The effects of dopaminergic receptor inhibitors such as thiothixine (D1/D2), fluphenazine (D1/D2), trifluoperazine (D1/D2), pimozide (D2), flupenthixol (D1/D2), (+/-)-SKF 83566 (D1), and spiperone (D2) on splenic natural killer (NK) cell cytotoxic activities were assessed in vitro using mouse spleen lymphocytes or enriched NK cells. Both the activities of the splenic NK cell cytotoxicity and the effector-target cell conjugation were suppressed by thiothixine, fluphenazine, and trifluoperazine at concentrations from 2.64 to 14.78 microM. In addition, the augmentation of the cytolytic activity of NK cells induced by interferon-alpha or interleukin-2 was antagonized by pretreatment with these neuroleptic compounds. However, neither the splenic NK cell cytotoxicity nor the effector-target cell conjugation were affected by treatment with other neuroleptic compounds such as pimozide, flupenthixol, (+/-)-SKF 83566, and spiperone. Thus, it appears that neuroleptic compounds such as thiothixine, fluphenazine, and trifluoperazine may act through the mechanisms other than a dopaminergic pathway to affect the NK cell-target cell interaction.