3 receptors in cocaine-related behaviors.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Antagonists; Drug Therapy, Combination; Drug-Seeking Behavior; Fluorenes; Male; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D3; Reinforcement, Psychology; Reward

The dopamine (DA) D3 receptor is posited to be importantly involved in drug reward and addiction, and D3 receptor antagonists have shown extraordinary promise as potential anti-addiction pharmacotherapeutic agents in animal models of drug addiction. SB-277011A is the best characterized D3 receptor antagonist in such models. However, the potential use of SB-277011A in humans is precluded by pharmacokinetic and toxicity problems. We here report a novel D3 receptor antagonist YQA14 that shows similar pharmacological properties as SB-277011A. In vitro receptor binding assays suggest that YQA14 has two binding sites on human cloned D3 receptors with K(i-High) (0.68 × 10(-4)  nM) and K(i-Low) (2.11 nM), and displays > 150-fold selectivity for D3 over D2 receptors and > 1000-fold selectivity for D3 over other DA receptors. Systemic administration of YQA14 (6.25-25 mg/kg) or SB-277011A (12.5-25 mg/kg) significantly and dose-dependently reduced intravenous cocaine self-administration under both low fixed-ratio and progressive-ratio reinforcement conditions in rats, while failing to alter oral sucrose self-administration and locomotor activity, suggesting a selective inhibition of drug reward. However, when the drug dose was increased to 50 mg/kg, YQA14 and SB-277011A significantly inhibited basal and cocaine-enhanced locomotion in rats. Finally, both D3 antagonists dose-dependently inhibited intravenous cocaine self-administration in wild-type mice, but not in D3 receptor-knockout mice, suggesting that their action is mediated by D3 receptor blockade. These findings suggest that YQA14 has a similar anti-addiction profile as SB-277011A, and deserves further study and development.

Topics: Animals; Benzoxazoles; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Dopamine Antagonists; Dose-Response Relationship, Drug; Fluorenes; Guanosine 5'-O-(3-Thiotriphosphate); Infusions, Intravenous; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nitriles; Piperazines; Quinpirole; Radioligand Assay; Random Allocation; Rats; Rats, Long-Evans; Receptors, Dopamine D3; Reinforcement, Psychology; Reward; Self Administration; Sucrose; Tetrahydroisoquinolines

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.

Topics: Animals; Behavior, Addictive; Behavior, Animal; Brain; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Dopamine Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Extinction, Psychological; Fluorenes; Male; Piperazines; Rats; Rats, Long-Evans; Reinforcement Schedule; Reward; Self Administration

Recent studies have shown that the novel dopamine (DA) D3 receptor antagonists SB-277011A and NGB 2904 inhibit cocaine- and/or stress-induced reinstatement of drug-seeking behavior. The present study sought to determine if SB-277011A, NGB 2904, or BP-897 (a mixed D3 agonist/antagonist) similarly inhibit cocaine-associated cue-induced reinstatement of drug-seeking behavior. Long-Evans rats were allowed to self-administer cocaine. Each cocaine infusion was paired with discrete conditioned cue-light and tone. Subsequently, drug-seeking (i.e., lever-pressing) behavior was extinguished in the absence of cocaine and cocaine-associated cues. Rats were then tested for cue-induced reinstatement of drug-seeking. We found that cocaine-associated cues evoked robust reinstatement of lever-pressing. Acute intraperitoneal (i.p.) administration of SB-277011A (6, 12, or 24 mg/kg) produced a dose-dependent inhibition of cue-induced reinstatement of drug-seeking behavior by 35, 65, and 85%, respectively, compared to vehicle-treated animals. Acute i.p. administration of NGB 2904 (0.1, 1.0, or 5.0 mg/kg) produced a 45, 30, and 70% inhibition of cue-induced reinstatement, respectively, compared to vehicle-treated animals. Acute i.p. administration of either 0.1 or 1 mg/kg of BP 897 did not produce a significant effect on cue-induced reinstatement, whereas a dose of 3 mg/kg produced a 70% inhibition of cue-induced reinstatement. These findings, combined with previous data, suggest that DA D3 receptor antagonism may underlie the inhibitory effects of SB-277011A and NGB 2904 on cocaine cue-induced reinstatement, while the effects of BP 897 may involve D3 and non-D3 receptor mechanisms.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cues; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Extinction, Psychological; Fluorenes; Male; Nitriles; Photic Stimulation; Piperazines; Rats; Rats, Long-Evans; Receptors, Dopamine D3; Recurrence; Self Administration; Tetrahydroisoquinolines