The hypothalamic-pituitary-adrenal (HPA) axis has been shown to be involved in mood and behavior. The possibility that adrenal glucocorticoids regulate components of the phosphatidylinositol (PI) signal transduction pathway was investigated. Two different doses of corticosterone (CORT) pellets (50 or 100 mg) were implanted in normal and bilaterally adrenalectomized (ADX) rats, and CORT regulation of the expression of G(q) α protein, phospholipase C (PLC) isozymes, inositol 1,4,5-trisphosphate receptor (IP3R) isoforms, and of PI-PLC activity, [3H]IP3 binding to IP3Rs, and IP3 levels were measured in various brain areas after 1 or 14 days. Fourteen days of CORT pellet implantation into normal rats dose dependently decreased PI-PLC activity and selectively the mRNA and protein expression of PLC β1 isozyme in cortex and hippocampus. Bilateral ADX caused the opposite changes in these measures, and simultaneous CORT pellet implantation into ADX rats reversed these effects. Furthermore, 14 days of CORT treatment of normal rats increased [3H]IP3 binding to IP3Rs and decreased IP3 levels in cortex, hippocampus, and cerebellum, without any changes in expression of IP3R-I, IP3R-II, or IP3R-III isoform. On the other hand, ADX decreased [3H]IP3 binding and increased levels of IP3, and simultaneous CORT treatment of ADX rats prevented these changes. ADX or CORT treatment had no significant effects on the expression of G(q/11) α protein. These results suggest that manipulation of the HPA axis alters various components of the PI signaling pathway in rat brain, which may have physiological relevance to the HPA axis-mediated changes in mood and behavior.