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.

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

“…These data suggest that the attenuation of METH-enhanced BSR by SB-277011A or NGB 2904 observed in the present study is most likely mediated by action on brain DA D 3 receptors in vivo. Furthermore, neither SB-277011A nor NGB 2904 had any significant effect on BSR itself, suggesting that selective D 3 receptor antagonists themselves have no intrinsic addictive potential, consistent with our previous reports (Vorel et al 2002;Xi et al 2006;Pak et al 2006). …”

“…It is also consistent with prior intravenous drug selfadministration experiments demonstrating that SB-277011A or NGB 2904 dose-dependently inhibits cocaine or nicotine self-administration under PR reinforcement schedules Ross et al 2007) and prevents reinstatement of drug-seeking behavior induced by cocaine or nicotine, drug-related cues, or stress (Vorel et al 2002;Xi et al 2004Xi et al , 2006Andreoli et al 2003;Cervo et al 2007). SB-277011A is a highly potent and selective D 3 receptor antagonist that has 80-to 100-fold selectivity for D 3 over other DA receptors and 100-fold selectivity over 180 other receptors, enzymes, ion channels, and transporters in the central nervous system (Reavill et al 2000;Stemp et al 2000;Micheli and Heidbreder 2006;Heidbreder et al, unpublished data).…”

“…These data support the potential use of selective D 3 receptor antagonists or partial agonists in the clinical treatment of drug craving and relapse to drug-taking or drug-seeking behavior (see reviews by Le Foll and Goldberg 2005;Heidbreder et al 2005;Xi and Gardner 2007). In contrast, the D 3 receptor antagonists SB-277011A and NGB 2904 or the partial D 3 agonist BP-897 have no significant effect on intravenous cocaine or nicotine self-administration under fixed-ratio reinforcement (Pilla et al 1999;Vorel et al 2002;Xi et al 2005Xi et al , 2006Ross et al 2007), but low doses attenuate cocaine-or nicotine-enhanced electrical brain stimulation reward (BSR; Pak et al 2006;Xi et al 2006;Xi and Gardner 2007). These data suggest that D 3 receptors may have a complex role in mediating acute rewarding effects produced by cocaine or nicotine, depending upon the doses of those addictive drugs and the animal models used to evaluate brain reward function.…”

“…Figure 1d shows that the same doses of METH had no effect on Ymax for BSR (F 5,20 =0.26,p=NS). In the subsequent experiments, we chose to observe the effects of test compounds on METH-enhanced BSR produced by 0.2 mg/kg METH because that dose of METH produced similar BSR enhancement (25-30%) as other addictive drugs against which we have tested DA D 3 receptor antagonists, including cocaine (2 mg/kg) and nicotine (0.25 mg/kg; Xi et al 2006;Pak et al 2006). Our previous studies have shown that the D 3 -selective antagonists SB-277011A or NGB 2904 significantly attenuate the enhanced BSR produced by those relatively low doses, but not higher doses, of cocaine or nicotine in rats Pak et al 2006).…”

“…Third, pharmacological studies demonstrate that DA D 3 receptors play an important role in emotion, motivation, and reinforcement, including the reinforcement produced by addictive drugs (Caine and Koob 1993;Duaux et al 1998;Sokoloff et al 2006). Growing evidence demonstrates that blockade of D 3 receptors by the selective D 3 receptor antagonists SB-277011A or NGB 2904 or by the putative partial D 3 receptor agonist BP-897 significantly inhibits reinstatement of drug-seeking behaviors triggered by addictive drugs, such as cocaine, nicotine, or alcohol, drug-associated cues or foot-shock stress (Vorel et al 2002;Andreoli et al 2003;Xi et al 2004Xi et al , 2006Cervo et al 2007), and also inhibits cocaine or nicotine self-administration under progressive-ratio (PR), second-order, or high-effort/low-payoff reinforcement schedules (Di Ciano et al 2003;Xi et al 2005Xi et al , 2006Ross et al 2007). These data support the potential use of selective D 3 receptor antagonists or partial agonists in the clinical treatment of drug craving and relapse to drug-taking or drug-seeking behavior (see reviews by Le Foll and Goldberg 2005;Heidbreder et al 2005;Xi and Gardner 2007).…”