CHARACTERIZATION OF THE DISCRIMINATIVE STIMULUS PRODUCED BY THE DOPAMINE ANTAGONIST TIAPRIDE

The ability of tiapride, a selective D-2/D-3 dopamine receptor antagon ist, to exert discriminative stimulus control of responding was invest igated by training rats to discriminate this drug (30 mg/kg) from sali ne in a two-lever, food-reinforcement procedure. Acquisition of tiapri de discrimination required a relatively lengthy training period (mean of 76 sessions) but stable performance was maintained throughout the 1 8-month study. The dose of tiapride eliciting 50% tiapride-lever choic e (ED50) was 2.2 mg/kg. After determination of the dose-effect curve w ith tiapride, substitution tests with several dopamine antagonists and other reference compounds were performed. All dopamine antagonists, i ncluding amisulpride (ED50 4 mg/kg), sulpiride (18 mg/kg), sultopride (1.5 mg/kg), clebopride (0.13 mg/kg), raclopride (0.16 mg/kg), metoclo pramide (1.4 mg/kg), remoxipride (4.8 mg/kg), pimozide (2.7 mg/kg), th ioridazine (3.4 mg/kg), olanzapine (0.97 mg/kg), chlorpromazine (1.9 m g/kg), risperidone (0.22 mg/kg) and haloperidol (0.14 mg/kg), except c lozapine (>10 mg/kg), produced dose-dependent substitution for tiaprid e. Tiapride-like stimulus effects were observed at doses that decrease d response rates. However, ED50 values for substitution by tiapride, a misulpride, sulpiride, sultopride, pimozide, clebopride and thioridazi ne were lower than ED50 values for decreasing responding. Additional s tudies were conducted to evaluate the ability of direct and indirect d opamine agonists to attenuate the tiapride discriminative stimulus. Pr etreatment with d-amphetamine and nomifensine antagonized the discrimi native stimulus effects of tiapride. Quinpirole, 7-OH-DPAT, bromocript ine and apomorphine partially blocked the stimulus effects of tiapride whereas SKF 38393 did not affect the discrimination. These results fr om substitution and antagonism tests indicated that the discriminative effects of tiapride are mediated by activity at D-2/D-3 dopamine rece ptors.