The dopamine D3 receptor antagonist PNU-99194A fails to block (+)-7-OH-DPAT substitution for D-amphetamine or cocaine.

The present study examined the role of dopamine D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate either D-amphetamine or cocaine from saline. Twelve male Sprague-Dawley rats were trained to discriminate D-amphetamine (1.0 mg/kg) and 12 rats were trained to discriminate cocaine (5.0 mg/kg) from saline in a two-choice, water-reinforced operant procedure. Stimulus generalization tests were administered with the D3 receptor-preferring agonist, (+)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin ((+)-7-OH-DPAT, 0.01-1.0 mg/kg) as well as the D3-preferring antagonist, 5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride (PNU-99194A, 5-40 mg/kg). PNU-99194A (10-40 mg/kg) was also administered in combination with the training dose of D-amphetamine or cocaine to test for antagonism of each training drug cue. Finally, to assess the role of D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT (0.1 mg/kg), PNU-99194A (10, 20 mg/kg) was tested in combination with this compound in each training group. The results showed complete stimulus generalization with (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine, although only partial stimulus generalization was observed with this compound in rats trained to discriminate cocaine. PNU-99194A produced partial substitution for both training drugs, and failed to block the discriminative stimulus effects of either D-amphetamine or cocaine. Moreover, this compound failed to block the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine. These results question the importance of D3 receptor actions in the discriminative stimulus effects of psychostimulants and their similarities to (+)-7-OH-DPAT.