Vilazodone Alleviates Neurogenesis-Induced Anxiety in the Chronic Unpredictable Mild Stress Female Rat Model: Role of Wnt/β-Catenin Signaling

Mol Neurobiol. 2024 Nov;61(11):9060-9077. doi: 10.1007/s12035-024-04142-3. Epub 2024 Apr 8.

Abstract

Defective β-catenin signaling is accompanied with compensatory neurogenesis process that may pave to anxiety. β-Catenin has a distinct role in alleviating anxiety in adolescence; however, it undergoes degradation by the degradation complex Axin and APC. Vilazodone (VZ) is a fast, effective antidepressant with SSRI activity and 5-HT1A partial agonism that amends somatic and/or psychic symptoms of anxiety. Yet, there is no data about anxiolytic effect of VZ on anxiety-related neurogenesis provoked by stress-reduced β-catenin signaling. Furthermore, females have specific susceptibility toward psychopathology. The aim of the present study is to uncover the molecular mechanism of VZ relative to Wnt/β-catenin signaling in female rats. Stress-induced anxiety was conducted by subjecting the rats to different stressful stimuli for 21 days. On the 15th day, stressed rats were treated with VZ(10 mg/kg, p.o.) alone or concomitant with the Wnt inhibitor: XAV939 (0.1 mg/kg, i.p.). Anxious rats showed low β-catenin level turned over by Axin-1 with unanticipated reduction of APC pursued with elevated protein levels of neurogenesis-stimulating proteins: c-Myc and pThr183-Erk likewise gene expressions of miR-17-5p and miR-18. Two weeks of VZ treatment showed anxiolytic effect figured by alleviation of hippocampal histological examination. VZ protected β-catenin signal via reduction in Axin-1 and elevation of APC conjugated with modulation of β-catenin downstream targets. The cytoplasmic β-catenin turnover by Axin-1 was restored by XAV939. Herein, VZ showed anti-anxiety effect, which may be in part through regaining the balance of the reduced β-catenin and its subsequent exaggerated response of p-Erk, c-Myc, Dicer-1, miR-17-5p, and miR-18.

Keywords: Anxiety; MicroRNAs; Neurogenesis; Stress; Vilazodone; Wnt/β-catenin.

MeSH terms

  • Animals
  • Anti-Anxiety Agents* / pharmacology
  • Anti-Anxiety Agents* / therapeutic use
  • Anxiety* / drug therapy
  • Anxiety* / metabolism
  • Chronic Disease
  • Disease Models, Animal
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Neurogenesis / drug effects
  • Rats
  • Rats, Wistar
  • Stress, Psychological / complications
  • Stress, Psychological / drug therapy
  • Vilazodone Hydrochloride* / pharmacology
  • Wnt Signaling Pathway* / drug effects
  • beta Catenin / metabolism

Substances

  • Anti-Anxiety Agents
  • beta Catenin
  • Vilazodone Hydrochloride