Analysis of D-2 and D-3 receptor-selective ligands in rats trained to discriminate cocaine from saline

This study examined the role of dopamine Dg receptors in the stimulus gener alization produced by 7-OH-DPAT and PD 128907 in rats trained to discrimina te cocaine from saline. Twelve male Sprague-Dawley rats were trained to dis criminate 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 generali zation to cocaine was observed with (+)7-OH-DPAT at doses that markedly sup pressed response rate. Only partial stimulus generalization was observed wi th (+/-)7-OH-DPAT and PD 128907 when these compounds were administered intr aperitoneally, although subcutaneous injections of these compounds produced complete substitution. Response rate was also significantly reduced by the se compounds. The selective D-2 agonist, PNU-91356 also fully substituted f or the cocaine cue and suppressed response rate in a dose-dependent manner. To ascertain the importance of D-3 receptor actions in the stimulus genera lization 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 te sted in combination with these compounds. Although PNU-99194A partially att enuated the stimulus generalization produced by (+/-)7-OH-DPAT, it failed t o block PD-128907 substitution for cocaine. These results indicate at least some involvement of Dg receptors in the stimulus effects of (+/-)-7-OH-DPA T, although further investigations are clearly warranted. The present resul ts also suggest that the cue properties of cocaine may be dissociated from the locomotor activating effects of this drug, because D-2/D-3 receptor ago nists suppress locomotor activity but produce stimulus generalization to co caine. (C) 1999 Elsevier Science Inc.