Angiotensin II (ANG II) type 1 receptors (AT₁-R) mediate most of the central effects of ANG II on cardiovascular function, fluid homeostasis and sympathetic drive. The mechanisms regulating AT₁-R expression in the brain are unknown. In some tissues, AT₁-R can be up-regulated by prolonged exposure to ANG II. We examined the hypothesis that ANG II upregulates AT₁-R in the brain by stimulating the intracellular mitogen-activated protein kinase (MAPK) signaling pathway. Using molecular and immunocytochemical approaches, we examined the expression of AT₁-R and phosphorylated MAPK in the paraventricular nucleus of hypothalamus (PVN) and the subfornical organ (SFO) of rats receiving a chronic (4 week) subcutaneous infusion of ANG II (0.6 µg/hr) or saline (vehicle control), with or without concomitant (4 week) intracerebroventricular (ICV) infusions of MAPK inhibitors or the AT₁-R blocker losartan. Subcutaneous infusion of ANG II markedly increased phosphorylation of MAPK and the expression of AT₁-R mRNA and protein and AT₁-R-like immunoreactivity in the PVN and the SFO. ANG II-induced AT₁-R expression was blocked by ICV infusion of the p44/42 MAPK inhibitors PD98059 (0.025 µg/hr) and the c-Jun N-terminal kinase (JNK) inhibitor SP600125 (0.125 µg/hr), but not by the p38 MAPK inhibitor SB203580 (0.125 µg/hr). The upregulation of AT₁-R in the PVN and SFO by peripheral ANG II was abolished by ICV losartan (10 µg/hr). The data indicate that blood-borne ANG II upregulates brain AT₁-R by activating intracellular p44/42 MAPK and JNK signaling pathways.