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

Rationale: Based on the differential distribution of dopamine (DA) D-3 receptors in mesolimbic regions relative to nigrostriatal regions, the hypothesis was that D-3-selective antagonists (i.e., higher affinity at D-3- than D-3-receptors) would be more potent than D-2-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 D-2 and D-3 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 D-3 binding affinity, were: 2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3.1]nonan-3 beta-yl benzamide (MABN) = eticlopride = 5-bromo-2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl] benzamide (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 D-3 receptors (r(2)=0.84) to a greater degree than D-2 receptor affinity (r(2)=0.34). Conclusions: These results, using a FI schedule of cocaine self-administration, suggest that D-3 receptor antagonists are more likely to selectively decrease intake relative to response rates than D-2 receptor antagonists.