, Volume 234, Issue 4, pp 559–573 | Cite as

Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex

  • Valentina Di Liberto
  • Monica Frinchi
  • Vincenzo Verdi
  • Angela Vitale
  • Fulvio Plescia
  • Carla Cannizzaro
  • Maria F. Massenti
  • Natale Belluardo
  • Giuseppa MudòEmail author
Original Investigation



In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation.


Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex.


The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2 mg/kg Oxo, and unstressed group treated with Oxo. After 21 days of CRS, the groups were treated for 10 days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels.


Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex


The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.


Cerebral cortex Chronic restraint stress Forced swimming test Novelty suppressed feeding test Elevated plus maze test mAChR Anxiety Neurotrophins Behavioral test 



This work was supported by grants from “Fondi Finanziamento della Ricerca (FFR),” University of Palermo.

Compliance with ethical standards

The experiments were carried out in accordance with the National Institute of Health Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (The National Academics Press, WA, USA), with the rules and principles of the European Communities Council Directive 2010/63/EU revising Directive 86/609/EEC, in accordance with the national D.L. March 4, 2014, no. 26, and were approved by the local Bioethical Committee.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Valentina Di Liberto
    • 1
  • Monica Frinchi
    • 1
  • Vincenzo Verdi
    • 1
  • Angela Vitale
    • 1
  • Fulvio Plescia
    • 2
  • Carla Cannizzaro
    • 2
  • Maria F. Massenti
    • 2
  • Natale Belluardo
    • 1
  • Giuseppa Mudò
    • 1
    Email author
  1. 1.Department of Experimental Biomedicine and Clinical NeurosciencesUniversity of PalermoPalermoItaly
  2. 2.Department of Sciences for Health Promotion and Mother and Child Care “Giuseppe D’Alessandro”University of PalermoPalermoItaly

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