Effect of lurasidone treatment on chronic mild stress-induced behavioural deficits in male rats: The potential role for glucocorticoid receptor signalling
Restricted accessResearch articleFirst published online April, 2020
Effect of lurasidone treatment on chronic mild stress-induced behavioural deficits in male rats: The potential role for glucocorticoid receptor signalling
Stress represents one of the main precipitating factors for psychiatric diseases, characterised by an altered function of glucocorticoid receptors (GR), known to play a role in mood and cognitive function. We investigated the ability of the antipsychotic lurasidone to modulate the involvement of genomic and non-genomic GR signalling in the behavioural alterations due to chronic stress exposure
Methods:
Male Wistar rats were exposed to seven weeks of chronic mild stress (CMS) and treated with lurasidone (3 mg/kg/day) starting from the second week of stress for more five weeks. Gene expression and protein analyses were conducted in dorsal hippocampus.
Results:
Seven weeks of CMS induced anhedonia and cognitive impairment, which were normalised by lurasidone. At molecular level, CMS rats showed an increase of GR protein levels by 60% (p<0.001 vs. CTRL/VEH) in the membrane compartment, which was paralleled by an up-regulation of phosphoSINAPSYN Ia/b by 88% (p<0.01 vs. CTRL/VEH) and of the mitochondrial marker Cox3 by 21% (p<0.05 vs. CTRL/VEH). Moreover, while exposure to the novel object recognition test increased the nuclear translocation of GRs by 96% (p<0.01 vs. CTRL/VEH/Naïve) and their transcriptional activity in non-stressed rats, such mechanisms were impaired in CMS rats. Interestingly, the genomic and non-genomic alterations of GR, induced by CMS, were normalised by lurasidone.
Conclusion:
Our results further support the role of glucocorticoid signalling in the dysfunction associated with stress exposure. We provide novel insights on the mechanism of lurasidone, suggesting its effectiveness on different domains associated with psychiatric disorders.
AdzicMDjordjevicADemonacosC, et al. (2009) The role of phosphorylated glucocorticoid receptor in mitochondrial functions and apoptotic signalling in brain tissue of stressed Wistar rats. Int J Biochem Cell Biol41: 2181–2188.
2.
AringhieriSCarliMKolachalamS, et al. (2018) Molecular targets of atypical antipsychotics: from mechanism of action to clinical differences. Pharmacol Ther192: 20–41.
3.
BeatoMBiesewigDBraendleW, et al. (1969) On the mechanism of hormone action. XV. Subcellular distribution and binding of [1,2-3H]cortisol in rat liver. Biochim Biophys Acta192: 494–507.
BrivioPCorsiniGRivaMA, et al. (2019) Chronic vortioxetine treatment improves the responsiveness to an acute stress acting through the ventral hippocampus in a glucocorticoid-dependent way. Pharmacol Res142: 14–21.
6.
CalabreseFBrivioPGrucaP, et al. (2017) Chronic mild stress-induced alterations of local protein synthesis: a role for cognitive impairment. ACS Chem Neurosci8: 817–825.
7.
CalabreseFSavinoEPappM, et al. (2016) Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment. Pharmacol Res104: 140–150.
8.
CameronHASchoenfeldTJ (2018) Behavioral and structural adaptations to stress. Front Neuroendocrinol49: 106–113.
9.
CarvalhoLAParianteCM (2008) In vitro modulation of the glucocorticoid receptor by antidepressants. Stress11: 411–424.
10.
CzéhBFuchsEWiborgO, et al. (2016) Animal models of major depression and their clinical implications. Progr Neuropsychopharmacol Biol Psychiatry64: 293–310.
11.
DemonacosCVKarayanniNHatzoglouE, et al. (1996) Mitochondrial genes as sites of primary action of steroid hormones. Steroids61: 226–232.
12.
De QuervainDSchwabeLRoozendaalB (2016) Stress, glucocorticoids and memory: implications for treating fear-related disorders. Nat Rev Neurosci18: 7–19.
13.
DuJWangYHunterR, et al. (2009) Dynamic regulation of mitochondrial function by glucocorticoids. Proc Natl Acad Sci U S A106: 3543–3548.
14.
FanselowMSDongHW (2010) Are the dorsal and ventral hippocampus functionally distinct structures?Neuron65: 7–19.
15.
GoldenthalMJAnanthakrishnanRMarín-GarcíaJ (2005) Nuclear-mitochondrial cross-talk in cardiomyocyte T3 signaling: a time-course analysis. J Mol Cell Cardiol39: 319–326.
16.
GrayJDKoganJFMarroccoJ, et al. (2017) Genomic and epigenomic mechanisms of glucocorticoids in the brain. Nat Rev Endocrinol131: 661–673.
17.
HawkJDAbelT (2011) The role of NR4A transcription factors in memory formation. Brain Res Bull85: 21–29.
18.
HillMNMcEwenBS (2010) Involvement of the endocannabinoid system in the neurobehavioural effects of stress and glucocorticoids. Prog Neuropsychopharmacol Biol Psychiatry34: 791–797.
19.
HunterRGSeligsohnMRubinTG, et al. (2016) Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor. Proc Natl Acad Sci U S A113: 9099–9104.
20.
JoëlsMBaramTZ (2009) The neuro-symphony of stress. Nat Rev Neurosci10: 459–466.
21.
KellyEAFudgeJL (2018) The neuroanatomic complexity of the CRF and DA systems and their interface: what we still don’t know. Neurosci Biobehav Rev90: 247–259.
22.
KheirbekMADrewLJBurghardtNS, et al. (2013) Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron77: 955–968.
23.
LeachPTPoplawskiSGKenneyJW, et al. (2012) Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory. Learn Mem19: 319–324.
24.
LevinERHammesSR (2016) Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol17:783–797.
25.
LiangHLOngwijitwatSWong-RileyMTT (2006) Bigenomic functional regulation of all 13 cytochrome c oxidase subunit transcripts in rat neurons in vitro and in vivo. Neuroscience140: 177–190.
26.
LuoniAMacchiFPappM, et al. (2015) Lurasidone exerts antidepressant properties in the chronic mild stress model through the regulation of synaptic and neuroplastic mechanisms in the rat prefrontal cortex. Int J Neuropsychopharmacol18.
27.
LupienSJJusterRPRaymondC, et al. (2018) The effects of chronic stress on the human brain: from neurotoxicity, to vulnerability, to opportunity. Front Neuroendocrinol49: 91–105.
28.
McEwenBS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev87: 873–904.
29.
MacfarlaneDPForbesSWalkerBR (2008) Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol197: 189–204.
30.
ManoliIAlesciSBlackmanMR, et al. (2007) Mitochondria as key components of the stress response. Trends Endocrinol Metab18: 190–198.
31.
MasonBLParianteCM (2006) The effects of antidepressants on the hypothalamic–pituitary–adrenal axis. Drug News Perspect19: 603–608.
32.
MoutsatsouPPsarraAMGTsiaparaA, et al. (2001) Localization of the glucocorticoid receptor in rat brain mitochondria. Arch Biochem Biophys386: 69–78.
33.
NewtonRShahSAltonsyMO, et al. (2017) Glucocorticoid and cytokine crosstalk: feedback, feedforward, and co-regulatory interactions determine repression or resistance. J Biol Chem292: 7163–7172.
34.
ParianteCM (2009) Risk factors for development of depression and psychosis: glucocorticoid receptors and pituitary implications for treatment with antidepressant and glucocorticoids. Ann N Y Acad Sci1179: 144–152.
35.
ParianteCMKimRBMakoffA, et al. (2003) Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters. Br J Pharmacol139: 1111–1118.
36.
PaxinosGWatsonC (2004) The Rat Brain in Stereotaxic Coordinates – The New Coronal Set. English. San Diego, CA: Academic Press.
37.
Peña de OrtizSMaldonado-VlaarCSCarrasquilloY (2000) Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning. Neurobiol Learn Mem74: 161–178.
38.
ReulJMHMde KloetER (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology117: 2505–2511.
39.
RevestJMKaouaneNMondinM, et al. (2010) The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib. Mol Psychiatry15: 1125, 1140–1151.
40.
RevolloJRCidlowskiJA (2009) Mechanisms generating diversity in glucocorticoid receptor signaling. Ann N Y Acad Sci1179: 167–178.
41.
RossettiAPaladiniMSColomboM, et al. (2018) Chronic stress exposure reduces parvalbumin expression in the rat hippocampus through an imbalance of redox mechanisms: restorative effect of the antipsychotic lurasidone. Int J Neuropsychopharmacol21: 883–893.
42.
RossettiACPappMGrucaP, et al. (2016) Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: restorative effect of pharmacological intervention. Pharmacol Res103: 1–12.
43.
SapolskyRMRomeroLMMunckAU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev21: 55–89.
44.
SionovRVCohenOKfirS, et al. (2006) Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis. J Exp Med203: 189–201.
45.
TaraziFIRivaMA (2013) The preclinical profile of lurasidone: clinical relevance for the treatment of schizophrenia. Exp Opin Drug Discov8: 1297–307.
46.
TsaiKJChenSKMaYL, et al. (2002) sgk, a primary glucocorticoid-induced gene, facilitates memory consolidation of spatial learning in rats. Proc Natl Acad Sci U S A99: 3990–3995.
47.
TsiriyotisCSpandidosDASekerisCE (1997) The mitochondrion as a primary site of action of glucocorticoids: mitochondrial nucleotide sequences, showing similarity to hormone response elements, confer dexamethasone inducibility to chimaeric genes transfected in LATK- cells. Biochem Biophys Res Commun235: 349–354.
48.
Von HertzenLSJGieseKP (2005) Memory reconsolidation engages only a subset of immediate-early genes induced during consolidation. J Neurosci25: 1935–1942.
49.
WegerBDWegerMGörlingB, et al. (2016) Extensive regulation of diurnal transcription and metabolism by glucocorticoids. PLoS Genet12: e1006512.
50.
WillnerP (2016) The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress6: 78–93.
51.
WuLMHanHWangQN, et al. (2007) Mifepristone repairs region-dependent alteration of synapsin I in hippocampus in rat model of depression. Neuropsychopharmacology32: 2500–2510.
52.
ZhangXYZhouDFCaoLY, et al. (2005) Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology30: 1532–1538.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
