DISCRIMINATIVE STIMULUS PROPERTIES OF THE DOPAMINE D-3 ANTAGONIST PNU-99194A

It was recently documented that the relatively selective dopamine D-3 receptor antagonist, PNU-99194A, is capable of establishing discrimina tive stimulus control in rats and that the discriminative cue associat ed with this compound is not similar to that produced by psychostimula nts. The present experiment further characterized the discriminative s timulus properties of PNU-99194A by examining several other dopaminerg ic agents for stimulus generalization in 23 male Sprague-Dawley rats t rained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle i n a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23-78 ). In substitution tests, the non-selective D-2 receptor antagonist, h aloperidol (0.01 - 0.1 mg/kg), and the mixed D-2/D-3 antagonists, amis ulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produc e stimulus generalization, while the D-3-preferring antagonists, (-)-D S121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimu lus generalization. Direct and indirect DA agonists, including apomorp hine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D-1 agonis t SKF-38393 (10-100 mg/kg), the D-2 selective agonist PNU-95666E (0.32 -3.2 mg/kg) and the D-3-preferring agonist pramipexole (0.032-1 mg/kg) , all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-9919 4A produces a distinctive subjective cue which is probably based on D- 1 receptor antagonism.