Analysis of D 2 and D 3 Receptor-Selective Ligands in Rats Trained to Discriminate Cocaine from Saline

Abstract

This study examined the role of dopamine D 3 receptors in the stimulus generalization produced by 7-OH-DPAT and PD 128907 in rats trained to discriminate cocaine from saline. Twelve male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-choice operant procedure using a FR20 schedule of water reinforcement. Stimulus generalization tests were administered with the D 3-preferring agonists (±)-7-OH-DPAT (0.01–0.3 mg/kg), (+)-7-OH-DPAT (0.01–0.3 mg/kg), and PD 128907 (0.01–0.3 mg/kg), and the selective D 2 agonist PNU-39156 (0.01–0.3 mg/kg). Complete generalization to cocaine was observed with (±)-7-OH-DPAT at doses that markedly suppressed response rate. Only partial stimulus generalization was observed with (+)-7-OH-DPAT and PD 128907 when these compounds were administered intraperitoneally, although subcutaneous injections of these compounds produced complete substitution. Response rate was also significantly reduced by these compounds. The selective D 2 agonist, PNU-91356 also fully substituted for the cocaine cue and suppressed response rate in a dose-dependent manner. To ascertain the importance of D 3 receptor actions in the stimulus generalization produced by (±)-7-OH-DPAT (0.1 mg/kg) and PD-128907 (0.3 mg/kg), the fairly selective D 3 antagonist, PNU-99194A (2.5–20 mg/kg) was also tested in combination with these compounds. Although PNU-99194A partially attenuated the stimulus generalization produced by (±)-7-OH-DPAT, it failed to block PD-128907 substitution for cocaine. These results indicate at least some involvement of D 3 receptors in the stimulus effects of (±)-7-OH-DPAT, although further investigations are clearly warranted. The present results also suggest that the cue properties of cocaine may be dissociated from the locomotor activating effects of this drug, because D 3/D 2 receptor agonists suppress locomotor activity but produce stimulus generalization to cocaine.