The effects of benzamide analogues on cocaine self-administration in rhesus monkeys

Abstract 

Rationale: Based on the differential distribution of dopamine (DA) D₃ receptors in mesolimbic regions relative to nigrostriatal regions, the hypothesis was that D₃-selective antagonists (i.e., higher affinity at D₃- than D₂-receptors) would be more potent than D₂-selective antagonists at decreasing total cocaine intake relative to disrupting rates of responding. Objective: To evaluate the effects of acute administration of seven DA antagonists with varying affinities for D₂ and D₃ receptors in monkeys self-administering cocaine. Methods: Rhesus monkeys were trained to self-administer intravenous cocaine (0.01–0.3 mg/kg per injection) under a fixed-interval (FI) 5-min schedule during daily 4-h sessions. The use of a FI schedule allowed for independent assessment of rate effects and changes in reinforcement frequency as a consequence of drug pretreatments. The compounds examined, in order of D₃ binding affinity, were: 2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3.1]nonan-3β-yl benzamide (MABN) = eticlopride = 5-bromo- 2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]benz-amide (BBP) > spiperone > fluoroclebopride (FCP) > 2,3-dimethoxy-N-(p-fluorobenzyl)piperdin-4-yl benzamide (MBP) > haloperidol. Results: In the absence of any pretreatments, cocaine-maintained responding varied as a function of dose and was characterized as an inverted U-shaped function, while cocaine intake increased in a dose-related fashion. When the dose of cocaine that maintained peak rates was available, all DA antagonists decreased response rates and cocaine intake in a dose- dependent manner. Increases in cocaine dose attenuated the effects of the DA antagonists, resulting in rightward shifts of the cocaine dose–response curves. Based on the ratio of behavioral potency at decreasing response rates relative to intake (ED₅₀ rate/ED₅₀ intake) when the highest cocaine dose was available, the order of potency and ED₅₀ ratio values were: MABN (2.5) > eticlopride (1.63) > BBP = spiperone (1.5) > FCP (1.35) > MBP = haloperidol (0.89). This order parallels each compound’s affinity at D₃ receptors (r ²=0.84) to a greater degree than D₂ receptor affinity (r ²=0.34). Conclusions: These results, using a FI schedule of cocaine self-administration, suggest that D₃ receptor antagonists are more likely to selectively decrease intake relative to response rates than D₂ receptor antagonists.