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We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan.

Background: Previously we observed in patients suffering from a metastatic carcinoid tumor that irritability, aggression and lack of impulse control are associated with low levels of plasma tryptophan and presumably with low brain serotonin function. In rats we showed that a diet of low tryptophan resulted in higher stress responses and higher corticosterone production. Here we tested in carcinoid patients whether tryptophan depletion due to tumor 5-HT overproduction is associated with high cortisol production., Methods: Urinary excretion of cortisol, serotonin, 5-hydroxyindole acetic acid (the main metabolite of serotonin a marker of tumor activity), plasma levels of tryptophan and platelet content of serotonin (index of peripheral serotonin synthesis) were determined in metastatic midgut carcinoid patients. Patients (N = 25) were divided into two groups based on their plasma tryptophan levels (< or = 25 micromol/l, n = 12 and > or = 49 micromol/l, n = 13)., Results: Carcinoid patients with low plasma tryptophan levels had significantly higher urinary excretion of free cortisol (p < 0.01), independent of tumor activity. The inter-individual differences in the low tryptophan group, however, were substantial., Conclusions: In a subgroup of the patients suffering from metastatic carcinoid disease the cerebral access of plasma tryptophan is impaired, thus rendering cerebral serotonin neurotransmission suboptimal and leading to hypercortisolism. The present study provides further support to the idea that low serotonergic function is a risk for developing stress-associated psychopathology.

Objective: We investigated whether postpartum blues was related to changes in parameters of noradrenergic and serotonergic functioning., Methods: From 26 healthy pregnant women blood was collected at the end of pregnancy and 5 days and 6 weeks postpartum. Serotonergic parameters were: platelet serotonin content; paroxetine binding to platelet membranes as an index of serotonin transporter activity; the serotonin precursor tryptophan in proportion to the large neutral amino acids, as an estimate of its cerebral influx. Noradrenergic indices were the noradrenaline precursor tyrosine and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). The Kennerly and Gath blues questionnaire was applied at day five postpartum., Results: The incidence of postpartum blues was 30%. The tryptophan ratio and serotonin content of platelets were decreased (p<0.01) at day five postpartum in all women. Bmax paroxetine at day five was correlated with blues score (beta=0.460; p=0.031). MHPG levels at 6 weeks were increased in women with blues (p<0.001). In a regression model MHPG at 6 weeks was related to blues score (beta=0.477; p=0.002) and MHPG at day five (beta=0.550; p=0.001), explaining >50% of the variation (R2=0.588; p<0.001)., Conclusions: A decreased serotonergic activity was found at the fifth day postpartum in all subjects. Increased SERT activity, reflected by higher paroxetine binding to platelets might be involved in the onset of blues. The elevated MHPG levels in women with blues are compatible with a higher stress sensitivity, or a decreased stress coping in those and is suggested to be involved with the onset of depression.

Objective: Several somatic illnesses are associated with psychiatric comorbidity. Evidence is provided that availability of the essential amino acid tryptophan, which is the precursor of serotonin, may cause this phenomenon., Methods: We performed a database search to find relevant articles published between 1966 and 2002. For our search strategy, we combined several diseases from the categories hormonal, gastrointestinal, and inflammatory with the search terms "tryptophan" and "serotonin.", Results: The catabolism of tryptophan is stimulated under the influence of stress, hormones and inflammation by the induction of the enzymes tryptophan pyrrolase (in the liver) and IDO (ubiquitous). Because of the reduction in blood levels of tryptophan under these circumstances the formation of cerebral serotonin is decreased., Conclusions: It is argued that the coupling of peripheral tryptophan levels and cerebral serotonin levels has physiological significance. The clinical implications and therapeutic consequences of changes in tryptophan and consequently serotonin metabolism are discussed.

The consequences of pharmacologically evoked augmented serotonin (5-hydroxytryptamine, 5-HT) release on neuronal activity in the brain, as reflected by the cellular expression of the immediate early gene c-fos, were studied. Wistar rats were treated with saline, the 5-HT reuptake inhibitor citalopram (10 micromol/kg s.c.), the 5-HT(1A) receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)-N-(2-pyridyl)cyclohexane carboxamine trihydrochloride (WAY 100635, 1 micromol/kg s.c.), or the combination of both drugs. At the given dosages, the combination of the drugs has previously been shown to enhance the cerebral release of 5-HT. Two hours and thirty minutes after administration, the brains were fixated, and Fos protein was histologically stained and quantified. The paraventricular nucleus of the hypothalamus, the central nucleus amygdala, the ventromedial hypothalamic nucleus, the dorsolateral striatum, and the nucleus accumbens shell were particularly responsive to increased 5-HT release. The results, illustrating the synergistic consequence of the combined drug treatments, are discussed in terms of activity of the limbic-hypothalamic-pituitary-adrenocortical system., (Copyright 2002 Elsevier Science B.V.)

Serum levels of 5-hydroxytryptophan ethyl ester, 5-hydroxytryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid (5-HTPE, 5-HTP, 5-HT and 5-HIAA, respectively), were measured after intravenous administration of L-5-HTPE in humans, premedicated with a peripheral decarboxylase inhibitor. Semi-automated methods for the estimation of the 5-hydroxyindole derivatives are described. Only serum levels of 5-HTP and 5-HIAA were found to be increased, indicating that the ethyl ester is rapidly hydrolyzed and that the decarboxylation of 5-HTP is in part inhibited. The levels of 5-HTP increased during the infusion, but dropped rapidly when the intravenous administration was terminated. Serum levels of 5-HIAA remained constant for at least 6 hours, although during the same period the levels of 5-HTP do change markedly. The persistently increased serum levels of 5-HIAA suggests, that this metabolite is formed from the 5-HT stored in peripheral or central tissue. Serum levels of 5-HIAA may therefore be indicative of changes of 5-HT metabolism during drug treatment. Levels of 5-HTP may be used for the estimation of the availability of the ethylester of 5-HTP.

Postmortem (pm) manipulations of brain tissue of decapitated mice produced a maximum decline in 5-HT and a maximum rise in 5-HIAA of 20 and 40%, respectively. The pm treatments included freezing and thawing, mincing, and leaving over. Microwave irradiation or pretreatment of the animals with the enzymatic inhibitors NSD 1015 or pargyline suppressed the pm effects. The possible role of pm effects in the initial accumulation of 5-HT and decline of 5-HIAA in the brain following administration of pargyline was studied. Out data suggest that, when MAO inhibitors are used, 5-HT turnover might be overestimated by pm changes.

Probenecid blocks the efflux of 5-hydroxyindole acetic acid (5-HIAA) from the central nervous system, and has therefore been used for turnover measurements of central 5-hydroxytryptamine (5-HT). This substance also elevates tryptophan (TP) levels in rat brain. In this investigation, the time courses of probenecid and TP levels in rat serum and brain after administration of probenecid were studied. Maximal levels of probenecid were reached within 15 min, followed by 50% decrease of serum TP and a 40% increase of brain TP. Brain levels of probenecid were about ten times lower than those in serum. Because TP level in brain is an important factor in the control of cerebral 5-HT synthesis, the effects of probenecid on 5-HT formation in rat brain were investigated. By means of the aromatic L-amino acid decarboxylase inhibitors Ro 4-4602 and NSD 1015, an enhancement of TP hydroxylation of about 35% was demonstrated. It was concluded that penetration of probenecid into the brain is very limited and that probenecid, in addition to blocking egress of 5-HIAA from the CNS, stimulates 5-HT synthesis.

Because tricyclic antidepressants (TAD) are usually given chronically to patients, both their acute and their chronic effects on 5-hydroxytryptamine (5-HT) metabolism were studied. The probenecid method was used and, in addition to 5-hydroxy-indoleacetic acid (5-HIAA), some other indole compounds in brain were measured. Simultaneously, TAD levels in brain and plasma were determined. Dimethylated as well as monomethylated TADs were administered, both at 10 and 25 mg/kg i.p. Treatment with either 10 mg/kg during 14 days or 25 mg/kg given acutely resulted in a similar brain level of TAD, so any differences found could be attributed to differences in administration schedule. Drug levels in brain and plasma differed considerably after chronic and acute treatments but no major differences in the effect on 5-HIAA level in the brain were found, although accumulation of 5-HIAA following probenecid treatment was mostly lowered after treatment with dimethylated TAD. The TAD level in rat brain was not decisive for the effect on central 5-HT turnover. The monomethylated TAD affected the 5-HT turnover very little, not only acutely but also chronically.

Levels of various compounds related to monoamines were assessed in 96 patients with a variety of depressive and nondepressive syndromes. The diagnostic categories were composed retrospectively after examination of International Classification of Diseases (ICD) classifications and all available data in medical reports. All patients underwent the 8-hour probenecid test. Administration of probenecid was partly intravenous (1 g) and partly oral (4 g). In all patients, the cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and probenecid were estimated, while in about half of the patients tryptophan and tyrosine were determined in CSF and serum. When the group is taken as a whole, significant positive correlations are found between the CSF levels of 5-HIAA, HVA and probenecid, between the CSF levels of tryptophan and tyrosine, and between tyrosine levels in serum and CSF. A negative correlation is found between CSF probenecid and serum tryptophan. The group of patients was divided in several ways into various subgroups. Analysis of covariance of clinical and biochemical data indicates no significant biochemical differences between any of the subgroups. This retrospective study lacks supportive evidence that any of the clinical syndromes, including the depressive syndromes, is characterized by specific deficiencies of monoamine neurotransmission.

There are indications for a functional deficiency of 5-HT and DA in certain kinds of depression. The question arises if these biochemical disturbances are primary or secondary, whether they contribute to the pathogenesis of the depression or whether they result from it. From research with MA precursors we drew the tentative conclusion that they are presumabely primary and interrelated with the depression in a causal and/or predisposing way.

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic–pituitary–adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.Molecular Psychiatry (2007) 12, 483–490. doi:10.1038/sj.mp.4001975; published online 6 March 2007 [ABSTRACT FROM AUTHOR]

In test animals, 4-chloro-N-methylamphetamine (CMA) and 4-chloro-amphetamine (4-CA) cause a decrease in the cerebral 5-HT and 5-HIAA concentrations; they exert no appreciable influence on catecholamine concentrations. In man, these compounds have a therapeutic effect on depression. In terms of antidepressant effect, they resemble not so much the nonchlorinated amphetamine derivatives as the true antidepressants. This paper considers the question whether the influence of CMA and 4-CA on the 5-HT metabolism is based on inhibition of 5-HT synthesis. No arguments to support this hypothesis were found; findings obtained did support the postulate that these compounds are 5-HT depletors. In conclusion, a possible explanation of the antidepressant effect of chlorinated amphetamine derivatives is offered. [ABSTRACT FROM AUTHOR]