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Water deprivation is a stress that has been associated with activation of several endocrine systems, including circumventricular organs of the central nervous system. The sub-comissural organ (SCO), characterized by its glycoprotein secretion called Reissner’s fiber has been suggested to play a role in the regulation of body water balance. Meriones shawi, a semi-desertic rodent characterized by its resistance to long periods of thirst was subjected to water deprivation for I and 3 months. Effect of water deprivation was evaluated immunohistochemically on 5-hydroxytryptamine (5-HT; serotonin) system and glycoprotein secretion of the SCO. Our findings demonstrate significant reduction of anti-Reissner’s fiber immunoreactive materials within basal and apical parts of the SCO ependymocytes. These changes seem to be the consequence of reduced control by 5-HT fibers reaching the SCO as a concomitant and significant reduction of anti-5-HT immunoreactive fibers are also observed following water deprivation. 5-HT immunoreactive reduction is seen in several regions in the brain including the neurons of origin within the dorsal raphe nucleus and the projecting supra and sub-ependymal fibers reaching the classical ependyma of the third ventricle. The extent of Reissner’s fiber and 5-HT immunoreactive changes significantly correlates with the severity of water restriction. We suggest that water deprivation causes changes of the classical ependyma and the specialized ependyma that differentiates into the SCO as well as other cirumventricular organs such as the subfornical organ and the organum vasculosum laminae terminalis known to control drinking behaviors. (C) 2009 Elsevier Ireland Ltd. All rights reserved.