EFFECTS OF PHENOTHIAZINE NEUROLEPTIC DRUGS ON THE MICROTUBULAR-MEMBRANE COMPLEX IN BLOOD-STREAM FORMS OF TRYPANOSOMA-BRUCEI

African trypanosomes are parasitic protozoa causing sleeping sickness in humans and related diseases in domestic animals against which no en tirely satisfactory forms of chemotherapy are yet available. II was pr eviously shown that related species of trypanosomes, as well as procyc lic (insect) forms of Trypanosoma brucei are extremely sensitive to th e action of phenothiazine neuroleptic drugs ii? vitro. In this work, w e have carried out a more detailed investigation of the effects of thi oridazine, one of the most potent neuroleptic phenothiazine drugs know n, on the morphology of the infective bloodstream forms of T. brucei, with particular reference to the parasite's prominent pellicular membr ane complex. Our data show that this drug induces rapid changes in cel l shape that appear to involve some reorganization oi the microtubular membrane skeleton, but does not affect the structural integrity of th e microtubular complex. Another early consequence of drug action invol ved damage to nuclear and cytoplasmic membranes and the appearance of tubular arrays of coated membrane within the flagellar pocket. It was also revealed that the drug induces a rapid release of the variant-spe cific glycoprotein (VSG) which makes up the surface coat protecting bl oodstream forms of the parasite against the host immune system. Our ev idence suggests that this release of VSG involves cleavage of the prot ein's glycosyl-phosphatidylinositol (GPI) membrane anchor by endogenou s GPI-specific phospholipase C, probably as a consequence of minor dam age to the parasite plasma membrane induced by the drug.