Nesfatin-1 is produced in the periphery and in brain where it has been demonstrated to regulate appetite, stress hormone secretion and cardiovascular function. The anorexigenic action of central nesfatin-1 requires recruitment of neurons producing the melanocortins and centrally-projecting oxytocin (OT) and corticotropin releasing hormone (CRH) neurons. We previously have shown that two components of this pathway, the central melanocortin and oxytocin systems, contribute to the hypertensive action of nesfatin-1 as well. We hypothesized that the cardiovascular effect of nesfatin-1 also was dependent upon activation of neurons expressing CRH receptors, and that the order of activation of the melanocortin-CRH-oxytocin circuit was preserved for both the anorexigenic and hypertensive actions of the peptide. Pretreatment of male rats with the CRH-2 receptor antagonist, astressin2B, abrogated nesfatin-1-induced increases in mean arterial pressure (MAP). Furthermore, the hypertensive action of CRH was blocked by pretreatment with an oxytocin receptor antagonist, OVT, indicating that the hypertensive effect of nesfatin-1 may require activation of OTergic neurons in addition to recruitment of CRH neurons. Interestingly, we found that the hypertensive effect of alpha-melanocyte stimulating hormone (alpha-MSH) itself was not blocked by either astressin2B or OVT. These data suggest that while alpha-MSH-producing neurons are part of a core melanocortin-CRH-oxytocin circuit regulating food intake, and a subpopulation of melanocortin neurons activated by nesfatin-1 do mediate the hypertensive action of the peptide, alpha-MSH can signal independently from this circuit to increase MAP.