Low tryptophan diet increases stress-sensitivity, but does not affect habituation in rats.
ABSTRACT Cerebral dysfunction of 5-HT (serotonin) has been associated with stress response and with affective disorders. Stress alone is insufficient to induce depression, since only a minor proportion of subjects that have experienced stressful life events develop depressive episodes. We investigated whether long-term brain 5-HT depletion induced in rats by a diet with low content of its precursor tryptophan affects stress-responsiveness in rats. Stress-sensitivity was measured through various physiological parameters and by measuring the rats' response to acoustic stimuli. One group of rats was subjected to daily acoustic stimulus sessions for 5 days. Other groups received both immobilization stress and acoustic stimulus sessions daily for either 9 days (chronic experiment) or 1 day (acute experiment). A low tryptophan diet led to decreases in plasma tryptophan levels, low ratio of tryptophan/large neutral amino acid, whole blood 5-HT, and neuronal 5-HT content in the Dorsal and Median Raphe Nuclei, as well as altered c-fos expression in the brain. Without concomitant immobilization, the diet alone did not affect reactivity and habituation to acoustic stimuli, although plasma corticosterone levels, but not the adrenal weights, were increased on day 5. Low tryptophan and chronic immobilization stress together with the acoustic testing procedure increased adrenal weight, plasma corticosterone levels and reactivity to the acoustic stimuli, but not the rate of habituation to acoustic stimuli. These results show that cerebral dysfunction of serotonin achieved through a low tryptophan diet, increases the sensitivity of rats to external and stressful stimuli, but does not impair the capacity to adapt to these stimuli. Accordingly, brain-serotonin modulates reactivity to stress, but not stress coping.
- Techniques in Gastrointestinal Endoscopy 01/2011; 13(3):161-166.
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ABSTRACT: BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation. METHODS: We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale). RESULTS: The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise. DISCUSSION: The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.Journal of Affective Disorders 05/2013; · 3.76 Impact Factor
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ABSTRACT: The effect of secondary fuel injection location on the effectiveness of active combustion control was studied in an atmospheric pressure, laboratory-scale dump combustor operating on natural gas with a nominal heat release rate of 75 kW. The combustor provided for secondary fuel injection from three different locations. The effectiveness of both open- and closed-loop control was found to be strongly dependent on the secondary fuel injection location. To understand this behavior, CO2 chemiluminescence imaging measurements were made of the spatial and temporal heat release distribution in the combustor, both to characterize the evolution of the heat release distribution during unstable combustion and to characterize the heat release produced by the injection of secondary fuel. The results indicate that the most effective approach to preventing unstable combustion is not necessarily to add heat in a manner which is out of phase with the instability but that effective control can also be achieved by disrupting the mechanism that is driving the instability. These results serve to illustrate that gaining an understanding of the phenomenology of the instability is a critical step in designing and optimizing an active combustion control system.Proceedings of The Combustion Institute - PROC COMBUST INST. 01/2000; 28(1):739-746.
Serotonin, Cortisol & Stress-Related
from bench to bed
Studies presented in this thesis were performed at the University Center Psychiatry, the
Department of Medical Oncology and the department of Pathology and Laboratory
Medicin, Umiversity Medical Center Groningen., Groningen the Netherlands, and the
department of Psychosocial Oncology, Erasmus University Medical Center, Rotterdam, the
Publication of this thesis was financially supported by Graduate School of Behavioral and
Cognitive Neurosciences, the University of Groningen, University Medical Center
Groningen, Astra Zeneca BV, Eli Lilly Nederland BV, Servier Nederland Farma BV,
Wyeth Pharmaceuticals BV.
Cover by: Gerard Tanke
Printed by: PrintPartners Ipskamp BV, Enschede, The Netherlands
ISBN printed version: 978-90-367-3715-9
ISBN electronic version: 978-90-367-3716-6
© Marit Tanke, 2008
Serotonin, cortisol and stress-related
from bench to bed
C Ch ha ap pt te er r 1 1
specific? response? of? the? body? to? any? demand? placed? upon? it”? (1).? ? Stress? may? also? be?
described? as? any? environmental? challenge,? either? internal? or? external,? that? disturbs? the?
enhance? the? probability? of? survival? (3;4).? Stress? may? become? problematic? when? the?
the? onset? of? first? episodes? of? MDD? occurs? (5?8).? However,? stressful? events? do? not?
automatically? lead? to? psychopathology,? indicating? that? not? the? stressor? itself,? but? the?
individual? sensitivity? to? stress? is? crucial? or? rather? the? interaction? between? stress? and?
genetic? factors,? but? also? by? psychosocial? and? biological? factors.? Thus,? a? genetic?
predisposition? in? combination? with? environmental? stressors? are? probably? necessary? to?
The stress response
A? sudden? stressor? enhances? sympathetic? activation? and? release? of? adrenaline? and?
noradrenaline? into? the? bloodstream? and? increases? heart? rate? and? blood? pressure? by?
reaction? leads? to? behavioral? changes,? altered? immunologic? and? autonomic? function? and?
The? HPA?axis? system? receives? input? from? stressors? via? the? cerebral? cortex? in? the?
Figure 1: Schematic depiction of the HPA-axis system, including negative feedback mechanisms.
acute? stress,? the? CRH? pulse? amplitude? in? the? hypothalamus? increases,? which? results? in?
(20).? The? enhanced? secretion? of? glucocorticoids? leads? to? mobilization? of? stored? energy,?
genes? coding? for? CRH? and? ACTH? via? binding? to? glucocorticoid? receptors? (GR)? or?
GR? are? not.? However,? during? stress? glucocorticoid? levels? increase? leading? to? additional?
HPA-axis dysregulation and depression
axis? dysfunction? because? persisting? impaired? feedback? constitutes? an? enhanced? risk? for?
relapse? or? recurrence? of? depression,? while? normalization? of? such? feedback? mechanisms?
In? animals? corticosterone? treatment? reduced? the? stress? response? (43?45)? and? facilitated?
habituation? by? altering? the? behavior? that? was? not?longer?necessary? (46).? Thus,? HPA?axis?
Figure 2:: The main metabolic pathways of tryptophan and serotonin
The central serotonin system
Serotonergic? cell? bodies? with? ascending? projections? to? cortical? and? limbic? areas? are?
predominantly? housed? in? the? midbrain? dorsal? and? median? raphe? nuclei.? The?
activates? both? pre?? and? postsynaptical? receptors.? Until? now,? 14? structurally? and?
are? now? assigned? to? one? of? seven? families? 5?HT1–7? (51).? Neuronal? release? of? 5?HT? is?
axon? terminal? areas? (52;53).? Most? other? 5?HT? receptor? subtypes? primarily? function? as?
Figure 3: Serotonin (5-HT) synthesis, reuptake and degradation in the presynaptic neuron
Serotonin dysfunction and psychiatric disorders
been? thought? to? cause? depression.? This? finding? is? explained? by? the? observation? that?
depletion? of?monoamine? stores?in?the? brain? by? reserpine? induced? depressive? symptoms,?
while?increasing? extracellular? monoamine?levels? in? the? brain? appeared? to? be? effective? in?
several? forms? of? depression? (57).? Indeed,? un?medicated? depressed? patients? have? shown?
reduced? metabolism? of? 5?HT? in? several? areas? of? the? brain? (e.g.? raphe? nuclei? and?
platelet? 5?HT? content,? and? reduced? plasma? TRP? levels? (58?61).? ? Reduced? 5?HT? function?
might? be? a? consequence? of? increased? sensitivity? of? 5?HT? receptor? subtypes? involved? in?
negative? feedback,? leading? to? a? reduced? turnover? of? 5?HT.? Manipulation? of? brain? 5?HT?
Interactions between the HPA-axis and serotonin system
animals? it? has? been? shown? that? liver? tryptophan? pyrrolase? (tryptophan? 2,3?dioxygenase)?
undergoing? immobilization? stress,? a? 20%? decrease? in? plasma? tryptophan? levels? was?
neuronal? activity? in? the? dorsal? and? median? raphe? nuclei? (83;84),? while? long?term?
well? as? 5?HT1A? receptor? binding? (85;86).? In? humans,? administration? of? dexamethasone?
Conversely,? serotonin? reportedly? influences? several? components? of? the? HPA?axis?
serotonin? precursors? 5?hydroxytryptophan? (5?HTP)? and? TRP,? as? well? as? 5?HT1A? agonists?
levels? in? patients? with? seasonal? affective? disorder? and? attenuates? cortisol? levels? after? a?
stressful? task? in? subjects? with? a? family? history? of? depression,? indicating? multiple? and?
complex? interactions? between? 5?HT? and? the? HPA?axis? (78;90).? It? is? also? noteworthy? that?
administration? of? antidepressants? stimulates? the? release? of? ACTH? and? corticosteroids?
A? genetic? polymorphism? of? the? serotonin? transporter? (5?HTT)? is? involved? in? increased?
version? were? described? in? the? 5?HTT? promoter? region? (5?HTTLPR),? but? recently? an?
allel.? The? alleles? are?currently? described? as? S,?LG? and? LA? (105).? The? S?and? LG? alleles? are?
the? degradation? of? the? neurotransmitters? dopamine,? serotonin,? and? norepinephrine?
and? drugs,? treatment? with? MAOIs? are? nowadays? restricted? to? cases? where? other?
supplementation? with? serotonin? precursors? such? as? TRP? and? 5?HTP? (107).? The? selective?
neuron? and? are? believed? to? increase? the? concentration? of? 5?HT? in? the? synapse,? but? this?
opinion? is? not? shared? by? everyone? (108).? The? most? selective? (racemic)? SSRI? currently?
available? is? citalopram? (109).? Recently,? it? was? found? that? long?term? citalopram?
(110).? Newer? classes? of? antidepressants? consist? of? specific? serotonin?norepinephrine?
Antidepressant discontinuation syndromes
Abrupt? termination? or? abrupt? dose?reduction? of? antidepressant? treatment? may? lead? to?
discontinuation? symptoms.? Discontinuation? symptoms? include? affective? symptoms?
(irritability,? anxiety/agitation,? low? mood),? sleep? disturbances,? general? somatic? symptoms?
An? adequate? animal? model? must? meet? three? important? validation? criteria? (117).? First,?
model? (face? validity).? Second,? etiology? or? the? alleged? pathological? mechanism? must? be?
comparable? in? patients? and? the? animal? model? (construct? validity).? Finally,? effective?
the? induction? of? depressive? episodes? (117).? Hence,? it? was? decided? to? use? a? design? that?
the? HPA?axis? and? the? serotonergic? system.? In? this? study? the? immobilization? stress? (10?
Arguably? this? will? minimize? the? neurochemical? and? behavioral? confounds? inherent? of?
The? acoustic? startle? response? (ASR)? is? a? fast,? involuntary,? defensive? muscular? response?
Figure 4: Simplified version of the acoustic startle pathway. Adapted from Koch et al. 1999
patients? that? are? treated? with? interferon??? (133).? Briefly,? carcinoids? are? neuro?endocrine?
excessive? TRP? consumption? by? the? carcinoid? tumor? may? thus? result? in? a? decreased?
availability?of?TRP?in? the? brain? and? hence? adversely? influence? central?5?HT? functioning.?
induction? of? the? enzyme? indoleamine? 2,3?dioxygenase? (IDO),? it? also? stimulates? the?
be? of? help? to? study? the? effects? of? chronic? TRP? depletion? on? mood? and? behavior? in? a?
Some diagnostic criteria
Psychiatric? disorders? are? diagnosed? according? to? the? consensus? criteria? stated? by? the?
Diagnostic? and? Statistical? Manual? of? Mental? Disorders? Version? IV,? 4th? edition? (DSM?IV;?
American? Psychiatric? Association,? 1994).? Diagnosis? usually? consists? of? on? or? two? key?
terms? of? scores? on? questionnaires,? which? contrasts? the? normal? clinical? practice.? Such?