PMC

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.

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.

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.

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.

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.