Antagonism of the discriminative stimulus effects of (+)-7-OH-DPAT by remoxipride but not PNU-99194A

The dopamine (DA) agonist 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin (7-OH-DPAT) has been used extensively as a tool to investigate the role of DA D₃ receptors in the reinforcing and discriminative stimulus properties of psychostimulant drugs. The present study examined the relative importance of D₃ vs. D₂ receptor actions in the discriminative stimulus effects of (+)-7-OH-DPAT (0.03 mg/kg, sc) in 16 male Sprague-Dawley rats trained to discriminate this compound from saline in a two-lever, water-reinforced operant procedure under a FR 20 schedule. Stimulus generalization and antagonism tests were conducted with cocaine and with various selective D₂ and D₃ receptor ligands. In contrast to previous findings that (+)-7-OH-DPAT substitutes for cocaine, the present results demonstrated that cocaine does not produce stimulus generalization in animals trained to discriminate (+)-7-OH-DPAT. Although two D₃-preferring agonists, PD-128907 and pramipexole, produced complete stimulus generalization to the training drug, two highly selective D₃ antagonists (PNU-99194A, PD 152255) failed to block the discriminative stimulus effects of (+)-7-OH-DPAT. However, the D₂ antagonist remoxipride (3.0 mg/kg) produced a rightward shift in the (+)-7-OH-DPAT dose-response curve. These findings suggest that D₂ receptors are critically involved in mediating the cue properties of (+)-7-OH-DPAT. However, alternative interpretations that PNU-99194A is not entirely D₃ receptor selective should also be considered.