Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A.

It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in 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 D2 receptor antagonist, haloperidol (0.01- 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produce stimulus generalization, while the D3-preferring antagonists, (-)-DS121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D1 agonist SKF38393 (10-100 mg/kg), the D2 selective agonist PNU-95666E (0.32-3.2 mg/kg) and the D3-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-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism.