Characterization of a novel vasopressin V_1b receptor antagonist, V1B-30N, in animal models of anxiety-like and depression-like behavior

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• 作者：Robert A. Hodgson^a ; ^{Robert.Hodgson@Merck.com" class="auth_mail} ; Deborra Mullins^b ; Sherry X. Lu^b ; Mario Guzzi^b ; Xiaoping Zhang^b ; Carina J. Bleickardt^a ; Jack D. Scott^c ; Michael W. Miller^c ; Andrew W. Stamford^c ; Eric M. Parker^b ; Geoffrey B. Varty^a
• 关键词：V1b receptor ; Vasopressin ; Rat ; Mouse ; Anxiety ; Depression
• 刊名：European Journal of Pharmacology
• 出版年：5 May, 2014
• 年：2014
• 卷：730
• 期：Complete
• 页码：157-163
• 全文大小：985 K

文摘

Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to affective disorders such as anxiety and depression. Dampening HPA activity has, therefore, been considered as a possible means of treating affective disorders. Given the important role of vasopressin in modulating the HPA axis, one strategy has focused on inhibiting activity of the vasopressin 1b (V_1b) receptor. In animals, V_1b receptor antagonists reduce plasma stress hormone levels and have been shown to have an anxiolytic-like effect. Recently, V1B-30N was identified as a highly potent V_1b receptor antagonist with selectivity over other vasopressin receptors, which is evaluated here in rodent models of anxiety-like and depression-like behaviors. V1B-30N (1-30 mg/kg, IP) dose-dependently reduced separation-induced vocalizations in rat pups without producing any sedative effects in the animals. Similarly, V1B-30N (3-30 mg/kg, IP) dose-dependently reduced separation-induced vocalizations in guinea pig pups. In a conflict assay, conditioned lick suppression, V1B-30N (3-30 mg/kg, IP) increased punished licking. To assess antidepressive-like properties, V1B-30N (1-30 mg/kg) was tested in the mouse and rat forced-swim tests but was found to be inactive. These results are consistent with previous findings with other V_1b antagonists, which suggest that acute pharmacological antagonism of the V_1b receptor has anxiolytic-like but not antidepressant-like properties.