Previous experiments with the first selective nonpeptide vasopressin V 1b receptor antagonist SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide) have shown that the drug elicits anxiolytic-and antidepressant-like effects following systemic administration. Extrahypothalamic V 1b receptors have been suggested to be involved in these effects as evidenced by the findings that hypophysectomized rats were still sensitive to the antistress action of SSR149415. The first objective of the present work aimed at locating V 1b receptors in the rat limbic brain using anti-V 1b receptor immunohistochemistry. The immunolabeling revealed high densities of V 1b receptors in the lateral septum, the amygdala, the bed nucleus of the stria terminalis, the hippocampal formation, and in several cortical areas. Since the lateral septum is well known to participate in the modulation of emotional processes, the second objective of this study went on to evaluate the behavioral effects of an infusion of SSR149415 into the lateral septum and to determine whether its behavioral effects are mediated by this structure. Animals were tested in models classically used for the screening of anxiolytics (ie the punished drinking and elevated plusmaze tests) and antidepressants (ie the forced-swimming test). Bilateral intraseptal infusion of SSR149415 (10 and 100 ng) produced a decrease in immobility time in the forced-swimming test, indicating antidepressant-like effects. In contrast, the behavior of rats in the punished drinking procedure or in the elevated plus-maze test was not modified by intraseptal infusion of SSR149415. These findings suggest that V 1b receptors located in the lateral septum participate in the antidepressant-but not the anxiolytic-like action of SSR149415 in rats.

Vasopressin (AVP) receptors present in In-R1-G9 cells, a hamster glucagon-secreting ␣-pancreatic cell line, were characterized using SSR-149415, a selective nonpeptide V 1b receptor antagonist, and reference AVP compounds. Binding experiments, using [ 3 H]AVP as a ligand, identified a single population of high-affinity binding sites. SSR-149415 competitively inhibited this binding and exhibited nanomolar and stereospecific affinity for these sites. The affinity of various AVP/oxytocin ligands confirmed a V 1b binding profile. In functional studies, AVP was a potent stimulant in inducing intracellular Ca 2ϩ increase, glucagon secretion, and cell proliferation. These effects were fully antagonized by SSR-149415 with a nanomolar potency, whereas its diasteroisomer as well as two selective V 1a and V2 receptor antagonists were much less potent. Additionally, the order of potency of AVP agonists and antagonists was in agreement with V 1b-mediated effects. By RT-PCR, we confirmed the presence of V 1b receptor mRNA in both In-R1-G9 cells and in human pancreas. The distribution pattern of V 1b receptors investigated in human pancreas by immunohistochemistry showed strong labeling in islets of Langerhans, and colocalization studies indicated that this receptor was expressed in ␣-glucagon, ␤-insulin, and somatostatin pancreatic cells. Thus, in In-R1-G9 cells, AVP mediates intracellular Ca 2ϩ increase, glucagon secretion, and cell proliferation by activating V 1b receptors, and these effects are potently antagonized by SSR-149415. Moreover, the presence of V 1b receptors also found in human Langerhans islets could suggest hormonal control of AVP in human pancreas.arginine vasopressin V 1b receptors; glucagon; SSR-149415 VASOPRESSIN (AVP) exerts a number of central and peripheral functions in mammals. Among them, it controls water excretion by the kidney, vascular smooth muscle cell and uterine contraction, platelet aggregation, clotting factor release, liver glycogenolysis, mitogenesis, and hormonal secretion (i.e., release of aldosterone by adrenals, glucagon, and insulin in pancreas and corticotropin release by the adenohypophysis). In concert with oxytocin (OT), a structurally related neurohypophysial nonapeptide, AVP also controls several behavioral and memory processes (4, 9). These actions are mediated by specific G protein-coupled receptors, named V 1a , V 1b , V 2 , and OT, which have been cloned and characterized in animals and in humans. The V 2 receptor is positively coupled to adenylyl cyclase, whereas the others are linked to phospholipase C activation and intracellular Ca 2ϩ mobilization (29). The V 1b (or V 3 ) receptor has been cloned in mice, rats, and humans (7,14,20,27,30). This receptor is involved mainly in the stimulating effect of AVP on corticotropin secretion in the pituitary, and its role in stress and emotional situations is now well documented (1). As recently demonstrated by RT-PCR, in situ hybridization, or immunohistochemistry, the V 1b receptor gene/protein is expressed not only in anterior ...

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Lipid peroxidation and activities of antioxidative enzymes were studied in the brain cortex after short (15 min) cerebral ischemia and reperfusion (10 min) in rats. Conjugated dienes (CD) and thiobarbituric acid-reactive substances (TBARS) were significantly elevated in the group of rats with ischemia followed by reperfusion in comparison to the ischemic animals. Superoxide dismutase (SOD) activity significantly increased in the group of animals with ischemia and reperfusion. No significant changes in the activities of glutathione peroxidase (GP) were observed. Stobadine administered before ischemia or before reperfusion decreased the level of TBARS. Stobadine probably prevents malondialdehyde (MDA) formation from hydroperoxide or might elevate the activity of aldehyde dehydrogenase. In contradiction to the findings after long-lasting (4 h) ischemia and subsequent reperfusion, no decrease in the concentration of CD or in the activity of SOD or GP was found.