The NOP antagonist BTRX-246040 increases stress resilience in mice without affecting adult neurogenesis in the hippocampus

Silva, Flora D'Oliveira da; Neto, Joaquim Azevedo; Sturaro, Chiara; Guarino, Annunziata; Robert, Cathaline; Gavioli, Elaine C.; Girolamo, Calo’; Moulédous, Lionel; Ruzza, Chiara

doi:10.1016/j.neuropharm.2022.109077

Cited by 7 publications

(11 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study showed that BTRX-246040 could produce a decrease in the LH phenotype ( D'Oliveira da Silva et al, 2022 ). In addition, the effect of BTRX-246040 in the vlPAG on depressive-like behavior is still unclear.…”

Section: Resultsmentioning

confidence: 99%

“…As a selective and potent NOP receptor antagonist ( Statnick et al, 2016 ; Ferrari et al, 2020 ), BTRX-246040 has been indicated to exert antidepressant-relevant actions ( D'Oliveira da Silva et al, 2022 ), and its drug development has currently entered clinical trials ( Post et al, 2016 ). To date, the underlying mechanisms of BTRX-246040 are largely acting on the N/OFQ system, which is involved in stress response brain areas such as amygdala, bed nucleus of stria terminalis, and hypothalamus ( Ubaldi et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…To date, the underlying mechanisms of BTRX-246040 are largely acting on the N/OFQ system, which is involved in stress response brain areas such as amygdala, bed nucleus of stria terminalis, and hypothalamus ( Ubaldi et al, 2021 ). Although both N/OFQ and NOP receptor are densely expressed within the vlPAG ( Meunier et al, 1995 ; Reinscheid et al, 1995 ; D'Oliveira da Silva et al, 2022 ), the action of BTRX-246040 in targeting the vlPAG remains unknown. Here, we report a vlPAG glutamatergic activity–dependent mechanism that underlies the BTRX-246040–mediated antidepressant-like effects on depressive-relevant behavior and helpless behavior.…”

Section: Discussionmentioning

confidence: 99%

“…The LH mouse model was used as described in our previous study ( Ye et al, 2022 ), and the protocol (to test the ability of a drug to reverse the acquired LH phenotype) was modified in accordance with previous studies ( Holanda et al, 2016 ; D'Oliveira da Silva et al, 2022 ), with training, screen, and test sessions. In the training session, a mouse was placed in the apparatus on one side of a shuttle box containing 2 chambers and subjected to 180 cycles of inescapable electric foot shocks (0.5 mA shock intensity, 1–10 seconds randomized shock duration, 1–20 seconds randomized inter-shock interval) for 2 consecutive days using the Gemini avoidance system (San Diego Instruments, San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Exposure to acute stress has been shown to elevate the expression of N/OFQ in the hippocampus ( Nativio et al, 2012 ), and bilateral intra-dorsal hippocampal application of a NOP receptor antagonist resulted in antidepressant-related behavioral effects ( Goeldner et al, 2010 ). Many preclinical and clinical studies have reported that blocking NOP signaling, including the use of the NOP receptor antagonists UFP-101 and SB-612111, evokes antidepressant-related effects, such as reverting acquired helpless behavior and depression-like behavior ( Gavioli and Calo, 2013 ; Holanda et al, 2016 ; Post et al, 2016 ; Gavioli et al, 2019 ; D'Oliveira da Silva et al, 2022 ). In addition, genetic and pharmacological inhibition of the NOP receptor produces stress resilience ( Holanda et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2023

International Journal of Neuropsychopharmacology

View full text Add to dashboard Cite

Background BTRX-246040, a nociceptin/orphanin FQ (N/OFQ) peptide (NOP) 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 (TST), forced swim test (FST), female urine sniffing test (FUST), sucrose preference test (SPT), and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and the 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 (mEPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of mEPSCs and enhanced the evoked excitatory postsynaptic currents (EPSCs) in the vlPAG, which were blocked by pretreatment with the NOP 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 CNQX 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.

show abstract

Section: Resultsmentioning

confidence: 99%