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

Abstract

Rationale 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. Objectives 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. Methods 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. Results 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 Conclusions 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.

The molecular mechanism underlying GABAergic dysfunction in nucleus accumbens of depression‐like behaviours in mice

“…51,52 All of these targetings have been confirmed in the process of depression pathophysiological mechanism. 53 These data provided evidence that the miR-15 family played an important role in the pathogenesis of depression by mediating GABA release and uptake.…”

Heat shock protein (Hsp) regulation by muscarinic acetylcholine receptor (mAChR) activation in the rat hippocampus

“…Additionally, in order to unveil a temporal behavior of the Oxo effect within each type of treatment, we analyzed a time‐course with three time points: 24, 48, and 72 hr from treatment, with exclusion of 10 days treatment in which we analyzed the time points 24 and 72 hr from treatment. For the single injection, we chose the Oxo dose of 0.4 mg/kg and for chronic treatment the dose of 0.2 mg/kg in relation to previous experience (Di Liberto, Frinchi, et al, ).…”

“…Notoriously, Hsps have strong impact in the brain not only on protein folding, with cellular protective role against protein aggregation in neurodegenerative disorders (Muchowski & Wacker, ), but also on various processes such as synaptic transmission, functional integrity of synapses (Karunanithi & Brown, ), cell stress response, protein kinase‐mediated signaling, cell death (Stetler et al, ), and inhibition of apoptosis by MAPK/ERK‐ and PI 3‐kinase‐independent signaling cascades (Leloup et al, ). Therefore, the observed induction of Hsps by mAChR activation may give account of several responses observed following treatment with mAChR agonists, including learning process (Lin et al, ), neuroprotection in neurodegenerative diseases (Su et al, ), such as Parkinson's disease (Klucken, Shin, Masliah, Hyman, & McLean, ) and Alzheimer's disease (Hoshino et al, ), and neuroplasticity (Di Liberto et al, ; Di Liberto, Borroto‐Escuela, et al, ; Di Liberto, Frinchi, et al, ).…”

“…In a recent study, we showed that Oxotremorine‐M (Oxo), a non‐selective mAChRs agonist, is able to transactivate the fibroblast growth factor receptor and to produce a significant increase in the hippocampal primary neurite outgrowth (Di Liberto, Borroto‐Escuela, et al, ). More recently we 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, the ventral hippocampal formation and medial prefrontal cortex (Di Liberto, Frinchi, et al, ).…”

“…The cholinergic system plays a crucial role in the central nervous system in modulating various physiological responses, such as neurogenesis, neuronal differentiation, synaptic plasticity, and neuroprotection (Belluardo et al, , ; Di Liberto, Mudò, Fuxe, & Belluardo, ; Mudò et al, ; Mudò, Belluardo, & Fuxe, ). The muscarinic acetylcholine receptors (mAChRs), include five subtype receptors (M 1 R‐M 5 R) with discrete distribution throughout the brain, including hippocampus where are expressed mainly M 1 R‐M 3 R, whose activation regulates synaptic plasticity, neuroprotection and many aspects of cognitive functions and behaviors (Di Liberto et al, ; Di Liberto, Frinchi, et al, ; Drever, Riedel, & Platt, ; Luchicchi, Bloem, Viana, Mansvelder, & Role, ; Veena, Srikumar, Mahati, Raju, & Shankaranarayana Rao, ). In a recent study, we showed that Oxotremorine‐M (Oxo), a non‐selective mAChRs agonist, is able to transactivate the fibroblast growth factor receptor and to produce a significant increase in the hippocampal primary neurite outgrowth (Di Liberto, Borroto‐Escuela, et al, ).…”