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

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

doi:10.1093/ijnp/pyad027

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

Int J Neuropsychopharmacol. 2023 Jul 31;26(7):483-495. doi: 10.1093/ijnp/pyad027.

Authors

Zhenlong Li¹, Yuanyuan Xu², Rourou Li¹, Zhenyu Sheng¹, Xinya Chen¹, Xueman Liu¹, Chau-Shoun Lee^{3

4}, Hsien-Yu Peng³, Tzer-Bin Lin^{5

6

7}, Ming-Chun Hsieh³, Cheng-Yuan Lai⁸, Han-Fang Wu⁹, Dylan Chou³

Affiliations

¹ School of Basic Medical Sciences, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China.
² Department of Pharmacology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China.
³ Department of Medicine, MacKay Medical College, New Taipei, Taiwan.
⁴ Department of Psychiatry, MacKay Memorial Hospital, Taipei, Taiwan.
⁵ Institute of New Drug Development, College of Medicine, China Medical University, Taichung, Taiwan.
⁶ Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
⁷ Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁸ Institute of Biomedical Sciences, MacKay Medical College, New Taipei, Taiwan.
⁹ Department of Optometry, MacKay Medical College, New Taipei, Taiwan.

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.

Keywords: BTRX-246040; antidepressant; depressive-like behavior; glutamatergic transmission; learned helplessness; ventrolateral periaqueductal gray.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / pharmacology
Female
Mice
Mice, Inbred C57BL
Neurons*
Periaqueductal Gray*
Receptors, Peptide

Substances

Antidepressive Agents
Receptors, Peptide