Prolactin blood level and apomorphine-induced yawning were studied in rats treated with the substituted benzamide amisulpride in association with bromocriptine or carmoxirole; two dopamine D(2) receptor agonists with high or low propensity to cross the brain-blood barrier, respectively. Administration of amisulpride produced a maximum increase in rat serum prolactin level (315+/-18%) vs. vehicle-treated animals (ED(50)=0.25+/-0.017 mg/kg, s.c.). The concurrent administration of carmoxirole or bromocriptine completely reversed the hyperprolactinemia induced by amisulpride (0.5 mg/kg, s.c.) (ID(50)=14.9+/-0.8 mg/kg and 0.81+/-0.03 mg/kg, respectively). Carmoxirole (15 mg/kg, i.p.) did not affect yawning induced by apomorphine (0.08 mg/kg, s.c.) nor amisulpride (0.5 mg/kg, s.c.) blockade of apomorphine-induced yawning. Conversely, a significant increase in the number of yawns was observed when bromocriptine (0.8 mg/kg, i.p.) was associated with apomorphine in the absence or presence of amisulpride. These results suggested that a peripheral dopamine D(2) receptor agonists could be a useful tool in alleviating amisulpride-induced hyperprolactinemia without possibly affecting its central effect.