Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats

Veena, Jayagopalan; Srikumar, B.N.; Mahati, K.; Raju, T.R.; Rao, B.S. Shankaranarayana

doi:10.1007/s00213-011-2279-3

Cited by 40 publications

(25 citation statements)

References 108 publications

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“…In the present study, according to previous report (Veena et al 2011), Oxo treatment in CRS and unstressed rats significantly increased hippocampal weight when compared to CRS group, showing that Oxo may not only restore the hippocampal volumes but also increase it beyond the normal control.…”

Section: Discussionsupporting

confidence: 85%

“…In addition to different tests used to establish the anxietylike behavior induced by CRS, further data supporting anxiety-depressive-like behavior profile in CRS group are provided indirectly by body weight reduction and hippocampi weight reduction (Bremner et al 2000;MacQueen et al 2003;Orlovsky et al 2014;Sheline et al 1996;Veena et al 2011). In the present study, according to previous report (Veena et al 2011), Oxo treatment in CRS and unstressed rats significantly increased hippocampal weight when compared to CRS group, showing that Oxo may not only restore the hippocampal volumes but also increase it beyond the normal control.…”

Section: Discussionsupporting

confidence: 79%

“…By several studies, CRS has been suggested as an animal model of anxiety/depression-like behavior (Veena et al 2011), and here, the degree of anxiety-induced by CRS was measured using four different paradigms, which confirmed protein levels or p-Erk1/2 levels in the CRS-induced anxiety-like behavior and in the Oxo anxiolytic treatment. a-c CRS induced reduction of BDNF and FGF2 protein levels or p-Erk1/2 levels as compared to control.…”

Section: Discussionsupporting

confidence: 78%

“…The Oxo dose (0.2 mg/kg) used in the present study was chosen based mainly on literature data (Srikumar et al 2006;Veena et al 2011) and on preliminary experiments in which the anxiolytic efficacy of 0.2 mg/kg b.w. was assessed by FST and EPM tests.…”

Section: Experimental Designmentioning

confidence: 99%

“…The muscarinic acetylcholine receptors (mAChRs), a family of metabotropic G protein-coupled receptors, include five subtypes (M1-5) with discrete distribution throughout the brain and whose activation regulates synaptic plasticity, neurogenesis, neuroprotection (Di Liberto et al 2014;Veena et al 2011), and many aspects of cognitive functions and behaviors (Drever et al 2011;Luchicchi et al 2014). Moreover, mAChR activation can modulate the production or/and the release of neurotrophic factors in neurons, such as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), which in turn could mediate synaptic plasticity, axon outgrowth, and neurogenesis (Barathi et al 2009;Lindholm et al 1994;Mudo et al 1996;Navakkode and Korte 2012).…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 78%

Section: Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2016

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

Frinchi

Scaduto

Cappello

et al. 2018

Journal Cellular Physiology

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The cholinergic system plays a crucial role in modulating in the central nervous system physiological responses such as neurogenesis, neuronal differentiation, synaptic plasticity, and neuroprotection. In a recent study, we showed that Oxotremorine-M, a non-selective muscarinic acetylcholine receptor agonist, is able to transactivate the fibroblast growth factor receptor and to produce a significant increase in the hippocampal primary neurite outgrowth. In the present study we aimed to explore in the rat hippocampus the possible effect of acute or chronic treatment with Oxotremorine-M on some heat shock proteins (Hsp60, Hsp70, Hsp90) and on activation of related transcription factor heat shock factor 1 (HSF1). Following single injection of Oxotremorine-M (0.4 mg/kg) all Hsps examined were significantly increased in at least one of the time points studied (24, 48, and 72 hr). Treatment with Oxotremorine-M significantly increased the level of phosphorylated HSF1 in all time points studied, without change of protein levels. Similar pattern of Hsps changes was obtained following chronic Oxotremorine-M treatment (0.2 mg/kg) for 5 days. Surprisingly, following chronic treatment for 10 days no changes were observed in Hsps. The muscarinic acetylcholine receptor antagonist scopolamine (1 mg/kg) was able to completely block Oxotremorine-M effects on Hsps. In conclusion, considering the function of Hsps in protecting neuronal cells from deleterious proteotoxic stress, for example, protein mis-folding and aggregation, the results obtained indicate that muscarinic acetylcholine receptor activation may have implications in potential treatment of neurodegenerative disorders linked to protein aggregation, such as Alzheimer disease.

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The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression

Bhagya

Srikumar

Raju

et al. 2014

J of Neuroscience Research

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Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression-associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression-associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression-induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long-term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight-arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression-associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments.

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Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats

Cited by 40 publications

References 108 publications

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

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

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

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression

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