Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction

Abstract

As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction.

Figure 1

Effects of NGB 2904 (0.1–10 mg/kg, i.p.) on cocaine self‐administration under fixed‐ratio 2 (FR2) and progressive‐ratio (PR) reinforcement schedules in rats. *P < 0.05, **P < 0.01, when compared with the vehicle (Veh) treatment group.

Figure 2

Effects of NGB 2904 (0.1–5 mg/kg, i.p.) on reinstatement of reward‐seeking behavior triggered by 10 mg/kg cocaine (Panel A), cocaine‐associated cues (Panel B) or sucrose (Panel C). *P < 0.05, when compared with the vehicle treatment group.

Figure 3

Effects of NGB 2904 on brain reward‐enhancing effects produced by cocaine (Panel A), methamphetamine (Panel B), nicotine (Panel C), or heroin (Panel D). *P < 0.05, when compared with the vehicle (i.e., 0 mg/kg NGB 2904) treatment group.

Figure 4

Effects of NGB 2904 pretreatment on cocaine‐induced increases in extracellular DA in the NAc. *P < 0.05, **P < 0.01, ***P < 0.001, when compared with baselines before 10 mg/kg cocaine administration. ^# P < 0.05, ^## P < 0.01, when compared with the “Vehicle + Cocaine” treatment group.

Figure 5

Dopamine (DA) hypothesis of drug reward and NGB 2904's actions. The mesolimbic DA system originates from the ventral tegmental area (VTA) in the midbrain and projects predominantly to the nucleus accumbens (NAc) in the forebrain. Almost all addictive drugs activate VTA DA neurons and/or increase extracellular DA levels in the NAc via distinct receptor and cellular mechanisms. DA D3 receptors are located on both presynaptic terminals and postsynaptic (GABAergic) neurons. Antagonism of postsynaptic D₃ receptors by NGB 2904 may block D₃ receptor‐mediated addictive effects, while blockade of presynaptic D₃ receptors by NGB 2904 may augment cocaine‐enhanced NAc DA (via a disinhibition mechanism), which may subsequently attenuate NGB 2904's therapeutic actions by inhibiting NGB 2904's binding to postsynaptic D₃ receptors and/or by activating other DA receptors.