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

Michael A. Nader, Kristen L. Green, Robert T. Luedtke, Robert H. Mach

Research output: Contribution to journalArticle

32 Scopus citations

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 D'3 binding affinity, were: 2,3-dimethoxy-N-(9-p- fluorobenzyl)-azabicyclo[3.3.1]nonan3β-yl benzamide (MABN) = eticlopride = 5-bromo2,3-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 (r2=0.84) to a greater degree than D2 receptor affinity (r2=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.

Original languageEnglish
Pages (from-to)143-152
Number of pages10
JournalPsychopharmacology
Volume147
Issue number2
DOIs
StatePublished - 1 Jan 1999

Keywords

  • D receptor antagonist
  • Fixed-interval schedule
  • Rhesus monkey
  • Self-administration

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