Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, United States.
Physiol Behav. 2011 Jun 1;103(3-4):393-403. doi: 10.1016/j.physbeh.2011.03.007. Epub 2011 Mar 22.
Chronic social stress in rodents produces behavioral and neuroendocrine patterns analogous to symptoms associated with psychopathologies in humans. Chronic social defeat in mice has been used to study the genetic and epigenetic precursors of stress-related social disorders. The neuropeptides arginine vasopressin (AVP) and oxytocin (OT) are released in central targets to modulate anti- and pro-social behaviors, respectively. AVP binds to V1a and V1b receptors (V1bRs) in discrete brain regions related to anxiety, depression and affiliative behaviors. Recent evidence suggests that V1bRs are involved in stress and anxiety and may be an attractive target for the treatment of associated disorders. In the present series of experiments, we aimed to evaluate the effects of chronic social defeat stress on: 1) anxiety-related behaviors in a social investigation paradigm and their potential modulation by an acute dose of SSR149415, a V1bR antagonist; 2) AVP and Fos protein levels in the paraventricular nucleus of the hypothalamus (PVN) and; 3) AVP- and OT-receptor (OTR) mRNA levels in brain regions associated with sociality. When compared to undefeated animals, socially defeated mice exhibited an anxiogenic behavioral profile towards a novel male conspecific, with SSR149415 partly attenuating these effects. Histochemistry using immunofluorescence showed defeat produced significant elevations of Fos and double labeling of AVP and Fos proteins in the paraventricular nucleus of the hypothalamus (PVN). SSR149415 attenuated the effects of defeat on Fos and AVP/Fos double labeling, consistent with an anxiolytic effect. Defeated mice showed elevated levels of OTR mRNA levels in the lateral septum (LS) in addition to increased V1bR and OTR mRNA in the medial amygdala (MeA). We suggest the involvement of V1bRs and OTRs in a circuit involving the PVN, MeA and LS in the effects of defeat on sociality. SSR149415 attenuated anxiogenesis in the social investigation model and both Fos and AVP/Fos labeling, suggesting V1bRs are an attractive target for the treatment of anxiety in general and disorders of sociality in particular.
慢性社会应激在啮齿动物中产生类似于人类精神病理学相关症状的行为和神经内分泌模式。慢性社会挫败在小鼠中被用于研究与应激相关的社会障碍的遗传和表观遗传前体。神经肽精氨酸加压素 (AVP) 和催产素 (OT) 分别在中枢靶标中释放，以调节抗和亲社会行为。AVP 结合到与焦虑、抑郁和亲和行为相关的离散脑区域中的 V1a 和 V1b 受体 (V1bR)。最近的证据表明，V1bR 参与应激和焦虑，可能是治疗相关疾病的有吸引力的靶点。在本系列实验中，我们旨在评估慢性社会挫败应激对以下方面的影响：1）社交调查范式中的焦虑相关行为及其对急性 SSR149415（V1bR 拮抗剂）剂量的潜在调节；2）下丘脑室旁核 (PVN) 中的 AVP 和 Fos 蛋白水平；3）与社交相关的脑区中的 AVP 和 OT 受体 (OTR) mRNA 水平。与未被击败的动物相比，被击败的老鼠对新的雄性同种动物表现出焦虑行为特征，SSR149415 部分减弱了这些作用。使用免疫荧光的组织化学显示，击败导致下丘脑室旁核 (PVN) 中的 Fos 和 AVP/Fos 蛋白的显著升高。SSR149415 减弱了击败对 Fos 和 AVP/Fos 双重标记的影响，这与抗焦虑作用一致。被击败的老鼠除了在中杏仁核 (MeA) 中增加 V1bR 和 OTR mRNA 外，还显示出外侧隔核 (LS) 中 OTR mRNA 水平升高。我们认为，PVN、MeA 和 LS 中的 V1bR 和 OTR 参与了与挫败对社交性的影响有关的回路。SSR149415 减弱了社交调查模型中的焦虑发生以及 Fos 和 AVP/Fos 标记，这表明 V1bR 是治疗一般焦虑症和社交障碍的有吸引力的靶点。
