BTRX-246040 Acts Through the Ventrolateral Periaqueductal Gray to Exert Antidepressant-Relevant Actions in Mice.

IF 4.5 2区医学 Q1 CLINICAL NEUROLOGY

International Journal of Neuropsychopharmacology Pub Date : 2023-07-31 DOI:10.1093/ijnp/pyad027

Zhenlong Li, Yuanyuan Xu, Rourou Li, Zhenyu Sheng, Xinya Chen, Xueman Liu, Chau-Shoun Lee, Hsien-Yu Peng, Tzer-Bin Lin, Ming-Chun Hsieh, Cheng-Yuan Lai, Han-Fang Wu, Dylan Chou

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引用次数: 1

Abstract

Background: BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG).

Methods: The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity.

Results: Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040-mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior.

Conclusions: The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040.

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BTRX-246040通过小鼠腹外侧导水管周围灰质发挥抗抑郁相关作用。

背景:BTRX-246040是一种痛感肽/孤啡肽FQ受体拮抗剂，正在开发用于治疗抑郁症患者。然而，这种潜在抗抑郁药的潜在机制仍不清楚。在此，我们研究了BTRX-246040在腹外侧导水管周围灰质(vlPAG)中的抗抑郁相关作用。方法:采用悬尾试验、强迫游泳试验、雌性嗅尿试验、蔗糖偏好试验、习得性无助(LH)试验等方法，结合药理学方法，观察h诱导C57BL/6J小鼠抑郁样行为的抗抑郁作用和药物作用。利用电生理记录研究vlPAG神经元的突触活动。结果:BTRX-246040腹腔注射具有剂量依赖性的抗抑郁样行为效应。全身BTRX-246040 (10 mg/kg)导致vlPAG中微型兴奋性突触后电流(EPSCs)的频率和幅度增加。此外，切片灌注BTRX-246040可直接提高微型EPSCs的频率和振幅，并增强被痛感肽/孤儿肽受体激动剂Ro 64-6198预处理的vlPAG中诱发的EPSCs。此外，在vlpag内应用BTRX-246040产生了剂量依赖的抗抑郁样行为效应。此外，6-氰基-7-硝基喹啉-2,3-二酮在vlpag内预处理可逆转全身和局部btrx -246040介导的抗抑郁样行为效应。此外，全身和局部BTRX-246040均可降低LH表型，并减少LH诱导的抑郁样行为。结论:BTRX-246040可能通过vlPAG发挥抗抑郁相关作用。本研究为BTRX-246040抗抑郁样作用的vlpag依赖机制提供了新的见解。

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来源期刊

International Journal of Neuropsychopharmacology 医学-精神病学

CiteScore

8.40

自引率

2.10%

发文量

230

审稿时长

4-8 weeks

期刊介绍： The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.