Desensitization of prostaglandin (PG) F2 alpha receptor-mediated phosphoinositide (PI) hydrolysis was investigated in cultured rat astrocytes. Prolonged exposure of astrocytes differentiated by dibutyryl cyclic AMP-treatment to PGF2 alpha caused the desensitization of subsequent PGF2 alpha-induced PI hydrolysis. The desensitization was time- and PGF2 alpha dose-dependent; maximal decrease in the PI hydrolysis was observed after exposure to 10 microM PGF2 alpha for 4 h and the degree of the desensitization was 31.7 +/- 2.7% of control. Pretreatment with either PGD2 or PGE2 also induced the desensitization of subsequent PGF2 alpha-stimulated PI hydrolysis and conversely pretreatment of PGF2 alpha decreased the PI responses to PGD2 and PGE2. The desensitization prevented by phloretin and was reversible upon removal of the agonist. Protein synthesis inhibitors blocked the recovery of the desensitization. Treatment of the cells with phorbol 12-myristate 13-acetate had no effect on the desensitization. These results suggest that prolonged exposure of the astrocytes to PGF2 alpha caused the desensitization of the receptors.