Abstract Body: Angiotensin (Ang)-(1-7) is a protective hormone of the renin-angiotensin system that lowers blood pressure in animal models of cardiovascular disease; however, the precise mechanisms remain incompletely understood. Recent data from our laboratory suggests that blood pressure lowering effects of Ang-(1-7) may involve the arcuate nucleus of the hypothalamus (ARC). We have shown that Ang-(1-7) activates proopiomelanocortin (POMC)-containing neurons in the ARC. While ARC POMC neuron activation canonically increases blood pressure by stimulating melanocortin-4 receptors (MC4R) in the hypothalamic paraventricular nucleus (PVN), these neurons also release the inhibitory neurotransmitter GABA. Selective activation of these GABAergic POMC neurons could serve as a novel mechanism to lower blood pressure. In this study, we hypothesized that Ang-(1-7) treatment inhibits PVN MC4R neuron activity via enhanced GABAergic function. To test this, male and female MC4R-GFP mice were implanted with osmotic mini pumps at 14 weeks of age and treated chronically with either Ang-(1-7) (400 ng/kg/min) or saline. After six weeks of drug administration, action potential firing of PVN MC4R-expressing neurons was examined using cell attached electrophysiology. To assess GABAergic function, changes in action potential firing frequency following bath application of the GABA_A receptor antagonist bicuculline (10 μm) were compared between Ang-(1-7) and saline treated animals (n=4-6 mice/group). While Ang-(1-7) did not alter baseline firing frequency of MC4R PVN neurons in male mice (1.5±0.6 vs. 1.1±0.3 Hz saline; p=0.630, unpaired t-test), it enhanced bicuculline responsiveness as indicated by a greater peak increase in action potential firing frequency (156.9±18.0 vs. 106.2±6.8 % saline; p=0.013). In female mice, Ang-(1-7) increased baseline action potential firing frequency of PVN MC4R neurons (1.5±0.4 vs. 0.3±0.1 Hz saline; p=0.026) but did not alter bicuculline responsiveness (111.0±5.3 vs. 143.2±25.3 % saline; p=0.241). Overall, our data suggest that Ang-(1-7) enhances GABAergic neurotransmission onto PVN MC4R neurons in a sex-specific manner. These data provide new insight into the neural mechanisms of Ang-(1-7), which could have implications for understanding the beneficial cardiovascular effects of this hormone. Additional studies are needed to examine this inhibitory neurocircuit in the context of hypertension as well as precise mechanisms underlying the observed sex differences.