Rasd2 Mediates Acute Fasting-Induced Antidepressant-Like Effects via Dopamine D2 Receptor Activation in Ovariectomized Mice

Abstract Background Previous studies have shown that estrogen and acute fasting for 9 hours have antidepressant-like effects by reducing immobility time in the forced swimming test. Estrogen and acute fasting share a common regulatory gene, Rasd2. RASD2 regulates dopamine D2 receptor (DRD2) transmission, but the role of Rasd2 in the DRD2-mediated antidepressant-like effect of acute fasting has not been examined. Methods In this study, open field test, forced swimming test, tail suspension test and sucrose preference test were used for behavioral assessments. RNA-seq, western blot, enzyme-linked immunosorbent assay, and co-immunoprecipitation were used to explore the role of Rasd2 in a depression model induced by ovariectomy and the antidepressant-like effects of 9-hour fasting. Results The RNA seq results showed that acute fasting induced a significant change in Rasd2 gene expression. Depression-like behaviors induced by ovariectomy were associated with decreased RASD2 and DRD2 protein levels in the hippocampus, and Rasd2 overexpression in the hippocampus alleviated depression-like behaviors and increased DRD2 expression. Nine-hour fasting had antidepressant-like effects in ovariectomized mice by upregulating the protein levels of RASD2, DRD2, CREB-BDNF, Akt, and estrogen receptor beta, and these effects can be blocked by DRD2 antagonists. Conclusions Our results suggest that Rasd2 and DRD2 play pivotal roles in depression-like behavior induced by ovariectomy. Rasd2 regulates DRD2-mediated antidepressant-like effects of acute fasting in ovariectomized mice. Rasd2 can therefore be postulated to be a potential therapeutic target for depression and perhaps also a potential predictive marker for depression.

[1]  V. Pak,et al.  The effects of time-restricted eating on sleep, cognitive decline, and Alzheimer's disease , 2022, Experimental Gerontology.

[2]  E. Ebrahimie,et al.  Long-Term Calorie Restriction Alters Anxiety-like Behaviour and the Brain and Adrenal Gland Transcriptomes of the Ageing Male Rat , 2022, Nutrients.

[3]  A. Pinborg,et al.  Hippocampal volume changes in a pharmacological sex-hormone manipulation risk model for depression in women , 2022, Hormones and Behavior.

[4]  Shuo Jiang,et al.  Selection of the Male or Female Sex in Chronic Unpredictable Mild Stress-Induced Animal Models of Depression , 2022, BioMed research international.

[5]  T. Lancet.  Ensuring care for people with depression , 2022, The Lancet.

[6]  The Lancet.  Ensuring care for people with depression. , 2022, The Lancet.

[7]  L. Pinto,et al.  The underestimated sex: A review on female animal models of depression , 2021, Neuroscience & Biobehavioral Reviews.

[8]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[9]  Xiao-yin Chen,et al.  Beneficial Effects on Brain Micro-Environment by Caloric Restriction in Alleviating Neurodegenerative Diseases and Brain Aging , 2021, Frontiers in Physiology.

[10]  Chenxi Xu,et al.  Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens , 2021, Molecular Psychiatry.

[11]  Xiaobai Li,et al.  Effects of enriched environment on depression and anxiety-like behavior induced by early life stress: A comparison between different periods , 2021, Behavioural Brain Research.

[12]  D. Xing,et al.  Photobiomodulation Therapy Ameliorates Glutamatergic Dysfunction in Mice with Chronic Unpredictable Mild Stress-Induced Depression , 2021, Oxidative medicine and cellular longevity.

[13]  Xiu-Min Li,et al.  PI3K–AKT Signaling Activation and Icariin: The Potential Effects on the Perimenopausal Depression-Like Rat Model , 2019, Molecules.

[14]  R. Cui,et al.  Additive antidepressant‐like effects of fasting with β‐estradiol in mice , 2019, Journal of cellular and molecular medicine.

[15]  T. Sun,et al.  CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice. , 2019, The Journal of clinical investigation.

[16]  V. Lessmann,et al.  Dopaminergic innervation and modulation of hippocampal networks , 2018, Cell and Tissue Research.

[17]  R. Cui,et al.  The mechanism of acute fasting‐induced antidepressant‐like effects in mice , 2017, Journal of cellular and molecular medicine.

[18]  I. Lucki,et al.  Removal of high-fat diet after chronic exposure drives binge behavior and dopaminergic dysregulation in female mice , 2016, Neuroscience.

[19]  P. Calabresi,et al.  The Small GTP‐Binding Protein Rhes Influences Nigrostriatal‐Dependent Motor Behavior During Aging , 2016, Movement disorders : official journal of the Movement Disorder Society.

[20]  M. Ratajczak,et al.  Caloric restriction increases ratio of estrogen to androgen receptors expression in murine ovaries - potential therapeutic implications , 2015, Journal of Ovarian Research.

[21]  B. Picconi,et al.  Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion , 2015, Scientific Reports.

[22]  A. Pisani,et al.  Rhes regulates dopamine D2 receptor transmission in striatal cholinergic interneurons , 2015, Neurobiology of Disease.

[23]  L. Partridge,et al.  Promoting Health and Longevity through Diet: From Model Organisms to Humans , 2015, Cell.

[24]  B. Davidson,et al.  Reinstating Aberrant mTORC1 Activity in Huntington’s Disease Mice Improves Disease Phenotypes , 2015, Neuron.

[25]  J. Flint,et al.  The Genetics of Major Depression , 2014, Neuron.

[26]  Jing Zhao,et al.  Additive antidepressant-like effects of fasting with imipramine via modulation of 5-HT2 receptors in the mice , 2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[27]  M. Sammel,et al.  Longitudinal pattern of depressive symptoms around natural menopause. , 2014, JAMA psychiatry.

[28]  S. Snyder,et al.  Rhes, a Striatal-selective Protein Implicated in Huntington Disease, Binds Beclin-1 and Activates Autophagy* , 2013, The Journal of Biological Chemistry.

[29]  Harold W Neighbors,et al.  The experience of symptoms of depression in men vs women: analysis of the National Comorbidity Survey Replication. , 2013, JAMA psychiatry.

[30]  L. Savegnago,et al.  Involvement of the dopaminergic and serotonergic systems in the antidepressant-like effect caused by 4-phenyl-1-(phenylselanylmethyl)-1,2,3-triazole. , 2013, Life sciences.

[31]  S. Muller,et al.  Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum , 2013, Neuroscience.

[32]  Sangwon F. Kim,et al.  Striatum specific protein, Rhes regulates AKT pathway , 2012, Neuroscience Letters.

[33]  A. Rodrigues,et al.  Antidepressant-like effect of creatine in mice involves dopaminergic activation , 2012, Journal of psychopharmacology.

[34]  D. Slattery,et al.  Using the rat forced swim test to assess antidepressant-like activity in rodents , 2012, Nature Protocols.

[35]  E. Palazidou.  The neurobiology of depression. , 2012, British medical bulletin.

[36]  S. Snyder,et al.  Rhes, a striatal–enriched small G–protein, mediates mTOR signaling and L–DOPA–induced dyskinesia , 2011, Nature Neuroscience.

[37]  R. Cui,et al.  Antidepressant-like effect of Fuzi total alkaloid on ovariectomized mice. , 2012, Journal of pharmacological sciences.

[38]  O. Picazo,et al.  Long-term ovariectomy modulates the antidepressant-like action of estrogens, but not of antidepressants , 2011, Journal of psychopharmacology.

[39]  H. Pijl,et al.  Blocking Dopamine D2 Receptors by Haloperidol Curtails the Beneficial Impact of Calorie Restriction on the Metabolic Phenotype of High‐Fat Diet Induced Obese Mice , 2011, Journal of neuroendocrinology.

[40]  J. A. Rogers,et al.  Forced swim test behavior in postpartum rats , 2010, Pharmacology Biochemistry and Behavior.

[41]  W. Kiosses,et al.  Short-term fasting induces profound neuronal autophagy , 2010, Autophagy.

[42]  G. Lahoste,et al.  The Ras homolog Rhes affects dopamine D1 and D2 receptor-mediated behavior in mice , 2008, Neuroreport.

[43]  M. Lutter,et al.  Orexin Signaling Mediates the Antidepressant-Like Effect of Calorie Restriction , 2008, The Journal of Neuroscience.

[44]  D. Centonze,et al.  The GTP-binding protein Rhes modulates dopamine signalling in striatal medium spiny neurons , 2008, Molecular and Cellular Neuroscience.

[45]  N. Volkow,et al.  Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in‐vivo μPET imaging ([11C] raclopride) and in‐vitro ([3H] spiperone) autoradiography , 2008, Synapse.

[46]  A. Gershon,et al.  Dopamine D2-Like Receptors and the Antidepressant Response , 2007, Biological Psychiatry.

[47]  G. Lahoste,et al.  Rhes, the Ras homolog enriched in striatum, is reduced under conditions of dopamine supersensitivity , 2006, Neuroscience.

[48]  I. Lucki,et al.  Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment , 2005, Psychopharmacology.

[49]  B. Rocha,et al.  17 Beta-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-beta knockout (BERKO) mice. , 2005, Psychopharmacology.

[50]  M. Karayiorgou,et al.  Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia , 2004, Nature Genetics.

[51]  A. Valencia,et al.  The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors , 2004, Oncogene.

[52]  Athina Markou,et al.  Assessing antidepressant activity in rodents: recent developments and future needs. , 2002, Trends in pharmacological sciences.

[53]  P. Sokoloff,et al.  BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization , 2001, Nature.

[54]  B. Madhukar,et al.  Xenobiotics released from fat during fasting produce estrogenic effects in ovariectomized mice. , 1997, Cancer research.

[55]  A. Lecci,et al.  Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity. , 1988, European journal of pharmacology.

[56]  J. Palacios,et al.  Dopamine D2 receptors in the rat brain: autoradiographic visualization using a high-affinity selective agonist ligand , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[57]  D. Ingram,et al.  Delayed loss of striatal dopamine receptors during aging of dietarily restricted rats , 1984, Brain Research.

[58]  P. L. Broadhurst.  DETERMINANTS OF EMOTIONALITY IN RAT , 1957 .

[59]  P. L. Broadhurst.  Determinants of emotionality in the rat. I. Situational factors. , 1957, British journal of psychology.