Review
Stress, depression and Parkinson's disease

https://doi.org/10.1016/j.expneurol.2011.09.035Get rights and content

Abstract

In this review, we focus on the relationship among Parkinson's disease (PD), stress and depression. Parkinson's disease patients have a high risk of developing depression, and it is possible that stress contributes to the development of both pathologies. Stress dysfunction may have a role in the etiology of preclinical non-motor symptoms of PD (such as depression) and, later in the course of the disease, may worsen motor symptoms. However, relatively few studies have examined stress or depression and the injured nigrostriatal system. This review discusses the effects of stress on neurodegeneration and depression, and their association with the symptoms and progression of PD.

Highlights

► Stress system dysfunction influences depression pathophysiology. ► Parkinson's disease and depression have a high rate of comorbidity. ► Depression and motor symptoms in Parkinson's disease may be affected by stress. ► Development of new animal model to examine stress effects on injured dopamine cells.

Introduction

For many years, studies of neuropsychiatric disorders have indicated that stress abnormalities are likely involved in the disease pathogenesis. More recently, it has also become apparent that dysfunction of the stress response may have a role in neurodegenerative disorders. Stress dysfunction is particularly intriguing when one considers the very high rate of neuropsychiatric comorbidities in patients with neurodegenerative diseases. For decades, studies have implicated the hypothalamic pituitary adrenal (HPA) axis in a variety of progressive neurodegenerative diseases including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease (PD) (Heuser et al., 1991, Patacchioli et al., 2003, Snyder et al., 1985, Swaab et al., 2005). However, the psychiatric aspect of the disease pathology and the role stress may play in the disease process are relatively understudied. For the purpose of this review, we will focus on PD, the high occurrence of depression in the disease, and the function of the stress response in the development of both PD and depression.

Section snippets

Neurobiological aspects of stress and depression

Appropriate responses to external or internal adversity (i.e., the ‘stress response’) are critical for adaptation and survival. The stress response involves the activation of multiple bodily systems, the most prominent of which are the HPA axis and autonomic nervous system. Activation of the HPA axis creates a neuroendocrine cascade that results in the elevation of glucocorticoid levels. Glucocorticoids (cortisol in humans and primarily corticosterone in rats and mice) subserve important

Stress and dopamine neurons

In some suicide victims, dopamine levels are elevated in the hypothalamus (Arranz et al., 1997). After receiving the dopamine receptor agonist apomorphine, patients with both depression and elevated cortisol levels exhibit a blunted cortisol response, suggesting cortisol feedback deficits may be associated with dopamine receptor dysfunction in the hypothalamus (Duval et al., 2006). The normal physiology of dopamine in the mesolimbic and mesocortical systems is also disrupted by stress (Pani et

Parkinson's disease and depression

Parkinson's disease is a progressive neurodegenerative disorder that affects about 1% of individuals over the age of 65 and is characterized by severe loss of dopaminergic neurons in the nigrostriatal pathway, resulting in motor dysfunction (Weintraub et al., 2008a). The exact etiology of PD is currently unknown, but the greatest risk factor for the disease is aging. While the cardinal motor symptoms of resting tremor, bradykinesia, postural instability and rigidity are the most identifiable

Parkinson's disease and stress

Stress may play a role in the development of PD. The principle risk factor for PD is aging, which may also be associated with elevated levels of cortisol (Gould and Tanapat, 1999). Cortisol is also elevated in PD patients compared to healthy age-matched controls (Charlett et al., 1998). Acute treatment with levodopa can reduce plasma cortisol levels in PD patients (Müller et al., 2007), suggesting a connection between dopamine hypofunction and HPA axis hyperactivity. Stressful life events may

A combined depression/PD animal model

In our own studies, we have developed an animal paradigm that combines the striatal 6-OHDA lesion model of PD with the CVS-induced model of depression. With this model we are able to examine the combined effects that chronic stress and relatively progressive dopaminergic neuron loss can have on motor symptoms and nigral cell degeneration. We have observed that CVS worsens motor symptoms and increases neurodegeneration of dopaminergic neurons in the SNpc (Hemmerle et al., 2008, Hemmerle et al.,

Conclusion

Dysfunction of the HPA axis is well tied to depression symptomatology and plays a part in neuropsychiatric disorder development. What is not known at this juncture is the exact role stress and affective disorders may play in the development of neurodegenerative disorders such as PD. In humans, motor symptoms appear only after 70–80% of striatal dopaminergic content is lost, likely due to compensatory mechanisms in the remaining neurons. Pre-clinically, there may be manifestations of non-motor

Acknowledgments

The work was supported by NIH grant NS060114, Udall Parkinson's Disease Centers of Excellence grant NS058830, and by grants from the Sunflower Revolution/University of Cincinnati Neuroscience Institute, the Gardner Family Center for Parkinson's Disease and Movement Disorders, and the Parkinson's Disease Support Network of Ohio, Kentucky and Indiana. AMH was supported by the Morris Braun Foundation and a University Research Council Fellowship.

References (156)

  • F. Duval et al.

    Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates

    Psychoneuroendocrinology

    (2006)
  • E. Fuchs et al.

    Stress, glucocorticoids and structural plasticity of the hippocampus

    Neurosci. Biobehav. Rev.

    (1998)
  • F.B. Gibberd et al.

    Neurological disease in ex-Far-East prisoners of war

    Lancet

    (1980)
  • E. Gould et al.

    Stress and hippocampal neurogenesis

    Biol. Psychiatry

    (1999)
  • A.J. Grippo et al.

    Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia

    Physiol. Behav.

    (2005)
  • J.P. Herman et al.

    Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis

    Trends Neurosci.

    (1997)
  • I.J. Heuser et al.

    The limbic-hypothalamic-pituitary-adrenal axis in Huntington's disease

    Biol. Psychiatry

    (1991)
  • F.M. Howells et al.

    Stress reduces the neuroprotective effect of exercise in a rat model for Parkinson's disease

    Behav. Brain Res.

    (2005)
  • A. Imperato et al.

    Stress activation of limbic and cortical dopamine release is prevented by ICS 205–930 but not by diazepam

    Eur. J. Pharmacol.

    (1990)
  • A.M. Kanner

    Is major depression a neurologic disorder with psychiatric symptoms?

    Epilepsy Behav.

    (2004)
  • R.J. Katz et al.

    Acute and chronic stress effects on open field activity in the rat: implications for a model of depression

    Neurosci. Biobehav. Rev.

    (1981)
  • K.A. Keefe et al.

    Environmental stress increases extracellular dopamine in striatum of 6-hydroxydopamine-treated rats: in vivo microdialysis studies

    Brain Res.

    (1990)
  • A. Kibel et al.

    Impact of glucocorticoids and chronic stress on progression of Parkinson's disease

    Med. Hypotheses

    (2008)
  • M. Kubera et al.

    In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2011)
  • P.W. Landfield et al.

    Increased affinity of type II corticosteroid binding in aged rat hippocampus

    Exp. Neurol.

    (1989)
  • G. Lucca et al.

    Effects of chronic mild stress on the oxidative parameters in the rat brain

    Neurochem. Int.

    (2009)
  • G. Lucca et al.

    Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm

    J. Psychiatr. Res.

    (2009)
  • M.V. Mabandla et al.

    Voluntary exercise reduces the neurotoxic effects of 6-hydroxydopamine in maternally separated rats

    Behav. Brain Res.

    (2010)
  • M. Macht et al.

    Stress affects hedonic responses but not reaching-grasping in Parkinson's disease

    Behav. Brain Res.

    (2007)
  • A.M. Magariños et al.

    Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors

    Neuroscience

    (1995)
  • A.M. Magariños et al.

    Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors

    Neuroscience

    (1995)
  • K. Matthews et al.

    Early experience as a determinant of adult behavioural responses to reward: the effects of repeated maternal separation in the rat

    Neurosci. Biobehav. Rev.

    (2003)
  • H.S. Mayberg et al.

    Deep brain stimulation for treatment-resistant depression

    Neuron

    (2005)
  • W.M. McDonald et al.

    Prevalence, etiology, and treatment of depression in Parkinson's disease

    Biol. Psychiatry

    (2003)
  • K. Mizoguchi et al.

    Persistent depressive state after chronic stress in rats is accompanied by HPA axis dysregulation and reduced prefrontal dopaminergic neurotransmission

    Pharmacol. Biochem. Behav.

    (2008)
  • E.J. Nestler et al.

    Neurobiology of depression

    Neuron

    (2002)
  • D. Aarsland et al.

    Neuropsychiatric symptoms in Parkinson's disease

    Mov. Disord.

    (2009)
  • E.D. Abercrombie et al.

    Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex

    J. Neurochem.

    (1989)
  • M. Adzic et al.

    Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain

    J. Endocrinol.

    (2009)
  • A. Ahmad et al.

    Alterations in monoamine levels and oxidative systems in frontal cortex, striatum, and hippocampus of the rat brain during chronic unpredictable stress

    Stress

    (2010)
  • P. Barone et al.

    Sumanirole versus placebo or ropinirole for the adjunctive treatment of patients with advanced Parkinson's disease

    Mov. Disord.

    (2007)
  • N.I. Bohnen et al.

    Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia

    J. Neurol. Neurosurg. Psychiatry

    (2007)
  • I. Boileau et al.

    Elevated serotonin transporter binding in depressed patients with Parkinson's disease: a preliminary PET study with [11C]DASB

    Mov. Disord.

    (2008)
  • A.S. Brown et al.

    Dopamine and depression

    J. Neural Transm. Gen. Sect.

    (1993)
  • R. Brown et al.

    Depression in Parkinson's disease: a psychosocial viewpoint

    Adv. Neurol.

    (1995)
  • J. Brown et al.

    Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis

    Eur. J. Neurosci.

    (2003)
  • J.J. Cerqueira et al.

    Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors

    J. Neurosci.

    (2005)
  • V. Chan-Palay et al.

    Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression

    J. Comp. Neurol.

    (1989)
  • V. Chan-Palay et al.

    Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson's disease with and without dementia and depression

    J. Comp. Neurol.

    (1989)
  • A. Charlett et al.

    Cortisol is higher in parkinsonism and associated with gait deficit

    Acta Neurol. Scand.

    (1998)
  • Cited by (151)

    View all citing articles on Scopus
    View full text