Analysis of D2 and D3 receptor-selective ligands in rats trained to discriminate cocaine from saline

This study examined the role of dopamine D3 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 D3-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 D2 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 D2 agonist, PNU-91356 also fully substituted for the cocaine cue and suppressed response rate in a dose-dependent manner. To ascertain the importance of D3 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 D3 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 D3 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 D3/D2 receptor agonists suppress locomotor activity but produce stimulus generalization to cocaine.