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.
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ABSTRACT: Obesity is associated with mood disorders, but underlying mechanisms are not well understood. We have recently described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We demonstrate that supplementation of either a high sucrose or a high fat diet with BCAA induces anxiety-like behavior in rats compared to control groups fed on unsupplemented diets. These behavioral changes are associated with a significant decrease in the concentration of tryptophan (Trp) in brain tissues and a consequent decrease in serotonin, but no difference in indices of serotonin synaptic function. The anxiety-like behaviors and decreased levels of Trp in the brain of BCAA-fed rats were reversed by supplementation of Trp in the drinking water, but not by administration of fluoxetine, a selective serotonin reuptake inhibitor, suggesting that the behavioral changes are independent of the serotonergic pathway of Trp metabolism. Instead, BCAA supplementation lowers the brain levels of another Trp-derived metabolite, kynurenic acid, and these levels are normalized by Trp supplementation. We conclude that supplementation of high energy diets with BCAA causes neurobehavioral impairment. Since BCAA are spontaneously elevated in human obesity, our studies suggest a potential mechanism for explaining the strong association of obesity and mood disorders.AJP Endocrinology and Metabolism 12/2012; · 4.51 Impact Factor
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ABSTRACT: Psycho-genetic studies have revealed a role for the brain serotonin system in gambling proneness and poor decision-making. We assessed whether manipulation of brain serotonin levels in rats affected performance in operant-based tasks for decision-making and gambling proneness. Male Wistar rats were exposed to an l-tryptophan (TRP) deficient diet (0.0 g/kg; T- group) or to a control, l-tryptophan containing diet (2.8 g/kg; T+ group). The same rats were tested for decision-making performance in the rodent Iowa Gambling Task (rIGT) using home-cage operant panels, and subsequently for gambling proneness in a Probabilistic Delivery Task (rPDT) using classic Skinnerboxes. At sacrifice, monoamines and metabolites were evaluated with HPLC analysis, confirming a drastically reduced serotonin synthesis, as well as altered dopamine turnover in the prefrontal cortex of T- rats. As expected, control rats (T+) progressively chose the option with the best long-term payoff in the rIGT, and also shifted from "Large & Luck-Linked" (LLL) to "Small & Sure" (SS) reinforcers in the rPDT. In contrast, depleted animals (T-) exhibited a weaker improvement of performance in the rIGT and maintained a sub-optimal attraction for LLL reinforcer in the rPDT. Comparing individual performances in both tests, we found a significant correlation between the two tasks in control (T+) but not in depleted (T-) rats. The present study revealed that (1) brain 5-HT depletion leads to poor decision-making and to gambling proneness; (2) the relationship between these two traits, shown in the control group, was disrupted in 5-HT depleted rats. The data are discussed in terms of changes within forebrain loops involved in cognitive and motivational/affective processes.Neuropharmacology 11/2011; 62(4):1640-50. · 4.11 Impact Factor
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ABSTRACT: Besides demonstrated efficacy, selective serotonin reuptake inhibitors (SSRIs) hold other advantages over earlier antidepressants such as greater tolerability and a wider range of clinical applications. However, there is a growing body of clinical evidence which suggests that SSRIs could, in some cases, be associated with a withdrawal reaction upon cessation of regular use. In addition to sensory and gastrointestinal-related symptoms, the somatic symptoms of the SSRI discontinuation syndrome include dizziness, lethargy, and sleep disturbances. Psychological symptoms have also been documented, usually developing within 1-7 days following SSRI discontinuation. The characteristics of the discontinuation syndrome have been linked to the half-life of a given SSRI, with a greater number of reports emerging from paroxetine compared to other SSRIs. However, many aspects of the neurobiology of the SSRI discontinuation syndrome (or SSRI withdrawal syndrome) remain unresolved. Following a comprehensive overview of the clinical evidence, we will discuss the underlying pathophysiology of the SSRI discontinuation syndrome and comment on the use of animal models to better understand this condition.Frontiers in Pharmacology 01/2013; 4:45.
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?