Objective To investigate the role of H1 and H2 receptors in the locus ceruleus (LC) in carotid sinus baroreceptor reflex (CSR) resetting induced by intracerebroventricular (i.c.v.) injection of histamine (HA). Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner in vivo. ISP-mean arterial pressure (MAP) relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H1 or H2 receptors selective antagonist, chlorpheniramine (CHL) or cimetidine (CIM) into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA (100 ng in 5 μl) significantly shifted the ISP-MAP relationship curve upwards (P ＜ 0.05) and obviously decreased the value of the reflex parameters such as MAP range and maximum gain (P ＜ 0.05), but increased the threshold pressure, saturation pressure and ISP at maximum gain (P ＜ 0.05). The pretreatment with CHL (0.5 μg in 1 μl) or CIM (1.5 μg in 1 μl) into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that ofCHL (P ＜ 0.05). Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly (P ＞ 0.05). Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H1 and H2 receptors activities in the LC, especially by H1 receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC.