The chronic mild stress (CMS) model of depression: History, evaluation and usage

Now 30 years old, the chronic mild stress (CMS) model of depression has been used in >1300 published studies, with a year-on-year increase rising to >200 papers in 2015. Data from a survey of users show that while a variety of names are in use (chronic mild/unpredictable/varied stress), these describe essentially the same procedure. This paper provides an update on the validity and reliability of the CMS model, and reviews recent data on the neurobiological basis of CMS effects and the mechanisms of antidepressant action: the volume of this research may be unique in providing a comprehensive account of antidepressant action within a single model. Also discussed is the use of CMS in drug discovery, with particular reference to hippocampal and extra-hippocampal targets. The high translational potential of the CMS model means that the neurobiological mechanisms described may be of particular relevance to human depression and mechanisms of clinical antidepressant action.

[1]  V. Camus,et al.  Olfactory anhedonia and negative olfactory alliesthesia in depressed patients , 2010, Psychiatry Research.

[2]  L. Fabbro,et al.  Chronic unpredictable mild stress decreases BDNF and NGF levels and Na+,K+-ATPase activity in the hippocampus and prefrontal cortex of mice: Antidepressant effect of chrysin , 2015, Neuroscience.

[3]  Paul J Carlson,et al.  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. , 2006, Archives of general psychiatry.

[4]  Nanxin Li,et al.  Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure , 2011, Biological Psychiatry.

[5]  N. Sousa,et al.  Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement , 2000, Neuroscience.

[6]  Abraham Zangen,et al.  Site-Specific Antidepressant Effects of Repeated Subconvulsive Electrical Stimulation: Potential Role of Brain-Derived Neurotrophic Factor , 2010, Biological Psychiatry.

[7]  R. Katz,et al.  A further parametric study of imipramine in an animal model of depression , 1982, Pharmacology Biochemistry and Behavior.

[8]  P. Willner,et al.  The validity of animal models of depression , 2004, Psychopharmacology.

[9]  Yan Zhu,et al.  Dynamic study of the hippocampal volume by structural MRI in a rat model of depression , 2014, Neurological Sciences.

[10]  Wim E Crusio,et al.  Functional implications of decreases in neurogenesis following chronic mild stress in mice , 2007, Neuroscience.

[11]  Jan Sijbers,et al.  Magnetic Resonance Imaging and Spectroscopy Reveal Differential Hippocampal Changes in Anhedonic and Resilient Subtypes of the Chronic Mild Stress Rat Model , 2011, Biological Psychiatry.

[12]  M. Nilsson,et al.  Acute and Chronic Stress-Induced Disturbances of Microglial Plasticity, Phenotype and Function , 2013, Current drug targets.

[13]  H. Anisman,et al.  Strain-specific alterations in consumption of a palatable diet following repeated stressor exposure , 1992, Pharmacology Biochemistry and Behavior.

[14]  D. Luckenbaugh,et al.  An open-label trial of riluzole in patients with treatment-resistant major depression. , 2004, The American journal of psychiatry.

[15]  O. Puciłowski,et al.  Chronic mild stress-induced anhedonia: Greater effect in a genetic rat model of depression , 1993, Physiology & Behavior.

[16]  A. Zangen,et al.  Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis , 2009, Molecular Psychiatry.

[17]  S. Christiansen,et al.  Candidate Hippocampal Biomarkers of Susceptibility and Resilience to Stress in a Rat Model of Depression* , 2012, Molecular & Cellular Proteomics.

[18]  Y. Temel,et al.  Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms , 2015, Translational Psychiatry.

[19]  De-xiang Liu,et al.  Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress , 2014, Behavioural Brain Research.

[20]  K. Hashimoto,et al.  Long-Lasting Antidepressant Action of Ketamine, but Not Glycogen Synthase Kinase-3 Inhibitor SB216763, in the Chronic Mild Stress Model of Mice , 2013, PloS one.

[21]  F. S. Bersani,et al.  l-Acetylcarnitine in dysthymic disorder in elderly patients: A double-blind, multicenter, controlled randomized study vs. fluoxetine , 2013, European Neuropsychopharmacology.

[22]  F. Walker,et al.  Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. , 2012, Cerebral cortex.

[23]  M. Papp,et al.  S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. , 2001, The Journal of pharmacology and experimental therapeutics.

[24]  G. Réus,et al.  Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[25]  Responding for brain stimulation: Stress and desmethylimipramine , 1984, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[26]  O. Almeida,et al.  Sustained remission from depressive-like behavior depends on hippocampal neurogenesis , 2013, Translational Psychiatry.

[27]  J. Bizot,et al.  Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress , 2004, Behavioural Brain Research.

[28]  J. Herman,et al.  Neural Regulation of the Stress Response: The Many Faces of Feedback , 2012, Cellular and molecular neurobiology.

[29]  F. Holsboer,et al.  Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. , 2000, Journal of psychiatric research.

[30]  M. Papp,et al.  The effect of MK-801 and imipramine on beta-adrenergic and 5-HT2 receptors in the chronic mild stress model of depression in rats. , 1994, Polish journal of pharmacology.

[31]  S. Totterdell,et al.  Hippocampal and prefrontal cortical inputs monosynaptically converge with individual projection neurons of the nucleus accumbens , 2002, The Journal of comparative neurology.

[32]  Ling Liu,et al.  Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: the role of the endocannabinoid system. , 2014, Journal of psychiatric research.

[33]  R. Hen,et al.  Neurogenesis and affective disorders , 2011, The European journal of neuroscience.

[34]  Michael Marriott,et al.  Lower hippocampal volume in patients suffering from depression: a meta-analysis. , 2004, The American journal of psychiatry.

[35]  P. Willner,et al.  Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole , 1994, Psychopharmacology.

[36]  T. Strekalova,et al.  Measuring behavior in mice with chronic stress depression paradigm , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[37]  A. Grace,et al.  Amygdala-Ventral Pallidum Pathway Decreases Dopamine Activity After Chronic Mild Stress in Rats , 2014, Biological Psychiatry.

[38]  J. Herman,et al.  Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis. , 1996, Critical reviews in neurobiology.

[39]  A. Young,et al.  Antiglucocorticoid treatments for mood disorders. , 2015, The Cochrane database of systematic reviews.

[40]  N. Sousa,et al.  An Efficient Chronic Unpredictable Stress Protocol to Induce Stress-Related Responses in C57BL/6 Mice , 2015, Front. Psychiatry.

[41]  G. Chiara,et al.  Chronic desipramine and fluoxetine differentially affect extracellular dopamine in the rat prefrontal cortex , 1996, Psychopharmacology.

[42]  M. Papp,et al.  Changes in dopamine receptor mRNA expression following chronic mild stress and chronic antidepressant treatment , 1997, Behavioural pharmacology.

[43]  C. Nemeroff,et al.  Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal , 2011, Neuropsychopharmacology.

[44]  H. Manji,et al.  New insights into BDNF function in depression and anxiety , 2007, Nature Neuroscience.

[45]  Xin-Min Li,et al.  Unpredictable chronic mild stress not chronic restraint stress induces depressive behaviours in mice , 2014, Neuroreport.

[46]  R. Hen,et al.  Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants , 2003, Science.

[47]  Nanxin Li,et al.  mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists , 2010, Science.

[48]  J. Duan,et al.  Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice , 2015, Scientific Reports.

[49]  B. Carroll,et al.  Acute and chronic stress effects on open field activity in the rat: Implications for a model of depression , 1981, Neuroscience & Biobehavioral Reviews.

[50]  G. Uhl,et al.  Functional Expression of Brain Neuronal CB2 Cannabinoid Receptors Are Involved in the Effects of Drugs of Abuse and in Depression , 2008, Annals of the New York Academy of Sciences.

[51]  P. Willner,et al.  Changes in sleep architecture following chronic mild stress , 1997, Biological Psychiatry.

[52]  S. Genedani,et al.  Influence of S‐adenosyl‐L‐methionine on chronic mild stress‐induced anhedonia in castrated rats , 1999, British journal of pharmacology.

[53]  M. Papp,et al.  Effect of Agomelatine in the Chronic Mild Stress Model of Depression in the Rat , 2003, Neuropsychopharmacology.

[54]  M. Barrot,et al.  Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy , 2008, Biological Psychiatry.

[55]  C. Sandi,et al.  Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity , 2012, Psychoneuroendocrinology.

[56]  K. Roth,et al.  Amphetamine and tranylcypromine in an animal model of depression: Pharmacological specificity of the reversal effect , 1981, Neuroscience & Biobehavioral Reviews.

[57]  Xin-ming Ma,et al.  Dendritic Spines in Depression: What We Learned from Animal Models , 2016, Neural plasticity.

[58]  M. Hofman,et al.  Increased expression level of corticotropin-releasing hormone in the amygdala and in the hypothalamus in rats exposed to chronic unpredictable mild stress , 2010, Neuroscience Bulletin.

[59]  J. E. Steiner,et al.  Taste and Odor: Reactivity in Depressive Disorders, a Multidisciplinary Approach , 1993, Perceptual and motor skills.

[60]  O. Valverde,et al.  CB1 receptor-deficient mice as a model for depression , 2012, Neuroscience.

[61]  P. Willner.  Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation , 1997, Psychopharmacology.

[62]  JaneR . Taylor,et al.  Chronic Unpredictable Stress Decreases Cell Proliferation in the Cerebral Cortex of the Adult Rat , 2007, Biological Psychiatry.

[63]  I. Goshen,et al.  Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression , 2008, Molecular Psychiatry.

[64]  A. Goel,et al.  Efficacy and Safety of Curcumin in Major Depressive Disorder: A Randomized Controlled Trial , 2014, Phytotherapy research : PTR.

[65]  B. Gorzalka,et al.  Neurobiology of chronic mild stress: Parallels to major depression , 2012, Neuroscience & Biobehavioral Reviews.

[66]  M. Papp,et al.  Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. , 1994, European journal of pharmacology.

[67]  A. Mørk,et al.  Stress sensitivity and resilience in the chronic mild stress rat model of depression; an in situ hybridization study , 2008, Brain Research.

[68]  M. Farina,et al.  Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. , 2012, Journal of psychiatric research.

[69]  R. Gallop,et al.  Unipolar depression does not moderate responses to the Sweet Taste Test , 2010, Depression and anxiety.

[70]  Pharmacological validation of the chronic mild stress model of depression , 2001, European Neuropsychopharmacology.

[71]  R. Hen,et al.  Drug-Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal , 2008, Biological Psychiatry.

[72]  M. Papp,et al.  Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression , 2017, Behavioural pharmacology.

[73]  R. Hen,et al.  Antidepressants recruit new neurons to improve stress response regulation , 2011, Molecular Psychiatry.

[74]  B. McEwen,et al.  Chronic Psychosocial Stress Causes Apical Dendritic Atrophy of Hippocampal CA3 Pyramidal Neurons in Subordinate Tree Shrews , 1996, The Journal of Neuroscience.

[75]  M. Banasr,et al.  Glial Loss in the Prefrontal Cortex Is Sufficient to Induce Depressive-like Behaviors , 2008, Biological Psychiatry.

[76]  D. Bartsch,et al.  Stress-Induced Anhedonia in Mice is Associated with Deficits in Forced Swimming and Exploration , 2004, Neuropsychopharmacology.

[77]  S. Preskorn,et al.  Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. , 2015, Journal of psychiatric practice.

[78]  Chronic deep brain stimulation of the medial forebrain bundle reverses depressive-like behavior in a hemiparkinsonian rodent model , 2015, Experimental Brain Research.

[79]  M. Joëls,et al.  Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress , 2007, The European journal of neuroscience.

[80]  H. Steinbusch,et al.  Update in the methodology of the chronic stress paradigm: internal control matters , 2011, Behavioral and Brain Functions.

[81]  K. Laws,et al.  The use of ketamine as an antidepressant: a systematic review and meta‐analysis , 2015, Human psychopharmacology.

[82]  Hai-shui Shi,et al.  Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. , 2013, Journal of psychiatry & neuroscience : JPN.

[83]  Y. Omidi,et al.  Asymmetrical expression of BDNF and NTRK3 genes in frontoparietal cortex of stress‐resilient rats in an animal model of depression , 2014, Synapse.

[84]  D. F. Drake,et al.  A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. , 2013, JAMA psychiatry.

[85]  C. Hommet,et al.  Long-term odor recognition memory in unipolar major depression and Alzheimer׳s disease , 2014, Psychiatry Research.

[86]  G. Aghajanian,et al.  Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. , 1990, Archives of general psychiatry.

[87]  Jiang-Ning Zhou,et al.  Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression , 2007, Neuropsychopharmacology.

[88]  E. Nestler,et al.  Behavioral / Systems / Cognitive Extracellular Signal-Regulated Kinase-2 within the Ventral Tegmental Area Regulates Responses to Stress , 2010 .

[89]  R. Depoortère,et al.  Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic , 2005, Neuropsychopharmacology.

[90]  J. Herman,et al.  Neural regulation of endocrine and autonomic stress responses , 2009, Nature Reviews Neuroscience.

[91]  Christophe D. Proulx,et al.  Reward processing by the lateral habenula in normal and depressive behaviors , 2014, Nature Neuroscience.

[92]  B. McEwen,et al.  Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling , 2010, Annals of the New York Academy of Sciences.

[93]  O. Wiborg,et al.  Biomarkers of anhedonic-like behavior, antidepressant drug refraction, and stress resilience in a rat model of depression , 2011, Neuroscience.

[94]  Hui-ling Wang,et al.  Differential expression of hippocampal EphA4 and ephrinA3 in anhedonic-like behavior, stress resilience, and antidepressant drug treatment after chronic unpredicted mild stress , 2014, Neuroscience Letters.

[95]  A. Fernández-Guasti,et al.  Estradiol valerate elicits antidepressant-like effects in middle-aged female rats under chronic mild stress , 2010, Behavioural pharmacology.

[96]  J. Kulkarni,et al.  Oestrogen: an overlooked mediator in the neuropsychopharmacology of treatment response? , 2011, The international journal of neuropsychopharmacology.

[97]  C. Belzung,et al.  The design of new antidepressants: can formal models help? A first attempt using a model of the hippocampal control over the HPA-axis based on a review from the literature , 2010, Behavioural pharmacology.

[98]  L. Lanfumey,et al.  Hippocampal and behavioral dysfunctions in a mouse model of environmental stress: normalization by agomelatine , 2014, Translational Psychiatry.

[99]  N. Chen,et al.  Effects of chronic mild stress on behavioral and neurobiological parameters — Role of glucocorticoid , 2016, Hormones and Behavior.

[100]  John H Krystal,et al.  Antidepressant effects of ketamine in depressed patients , 2000, Biological Psychiatry.

[101]  Aaron S. Andalman,et al.  Dopamine neurons modulate neural encoding and expression of depression-related behaviour , 2012, Nature.

[102]  V. Sturm,et al.  Long-Term Effects of Nucleus Accumbens Deep Brain Stimulation in Treatment-Resistant Depression: Evidence for Sustained Efficacy , 2012, Neuropsychopharmacology.

[103]  W. Haefely,et al.  Effects of Moclobemide, a New Generation Reversible Mao-A Inhibitor, in a Novel Animal Model of Depression , 1993, Pharmacopsychiatry.

[104]  M. Barrot,et al.  Essential role of brain-derived neurotrophic factor in adult hippocampal function. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[105]  S. Thompson,et al.  Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. , 2015, Journal of neurophysiology.

[106]  R. Sapolsky,et al.  The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. , 1991, Endocrine reviews.

[107]  M. Papp,et al.  Antidepressant, anxiolytic and procognitive effects of rivastigmine and donepezil in the chronic mild stress model in rats , 2016, Psychopharmacology.

[108]  C. Bell.  DSM-IV: Diagnostic and Statistical Manual of Mental Disorders , 1994 .

[109]  S. Maier,et al.  Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis , 2014, Molecular Psychiatry.

[110]  E. Castrén,et al.  Activation of the TrkB Neurotrophin Receptor Is Induced by Antidepressant Drugs and Is Required for Antidepressant-Induced Behavioral Effects , 2003, The Journal of Neuroscience.

[111]  G. Griebel,et al.  Deep brain stimulation in treatment-resistant depression in mice: Comparison with the CRF1 antagonist, SSR125543 , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[112]  P. Stanton,et al.  Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: Characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats , 2015, Behavioural Brain Research.

[113]  G. Hu,et al.  Requirement of AQP4 for Antidepressive Efficiency of Fluoxetine: Implication in Adult Hippocampal Neurogenesis , 2009, Neuropsychopharmacology.

[114]  J. Harro,et al.  Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1 , 2009, Biological Psychiatry.

[115]  J. Manzanares,et al.  Depression‐resistant endophenotype in mice overexpressing cannabinoid CB2 receptors , 2010, British journal of pharmacology.

[116]  G. Drolet,et al.  Enkephalin Knockdown in the Basolateral Amygdala Reproduces Vulnerable Anxiety-Like Responses to Chronic Unpredictable Stress , 2014, Neuropsychopharmacology.

[117]  D. Luckenbaugh,et al.  A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. , 2010, Archives of general psychiatry.

[118]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[119]  N. Sousa,et al.  The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition , 2014, Journal of psychopharmacology.

[120]  Li-Tao Yi,et al.  Hippocampal BDNF signaling restored with chronic asiaticoside treatment in depression-like mice , 2015, Brain Research Bulletin.

[121]  S. Thompson,et al.  Chronic Stress Induces a Selective Decrease in AMPA Receptor-Mediated Synaptic Excitation at Hippocampal Temporoammonic-CA1 Synapses , 2013, The Journal of Neuroscience.

[122]  F. Gil-Bea,et al.  Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment , 2008, Psychopharmacology.

[123]  M. Lapiz-Bluhm,et al.  5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats. , 2012, The international journal of neuropsychopharmacology.

[124]  Zhen Yan,et al.  Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C‐dependent mechanism in pyramidal neurones of rat prefrontal cortex , 2004, The Journal of physiology.

[125]  P. Willner,et al.  Suppression of sucrose drinking by chronic mild unpredictable stress: A methodological analysis , 1992, Neuroscience & Biobehavioral Reviews.

[126]  C. Belzung,et al.  Correlations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: evidence from inbred strains of mice , 2005, Behavioural Brain Research.

[127]  Ding-ping Wu,et al.  BDNF signaling is necessary for the antidepressant-like effect of naringenin , 2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[128]  W. Haefely,et al.  Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats , 1992, European Neuropsychopharmacology.

[129]  Richard Muscat,et al.  An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress , 2005, Psychopharmacology.

[130]  Clement Hamani,et al.  Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Role of Serotonin and Brain Derived Neurotrophic Factor , 2012, Biological Psychiatry.

[131]  J. Schulkin,et al.  Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus? , 2009, Depression and anxiety.

[132]  O. Hikosaka.  The habenula: from stress evasion to value-based decision-making , 2010, Nature Reviews Neuroscience.

[133]  R. Salomon,et al.  Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. , 1996, Archives of general psychiatry.

[134]  D. Morilak,et al.  Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by α1-adrenergic receptors in medial prefrontal cortex , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[135]  C. Belzung,et al.  Deficit in BDNF does not increase vulnerability to stress but dampens antidepressant-like effects in the unpredictable chronic mild stress , 2009, Behavioural Brain Research.

[136]  R. Duman,et al.  Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[137]  J. Herman,et al.  Limbic Regulation of Hypothalamo‐Pituitary‐Adrenocortical Function during Acute and Chronic Stress , 2008, Annals of the New York Academy of Sciences.

[138]  S. Totterdell,et al.  Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats , 2003, Neuroscience.

[139]  S. Lakhan,et al.  Efficacy of vitamin C as an adjunct to fluoxetine therapy in pediatric major depressive disorder: a randomized, double-blind, placebo-controlled pilot study , 2013, Nutrition Journal.

[140]  P. Willner.  Reliability of the chronic mild stress model of depression: A user survey , 2016, Neurobiology of Stress.

[141]  R. Salomon,et al.  Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action , 1999, Biological Psychiatry.

[142]  C. Otte,et al.  Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor , 2016, Journal of neuroendocrinology.

[143]  C. Belzung,et al.  Behaviour in the elevated plus-maze predicts coping after subchronic mild stress in mice , 2004, Physiology & Behavior.

[144]  C. Beevers,et al.  Neural mechanisms of the cognitive model of depression , 2011, Nature Reviews Neuroscience.

[145]  R. J. Katz,et al.  Amitriptyline and scopolamine in an animal model of depression , 1981, Neuroscience and Biobehavioral Reviews.

[146]  Connie Sanchez,et al.  Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. , 2001 .

[147]  R. Salomon,et al.  Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants. , 1993, Psychopharmacology bulletin.

[148]  Guojun Liu,et al.  Stress-induced anhedonia correlates with lower hippocampal serotonin transporter protein expression , 2013, Brain Research.

[149]  Rafael Delgado y Palacios,et al.  Diffusion Kurtosis Imaging and High-Resolution MRI Demonstrate Structural Aberrations of Caudate Putamen and Amygdala after Chronic Mild Stress , 2014, PloS one.

[150]  B. Gorzalka,et al.  Putative role of endocannabinoid signaling in the etiology of depression and actions of antidepressants , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[151]  P. Licznerski,et al.  Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression , 2013, Neuroscience.

[152]  M. Papp,et al.  Attenuation of place preference conditioning but not place aversion conditioning by chronic mild stress , 1992, Journal of psychopharmacology.

[153]  Hai-ling Yu,et al.  Antidepressant-like effects of oleoylethanolamide in a mouse model of chronic unpredictable mild stress , 2015, Pharmacology Biochemistry and Behavior.

[154]  J. Seckl,et al.  Overexpression of Mineralocorticoid Receptors Partially Prevents Chronic Stress-Induced Reductions in Hippocampal Memory and Structural Plasticity , 2015, PloS one.

[155]  W. Löscher,et al.  Behavioral differences of male Wistar rats from different vendors in vulnerability and resilience to chronic mild stress are reflected in epigenetic regulation and expression of p11 , 2016, Brain Research.

[156]  K. Manda,et al.  Melatonin ameliorates chronic mild stress induced behavioral dysfunctions in mice , 2013, Physiology & Behavior.

[157]  G. Griebel,et al.  Effects of the selective nonpeptide corticotropin-releasing factor receptor 1 antagonist antalarmin in the chronic mild stress model of depression in mice , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[158]  P. Willner,et al.  Effects of chronic mild stress on performance in behavioural tests relevant to anxiety and depression , 1994, Physiology & Behavior.

[159]  P. Willner,et al.  Reversal of antidepressant action by dopamine antagonists in an animal model of depression , 2005, Psychopharmacology.

[160]  A. Grace,et al.  Cortico-Basal Ganglia Reward Network: Microcircuitry , 2010, Neuropsychopharmacology.

[161]  M. Papp,et al.  Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine , 1994, Psychopharmacology.

[162]  C. Belzung,et al.  n-3 Polyunsaturated fatty acid supplementation reverses stress-induced modifications on brain monoamine levels in mice Published, JLR Papers in Press, November 8, 2007. , 2008, Journal of Lipid Research.

[163]  M. West,et al.  The number of granule cells in rat hippocampus is reduced after chronic mild stress and re-established after chronic escitalopram treatment , 2008, Neuropharmacology.

[164]  L. Luo,et al.  Fluoxetine inhibits dendrite atrophy of hippocampal neurons by decreasing nitric oxide synthase expression in rat depression model. , 2001, Acta pharmacologica Sinica.

[165]  R. Duman,et al.  A Neurotrophic Model for Stress-Related Mood Disorders , 2006, Biological Psychiatry.

[166]  A. Eisch,et al.  The neurogenesis hypothesis of affective and anxiety disorders: Are we mistaking the scaffolding for the building? , 2012, Neuropharmacology.

[167]  Richard Muscat,et al.  Chronic mild stress-induced anhedonia: A realistic animal model of depression , 1992, Neuroscience & Biobehavioral Reviews.

[168]  H. Gong,et al.  Antidepressant-like effect of n-3 PUFAs in CUMS rats: role of tPA/PAI-1 system , 2015, Physiology & Behavior.

[169]  Wang Min-wei,et al.  Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress , 2006, Pharmacology Biochemistry and Behavior.

[170]  P. Houck,et al.  Pramipexole in treatment-resistant depression: a 16-week naturalistic study. , 2002, Bipolar disorders.

[171]  B. Cubelos,et al.  Localization of the GLYT1 glycine transporter at glutamatergic synapses in the rat brain. , 2005, Cerebral cortex.

[172]  P. Willner,et al.  Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant , 2004, Psychopharmacology.

[173]  J. Mazziotta,et al.  Cerebral correlates of depressed behavior in rats, visualized using 14C- 2-deoxyglucose autoradiography , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[174]  M. Papp,et al.  Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention. , 2016, Pharmacological research.

[175]  J. Herbert,et al.  The corticoid environment: a determining factor for neural progenitors' survival in the adult hippocampus , 2004, The European journal of neuroscience.

[176]  Jianguo Dai,et al.  Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice , 2012, Behavioural Brain Research.

[177]  K. Hasan,et al.  The medial forebrain bundle as a deep brain stimulation target for treatment resistant depression: A review of published data , 2015, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[178]  K. Behar,et al.  Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole , 2010, Molecular Psychiatry.

[179]  P. Willner,et al.  Dopaminergic mechanism of antidepressant action in depressed patients. , 2005, Journal of affective disorders.

[180]  Clement Hamani,et al.  The Subcallosal Cingulate Gyrus in the Context of Major Depression , 2011, Biological Psychiatry.

[181]  C. Belzung,et al.  State and Trait Olfactory Markers of Major Depression , 2012, PloS one.

[182]  R. Duman,et al.  VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants , 2007, Proceedings of the National Academy of Sciences.

[183]  K. Matthews,et al.  Sucrose consumption as an hedonic measure following chronic unpredictable mild stress , 1995, Physiology & Behavior.

[184]  A. Zangen,et al.  Resilience to Chronic Stress Is Mediated by Hippocampal Brain-Derived Neurotrophic Factor , 2011, The Journal of Neuroscience.

[185]  R. Costa,et al.  Chronic Stress Causes Frontostriatal Reorganization and Affects Decision-Making , 2009, Science.

[186]  M. West,et al.  A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression , 2010, Stress.

[187]  P. Licznerski,et al.  Antidepressant Effects of Fibroblast Growth Factor-2 in Behavioral and Cellular Models of Depression , 2012, Biological Psychiatry.

[188]  M. Papp,et al.  Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. , 2001, Pharmacology & toxicology.

[189]  Peter Kirsch,et al.  Remission of Major Depression Under Deep Brain Stimulation of the Lateral Habenula in a Therapy-Refractory Patient , 2010, Biological Psychiatry.

[190]  E. Klann,et al.  mTOR signaling: At the crossroads of plasticity, memory and disease , 2010, Trends in Neurosciences.

[191]  M. Cuadrado-Tejedor,et al.  Chronic mild stress in mice promotes cognitive impairment and CDK5-dependent tau hyperphosphorylation , 2011, Behavioural Brain Research.

[192]  P. Willner,et al.  Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer , 1994, Psychopharmacology.

[193]  M. Papp,et al.  Decreased hedonic responsiveness following chronic mild stress is not secondary to loss of body weight , 1996, Physiology & Behavior.

[194]  N. Sousa,et al.  The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling , 2009, Molecular Psychiatry.

[195]  P. Xie,et al.  iTRAQ-based quantitative analysis of hippocampal postsynaptic density-associated proteins in a rat chronic mild stress model of depression , 2015, Neuroscience.

[196]  B. McEwen,et al.  Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[197]  Mesolimbic dopamine D2 receptor plasticity contributes to stress resilience in rats subjected to chronic mild stress , 2013, Psychopharmacology.

[198]  O. Wiborg,et al.  Presynaptic Plasticity as a Hallmark of Rat Stress Susceptibility and Antidepressant Response , 2015, PloS one.

[199]  J. Chae,et al.  Chronic repetitive transcranial magnetic stimulation enhances GABAergic and cholinergic metabolism in chronic unpredictable mild stress rat model: 1H-NMR spectroscopy study at 11.7T , 2014, Neuroscience Letters.

[200]  H. Ríos,et al.  Stress induced cognitive deficit is differentially modulated in BALB/c and C57Bl/6 mice Correlation with Th1/Th2 balance after stress exposure , 2010, Journal of Neuroimmunology.

[201]  N. Kalin,et al.  The mediating role of hippocampal networks on stress regulation in amnestic mild cognitive impairment , 2019, Neurobiology of Stress.

[202]  L. Kriston,et al.  EFFICACY AND ACCEPTABILITY OF ACUTE TREATMENTS FOR PERSISTENT DEPRESSIVE DISORDER: A NETWORK META‐ANALYSIS , 2014, Depression and anxiety.

[203]  C. Novak,et al.  Interaction of metabolic stress with chronic mild stress in altering brain cytokines and sucrose preference. , 2015, Behavioral neuroscience.

[204]  Chenggang Huang,et al.  Burst‐firing patterns in the prefrontal cortex underlying the neuronal mechanisms of depression probed by antidepressants , 2014, The European journal of neuroscience.

[205]  M. Jensen,et al.  Cognitive deficits in the rat chronic mild stress model for depression: Relation to anhedonic-like responses , 2009, Behavioural Brain Research.

[206]  P. Willner,et al.  Dopaminergic mechanism of imipramine action in an animal model of depression , 1990, Biological Psychiatry.

[207]  Nanxin Li,et al.  Signaling pathways underlying the rapid antidepressant actions of ketamine , 2012, Neuropharmacology.

[208]  P. Willner,et al.  Attenuation of sucrose consumption in mice by chronic mild stress and its restoration by imipramine , 1995, Psychopharmacology.

[209]  C. Belzung,et al.  Susceptibility to subchronic unpredictable stress is related to individual reactivity to threat stimuli in mice , 2004, Behavioural Brain Research.

[210]  S. Varma.  Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies , 2014, BMJ : British Medical Journal.

[211]  R. Katz,et al.  Animal model of depression: Pharmacological sensitivity of a hedonic deficit , 1982, Pharmacology Biochemistry and Behavior.

[212]  Enrico Smeraldi,et al.  Transcranial magnetic stimulation in treatment-resistant depressed patients: A double-blind, placebo-controlled trial , 2005, Psychiatry Research.

[213]  O. Wiborg.  Chronic mild stress for modeling anhedonia , 2013, Cell and Tissue Research.

[214]  JaneR . Taylor,et al.  Recapitulation and Reversal of a Persistent Depression‐like Syndrome in Rodents , 2009, Current protocols in neuroscience.

[215]  P. Willner,et al.  Resistance to antidepressant drugs: the case for a more predisposition-based and less hippocampocentric research paradigm , 2014, Behavioural pharmacology.

[216]  K. Matthews,et al.  Chronic Mild Stress and Sucrose Consumption: Validity as a Model of Depression , 1996, Physiology & Behavior.

[217]  M. Huang,et al.  Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression , 2011, Brain Research.

[218]  G. Forster,et al.  The Role of the Amygdala in Anxiety Disorders , 2012 .

[219]  M. Banasr,et al.  Vascular Endothelial Growth Factor Signaling is Required for the Behavioral Actions of Antidepressant Treatment: Pharmacological and Cellular Characterization , 2009, Neuropsychopharmacology.

[220]  S. Ip,et al.  Brain-derived neurotrophic factor signalling mediates the antidepressant-like effect of piperine in chronically stressed mice , 2014, Behavioural Brain Research.

[221]  H. Mayberg.  Targeted electrode-based modulation of neural circuits for depression. , 2009, The Journal of clinical investigation.

[222]  M. Fava,et al.  Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. , 2018, Focus.

[223]  M. Thakur,et al.  Correlation of ERα/ERβ expression with dendritic and behavioural changes in CUMS mice , 2015, Physiology & Behavior.

[224]  James P. Herman,et al.  Limbic system mechanisms of stress regulation: Hypothalamo-pituitary-adrenocortical axis , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[225]  F. Gage,et al.  An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. , 2012, Journal of Psychiatric Research.

[226]  B. Ravnkilde,et al.  Hippocampal volume and depression: a meta-analysis of MRI studies. , 2004, The American journal of psychiatry.

[227]  P. Willner,et al.  The neurobiology of depression and antidepressant action , 2013, Neuroscience & Biobehavioral Reviews.

[228]  G. Aghajanian,et al.  Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: Role of corticosterone-mediated apical dendritic atrophy , 2008, Proceedings of the National Academy of Sciences.

[229]  B. Giros,et al.  Increased expression of the Vesicular Glutamate Transporter-1 (VGLUT1) in the prefrontal cortex correlates with differential vulnerability to chronic stress in various mouse strains: Effects of fluoxetine and MK-801 , 2012, Neuropharmacology.

[230]  Nanxin Li,et al.  Brain-derived neurotrophic factor signalling mediates antidepressant effects of lamotrigine. , 2011, The international journal of neuropsychopharmacology.

[231]  Jaime S. Ide,et al.  Human Neuroscience , 2022 .

[232]  J. Stamford,et al.  Voltammetric evidence that subsensitivity to reward following chronic mild stress is associated with increased release of mesolimbic dopamine , 2005, Psychopharmacology.

[233]  Yonggui Yuan,et al.  Changed Synaptic Plasticity in Neural Circuits of Depressive-Like and Escitalopram-Treated Rats , 2015, The international journal of neuropsychopharmacology.

[234]  H. Steinbusch,et al.  Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia , 2013, Brain, Behavior, and Immunity.

[235]  G. Chiara,et al.  Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression , 1999, Biological Psychiatry.

[236]  P. Sawchenko,et al.  Evidence for involvement of a limbic paraventricular hypothalamic inhibitory network in hypothalamic‐pituitary‐adrenal axis adaptations to repeated stress , 2015, The Journal of comparative neurology.

[237]  J. Enghild,et al.  Proteomic Investigation of the Ventral Rat Hippocampus Links DRP-2 to Escitalopram Treatment Resistance and SNAP to Stress Resilience in the Chronic Mild Stress Model of Depression , 2007, Journal of Molecular Neuroscience.

[238]  P. Canonico,et al.  Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats. , 2007, The international journal of neuropsychopharmacology.

[239]  M. Papp,et al.  Antidepressant-like activity of amisulpride in two animal models of depression , 2000, Journal of psychopharmacology.

[240]  M. Papp,et al.  Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline , 2005, Psychopharmacology.

[241]  H. Anisman,et al.  Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes , 1983, Behavioural Brain Research.

[242]  B. Giros,et al.  Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling , 2014, Molecular Psychiatry.

[243]  F. Nicoletti,et al.  L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors , 2013, Proceedings of the National Academy of Sciences.

[244]  H. Akil,et al.  Novelty-seeking behavior predicts vulnerability in a rodent model of depression , 2011, Physiology & Behavior.

[245]  P. Willner,et al.  Treatment-resistant depression: are animal models of depression fit for purpose? , 2015, Psychopharmacology.

[246]  Q. Tan,et al.  Long-lasting effects of chronic rTMS to treat chronic rodent model of depression , 2012, Behavioural Brain Research.

[247]  R. Murison,et al.  Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper , 2006, Pharmacology Biochemistry and Behavior.