Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848237 (acute stress)
 4,619 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in brain tryptophan concentrations may affect the synthesis of brain serotonin (5-hydroxytryptamine, 5-HT). Concentrations of tryptophan are regulated more than those of any other amino acid. Such stimuli as acute stress, carbohydrate ingestion, and treatment with various drugs increase the brain content of tryptophan. Treatment of rats and mice with interleukin-1 (IL-1), interleukin-6 (IL-6), lipopolysaccharide (LPS), and beta-adrenoceptor agonists, as well as a variety of stressors, such as footshock and restraint, all increase brain concentrations of tryptophan. The peak effect following both acute stress and beta-adrenoceptor agonist administration occurs within 30-60 min, whereas the peak effect following LPS and the cytokines occurs much later at around 4-8 h. Experiments using the ganglionic blocker chlorisondamine, and beta-adrenoceptor antagonists suggest that the sympathetic nervous system plays an important role in the modulation of brain tryptophan concentrations. The mechanisms involved in the increases observed in brain tryptophan are discussed, as well as their possible biological significance.
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PMID:Mechanisms and significance of the increased brain uptake of tryptophan. 1636 73

The serotoninergic system and the 5-HT1A receptors have been involved in the brain response to acute stress. The aim of our study was evaluate the role of the 5-HT1A receptors in serotoninergic cells of rostral and caudal raphe nuclei under acute immobilization in rats. Double immunocytochemical staining of 5-hydroxy-tryptamine and c-Fos protein and stereology techniques were used to study the specific cell activation in the raphe nuclei neurons in five groups (control group, immobilization group (immobilization lasting 1 h), DPAT group (8-OH-DPAT 0.3 mg/kg, s.c.), DPAT+IMMO group (8-OH-DPAT 0.3 mg/kg, s.c., 30' prior acute immobilization) and WAY+DPAT+IMMO group (WAY-100635 0.3 mg/kg, s.c. and 8-OH-DPAT 0.3 mg/kg, s.c., 45' and 30', respectively, before immobilization). Our results showed an increase in the number of c-Fos immunoreactive nuclei in serotoninergic cells in both dorsal and median raphe nuclei in the immobilized group. The 8-OH-DPAT pretreatment counteracted the excitatory effects of the acute immobilization in these brain regions. In addition, WAY-100635 administration reduced the effect of 8-OH-DPAT injection, suggesting a selective 5-HT1A receptor role. Raphe pallidus and raphe obscurus did not show any differences among experimental groups. We suggest that somatodendritic 5-HT1A receptors in rostral raphe nuclei may play a crucial role in both mediating the consequences of uncontrollable stress and the possible beneficial effects of treatment with 5-HT1A receptor agonists.
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PMID:5-HT1A receptor activation counteracts c-Fos immunoreactivity induced in serotonin neurons of the raphe nuclei after immobilization stress in the male rat. 1640 67

Animal models have shown progressive development and have undoubtedly proven their supportive value in OCD research. Thus, various animal models have confirmed the importance of the 5-HT [72-74] and dopamine systems [104,111] in the neurobiology and treatment of OCD. Given the neurochemical, emotional, and cognitive complexity of the disorder, how-ever, animal models are being used to investigate more and more complicated neurochemical and behavioral theories purported to underlie OCD. The lever-press model, for example, has implicated deficient response feed-back in a neural system that regulates operant behavior [74]. Studies on stereotypic movement disorder [89] have opened a new avenue of investigation into the neurobiology of stereotypy that may be applicable to more complex syndromes such as OCD. Models that have focused on specific neuropsychologic aspects of OCD such as reward [74], displacement behavior[63,101], perseveration and indecisiveness [73,102], and spontaneous stereotypy [90,94] are important in their attempt to unify the diverse behavioral manifestations of this disorder. It is clear that for a deeper, more holistic understanding of OCD, multiple animal models will be needed to allow investigation of the various aspects of the disorder and to provide convergent validation of the research findings. The heterogeneous nature of OCD, the various subtypes that exist within the disorder, and the range of obsessive-compulsive spectrum disorders suggest that particular questions regarding OCD may be addressed best by us-ing a particular ethologic model, whereas other questions might require a pharmacologic model or a combination of both for meaningful results[62,115]. Genetic models will be extremely useful for studying the genetics of pathologic behavior and for relating these findings to neuroanatomic and neurochemical changes in the model (eg, DICT-7 mice as a model for Tourette's syndrome and OCD). Neither ethologic nor pharmacologic models, however, can assess whether the "compulsive" behavior is a response to an "obsessive" anxiety or fear. Perhaps the symptoms seen in patients who have OCD, which may be exacerbated by everyday stress, are analogous to displacement behaviors in animals and also reflect some form of anxiety or stress [98]. In this regard, the bank vole model [116]has provided evidence that previously developed stereotypies increase markedly after acute stress and argues that healthy individuals "habituate" to everyday stress, whereas patients who have OCD do not. Interindividual variation in behavioral response and attempts to replicate studies in different laboratories often is the nemesis of the behavioral scientist. Small within- and between-subject variability is usually desirable, how-ever, because there are cases in which the study of the variability of the model could lead to a better understanding of the disorder. Variability can-not always be considered an error; it is possible that previously disregarded neuronal systems may have a place in the observed variation and, indeed, in the pathophysiology of OCD. In this regard, SRIs are not always effective for OCD [6,29,30] such that a lack of effect in a model may reflect an un-known neurobiological basis for compulsive behavior in a sub-group of SRI refractory patients. Similarly, separating the afflicted (ie, working with animals that show greater behavioral change in a model and/or after drug treatment) would have distinct benefits. To increase successful implementation of an ethologic animal model, especially when reinforcement models or signal attenuation models are used,the laboratory must be equipped with the essential behavioral testing apparatus as well as the operant chambers/rooms in which to conduct the train-ing and data collection. Quantification of certain stereotypy behaviors also requires experienced or trained observers. An illustration of the difficulty in measuring behavioral changes is that in the rewarded alternation model,a good response to behavioral treatment (alternation training) may lead to a floor effect [73] which, after successful drug treatment of the animal,produces no residual persistence (ie, measurable behavioral change) on which a drug treatment can be tested. Clearly, the choice of ethologic, pharmacologic, or genetic models should be considered carefully. A well-validated model may quell many of the limitations and considerations described previously. Noninvasive neuroimaging(eg, the use of small-animal single-photon emission CT) to explore the neuroanatomic basis of OCD offers an exciting future challenge, especially if combined with pharmacologic or ethologic models, and could confirm or ex-tend knowledge of the neuroanatomy of OCD. Although studies to investigate further the interactive role of 5-HT, dopamine, GABA, and glutamate are still needed, the role of neuroactive peptides such as cholecystokinin, corticotrophin-releasing factor, neuropeptide Y, tachykinins (ie, substance P),and natriuretic peptides in OCD should also be considered. Genetically engineered animal models will become increasingly valuable in combination with new technologies such as gene-chip microarrays, RNA interference, and advanced proteomics that will help further the understanding of OCD. Animal models of OCD are poised to play a vital role in extending the knowledge of the disorder now and in the future.
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PMID:Animal models of obsessive-compulsive disorder: rationale to understanding psychobiology and pharmacology. 1665 Jul 14

Serotonin-promoting drugs show cardioprotective properties in patients with anxiety or depression, but it is not known if this is a direct effect of increasing serotonin. We aimed to characterize the effect of serotonin manipulation through acute tryptophan depletion on cardiovascular and psychological responses to stress challenge in recovered patients with anxiety disorders. In 27 recovered patients with anxiety disorders (panic disorder treated by selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy, social anxiety disorder treated by SSRIs), we performed a double-blind randomized crossover study. On 2 separate days, the subjects ingested an acute tryptophan-depleting (aTD) or nondepleting (nD) drink in random order and underwent a stress challenge at time of maximum depletion. Systolic blood pressure (P = 0.007; diff = 9.0 mm Hg; 95% confidence interval (CI), 2.6-15.3 mm Hg) and diastolic blood pressure (P = 0.032; diff = 5.7 mm Hg; 95% CI, 0.6-10.9 mm Hg) responses to stress were significantly greater under aTD than nD, as were the psychological responses to stress (for Spielberger state anxiety, difference in stress response between aTD and nD = 7.11; P = 0.025). Blood pressure responses to stress showed no correlation with psychological responses. The significant increases in acute stress sensitivity in both cardiovascular and psychological domains on serotonin depletion suggest that serotonin is involved in the control of both cardiovascular and psychological aspects of the acute stress response. The lack of correlation in the difference between aTD and nD conditions in cardiovascular and psychological responses suggests that serotonin may have distinct effects on these 2 domains, rather than the cardiovascular responses being merely a secondary consequence of psychological changes.
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PMID:Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders. 1685 62

The aim of our study was to evaluate the effect of acute stress and the 5-HT(1A) receptor involvement in both, the hippocampus noradrenaline (NA) tissue levels and the c-Fos immunoreactivity (c-Fos-IR) in the catecholaminergic neurons of the locus coeruleus (LC). Double immunocytochemical staining of tyrosine hydroxilase (TH) and c-Fos protein combined with stereological techniques were used to study the specific cell activation in the LC neurons in five experimental groups (control group, immobilization (1h) group, 8-OH-DPAT group (8-OH-DPAT 0.3mg/kg, s.c.), DPAT+IMMO group (8-OH-DPAT 0.3mg/kg, s.c., 30' prior acute immobilization) and WAY+DPAT+IMMO group (WAY-100635 0.3mg/kg, s.c. and 8-OH-DPAT 0.3mg/kg, s.c., 45'and 30', respectively, before immobilization). The results showed that hippocampal NA tissue levels and c-Fos-IR in the TH positive neurons of the LC were significantly increased immediately and after 90', respectively, after the immobilization period. Pre-treatment with 8-OH-DPAT counteracted the effects induced by immobilization, but pre-treatment with WAY-100635 did not block the effects induced by 8-OH-DPAT. These results suggest that noradrenaline system is associated in a significant way with immobilization stress. The role of 5-HT(1A) receptor activation in this stress response is also discussed.
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PMID:5-HT1A receptor activation counteracted the effect of acute immobilization of noradrenergic neurons in the rat locus coeruleus. 1719 87

Adverse experiences early in life are associated with an increased incidence of later psychopathology including depression. Based on evidence that dysfunction of central monoaminergic systems is involved in the pathophysiology of depression, we hypothesize that early adversity could negatively affect these systems. To test this we have investigated the effects of maternal separation, which has been suggested to model early-life stress and the development of a depression-like syndrome in the rat, on brain monoaminergic systems. Since depression is more common in women and the risk of developing this disorder appears to increase with age, we have studied such effects in middle-aged female rats. Rat pups were separated for 180 min (long maternal separation; LMS) or 15 min (brief maternal separation; BMS, often referred to as neonatal handling) twice daily for 2 weeks postpartum. An animal facility-reared (AFR) group was also included. At 15 months of age tissue levels of monoamines and their metabolites in several different brain regions were analyzed. In the LMS females tissue levels of both 5-HT and 5-hydroxyindole acetic acid (5-HIAA) were significantly increased in the dorsal raphe nucleus, and 5-HIAA and homovanillic acid levels were also elevated in the nucleus accumbens as compared with AFR and BMS rats. In the cingulate cortex both LMS and BMS decreased noradrenaline (NA) levels, although this effect was more pronounced in the LMS rats. On the other hand, BMS decreased 5-HT, 5-HIAA, dopamine (DA) as well as NA levels in the amygdala and produced an increase in DA levels in response to acute stress in the hypothalamus, an effect not seen in AFR rats. Our results demonstrate that LMS produced persistent alterations in both serotonergic, noradrenergic and dopaminergic systems in brain regions that have been suggested to be implicated in the pathophysiology of depression. In addition, BMS affected brain monoaminergic levels mainly in the amygdala.
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PMID:Both long and brief maternal separation produces persistent changes in tissue levels of brain monoamines in middle-aged female rats. 1722 17

Bacopa monniera (BM) is well known for its neuropharmacological effects. Our previous studies indicated the adaptogenic effect of standardized extract of BM in various stress models. In the present study, effect of BM was evaluated on acute stress (AS) and chronic unpredictable stress (CUS) induced changes in plasma corticosterone and monoamines-noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in cortex and hippocampus regions of brain in rats. Panax root powder (Panax quinquefolium) was taken as standard. Subjecting animals to AS (immobilization for 150 min once only) and CUS (different stressors for 7 days) resulted in significant elevation in plasma corticosterone levels, which was significantly countered by treatment with BM at a dose of 40 and 80 mg/kg p.o. similar to the effects of Panax quinquefolium (PQ) at 100 mg/kg p.o. AS exposure significantly increased the levels of 5-HT and decreased NA content in both the brain regions while DA content was significantly increased in cortex and decreased in hippocampus regions. In CUS regimen, levels of NA, DA and 5-HT were significantly depleted in cortex and hippocampus regions of brain. Treatment with BM (40 and 80 mg/kg) attenuated the stress induced changes in levels of 5-HT and DA in cortex and hippocampus regions but was ineffective in normalizing the NA levels in AS model, whereas PQ treatment significantly reverted back the effects of stress. In CUS model, pretreatment with BM and PQ significantly elevated the levels of NA, DA and 5-HT levels in cortex and levels of NA and 5-HT in hippocampus regions. Hence, our study indicates that the adaptogenic activity of BM might be due to the normalization of stress induced alteration in plasma corticosterone and levels of monoamines like NA, 5-HT and DA in cortex and hippocampus regions of the brain, which are more vulnerable to stressful conditions analogous to the effects of PQ.
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PMID:Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats. 1732 Oct 89

Both serotonin and NMDA signaling in prefrontal cortex (PFC) are implicated in mental disorders, including depression and anxiety. To understand their potential contributions to PFC neuronal excitability, we examined the effect of co-activation of 5-HT and NMDA receptors on action potential firing elicited by depolarizing current injection in PFC pyramidal neurons. In the presence of NMDA, a low concentration of the 5-HT(1A) agonist 8-OH-DPAT substantially reduced the number of spikes, and a low concentration of the 5-HT(2A/C) agonist alpha-Me-5HT significantly enhanced it, while both agonists were ineffective when applied alone. The 8-OH-DPAT effect on firing was mediated by inhibition of protein kinase A (PKA), whereas the alpha-Me-5HT effect was mediated by activation of protein kinase C (PKC). Moreover, the extracellular signal-regulated kinase (ERK), a signaling molecule downstream of PKA and PKC, was involved in both 5-HT(1A) and 5-HT(2A/C) modulation of neuronal excitability. Biochemical evidence showed that 5-HT(1A) decreased, whereas 5-HT(2A/C) increased the activation of ERK in an NMDA-dependent manner. In animals exposed to acute stress, the enhancing effect of 5-HT(2A/C) on firing was lost, while the decreasing effect of 5-HT(1A) on firing was intact. Concomitantly, the effect of 5-HT(2A/C), but not 5-HT(1A), on ERK activation was abolished in stressed animals. Taken together, our results demonstrate that distinct 5-HT receptor subtypes, by interacting with NMDA receptors, differentially regulate PFC neuronal firing, and the complex effects of 5-HT receptors on excitability are selectively altered under stressful conditions, which are often associated with mental disorders.
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PMID:Modulation of neuronal excitability by serotonin-NMDA interactions in prefrontal cortex. 1845 31

The serotonin system in prefrontal cortex (PFC) is critically involved in the regulation of cognition and emotion. To understand the cellular mechanisms underlying its physiological actions, we investigated the role of serotonin in regulating synaptic plasticity in PFC circuits. We found that tetanic stimuli coupled to bath application of serotonin induced long-term depression (LTD) at excitatory synapses of PFC pyramidal neurons. This effect was mediated by 5-HT(2A/C) receptors and was independent of NMDA receptor activation. A group I metabotropic glutamate receptor (mGluR) antagonist blocked the LTD induction by serotonin + tetani, and co-application of a group I mGluR agonist and serotonin, but not application of either drug alone, induced LTD without tetani. The effect of serotonin on LTD was blocked by selective inhibitors of p38 mitogen-activated protein kinase (MAPK), but not p42/44 MAPK. Biochemical evidence also indicated that serotonin and a group I mGluR agonist synergistically activated p38 MAPK in PFC slices. The serotonin-facilitated LTD induction was prevented by blocking the activation of the small GTPase Rab5, as well as by blocking the clathrin-dependent internalization of AMPA receptors with postsynaptic injection of a dynamin inhibitory peptide, while it was unaffected by manipulating the cytoskeleton. Interestingly, in animals exposed to acute stress, the LTD induction by serotonin + tetani was significantly impaired. Taken together, these results suggest that serotonin, by cooperating with mGluRs, regulates synaptic plasticity through a mechanism dependent on p38 MAPK/Rab5-mediated enhancement of AMPA receptor internalization in a clathrin/dynamin-dependent manner. It provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes that are mediated by synaptic plasticity in PFC neurons.
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PMID:Serotonin facilitates long-term depression induction in prefrontal cortex via p38 MAPK/Rab5-mediated enhancement of AMPA receptor internalization. 1865 60

Earlier data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may affect depression particularly in the face of stress due to interactions between 5-HT vulnerability and stress exposure. However, this interaction between 5-HT transporter-linked transcriptional promoter region (5-HTTLPR), 5-HT vulnerability and the affective effects of stress exposure has not yet been investigated. As participants with short-allele 5-HTTLPR genotypes may exhibit enhanced 5-HT vulnerability, this study examines the effects of tryptophan challenge on stress reactivity and performance in healthy participants with S'/S' vs L'/L' genotypes. Sixteen healthy subjects with homozygotic short alleles (S'/S'=S/L(G,) L(G)/L(G)) and 14 subjects with homozygotic long alleles (L'/L'=L(A)/L(A)) of the 5-HTTLPR were tested in a double-blind placebo-controlled design under acute stress exposure following tryptophan challenge or placebo. Although there were no 5-HTTLPR-related differences in stress responses, significant beneficial effects of tryptophan challenge on mood and stress performance were exclusively found in participants with S'/S' genotypes. These findings suggest greater brain 5-HT vulnerability to tryptophan manipulations in participants with S'/S' as compared with L'/L' 5-HTTLPR genotypes. This apparent genetic 5-HT vulnerability may become a meaningful risk factor for depression when brain 5-HT falls below functional need in the face of real severe stressful life events.
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PMID:Differential effects of tri-allelic 5-HTTLPR polymorphisms in healthy subjects on mood and stress performance after tryptophan challenge. 1967 33


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