Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate–glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate–glutamine cycle involving astrocytes using an animal model of depression.Methods: Male and female adult Long-Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident-intruder paradigm. Territorial aggression was used for males and maternal aggression was used for females to induce depressive-like deficits for intruders. The depressive-like phenotype was assessed with intake for saccharin solution, weight gain, estrous cycle, and corticosterone (CORT). Behaviors displayed by the intruders during daily encounters with residents were characterized. Rats with daily handling were used as controls for each sex. Ten days after the last encounter, both the intruders and controls were subjected to a no-net-flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the nucleus accumbens (NAc). The contralateral hemispheres were used for determining changes in astrocytic markers, including glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1).Results: Both male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre-stress period and to their respective controls. Male intruders exhibited submissive/defensive behaviors to territorial aggression by receiving sideways threats and bites. These males showed reductions in striatal GLT-1 and spontaneous glutamine in the NAc, compared to controls. Female intruders exhibited isolated behaviors to maternal aggression, including immobility, rearing, and selfgrooming. Their non-reproductive days were extended. Also, they showed reductions in prefrontal and accumbal GFAP+ cells and prefrontal GLT-1, compared to controls. When 10 μM of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. Infusions of glutamate reduced extracellular glutamine for both male and female intruders compared to their respective controls.Conclusion: Twenty-one days of territorial or maternal aggression produced a depressive-like phenotype and impaired astrocytes in both male and female intruders. Disruption of the glutamate–glutamine cycle in the PFC-striatal network may be linked to depressive-like deficits more in females than in males.

Bradykinin 1-5 is a major stable metabolite of bradykinin, formed by the proteolytic action of angiotensin-converting enzyme. In vitro and animal studies suggest that bradykinin 1-5 possesses biological activity. This study tests the hypothesis that bradykinin 1-5 affects vasodilation, fibrinolysis, or platelet aggregation in humans. Graded doses of bradykinin (47-377 pmol/min) and bradykinin 1-5 (47-18,850 pmol/min) were infused in the brachial artery in random order in 36 healthy subjects. Forearm blood flow (FBF) was measured, and simultaneously obtained venous and arterial plasma samples were analyzed for tissue plasminogen activator (t-PA) antigen. In seven subjects each, ␣-and ␥-thrombin-induced platelet aggregation was measured in platelet-rich plasma obtained from antecubital venous blood at baseline and during peptide infusions. Bradykinin caused dose-dependent increases in FBF and net t-PA release (P Ͻ 0.001 for both). Bradykinin 1-5 did not affect FBF (P ϭ 0.13) or net t-PA release (P ϭ 0.46) at concentrations Ͼ1500 times physiologic. In contrast, both bradykinin and bradykinin 1-5 inhibited ␣-and ␥-thrombin-induced platelet aggregation (P Ͻ 0.01 versus baseline). Bradykinin 1-5 inhibited ␥-thrombin-induced platelet aggregation 50% at a calculated dose of 183 Ϯ 3 pmol/min. Neither bradykinin nor bradykinin 1-5 affected thrombin receptor-activating peptideinduced platelet aggregation, consistent with the hypothesis that bradykinin and bradykinin 1-5 inhibit thrombin-induced platelet aggregation by preventing cleavage of the thrombin receptor and liberation of thrombin receptor-activating peptide. This study is the first to demonstrate biological activity of bradykinin 1-5 following in vivo administration to humans. By inhibiting thrombin-induced platelet aggregation without causing vasodilation, bradykinin 1-5 may provide a model for small molecule substrate-selective thrombin inhibitors.Bradykinin (BK) is a vasoactive peptide that exhibits cardioprotective effects. Bradykinin promotes vasodilation (Vanhoutte, 1989), exerts antiproliferative effects (Linz and Scholkens, 1992), inhibits thrombin-induced platelet activation (TRAP) in vitro (Hasan et al., 1996), stimulates endothelial tissue plasminogen activator (t-PA) release (Smith et al., 1985), and contributes to many of the effects of angiotensin-converting enzyme (ACE) inhibition (Gainer et al., 1998;Labinjoh et al., 2001;Minai et al., 2001). Bradykinin stimulates t-PA release from the human forearm vasculature in a dose-dependent manner through a bradykinin B 2 receptordependent pathway (Brown et al., 2000). Systemic bradykinin is rapidly metabolized via ACE in humans to BK1-5 (Murphey et al., 2000a). The identification of BK1-5 as the major stable metabolite of systemic bradykinin in humans raises the question of whether this peptide itself exhibits biological activity, just as studies have demonstrated that degradation products of angiotensin II, once thought to be inactive, have biological activity (Kerins et al., 1995;Brosnihan et al...

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