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The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function., (© 2024. The Author(s).)

Background: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT 4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT 4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown., Methods: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT 4 receptor agonist) and 25 received placebo in a randomized double-blind design., Results: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions., Conclusions: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT 4 receptor agonists in humans and supports the potential for 5-HT 4 receptor agonists to be used in clinical psychiatric populations., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT 1A ) receptor in the pathophysiology of depression. Stimulation of the 5-HT 1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT 1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT 1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT 1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT 1A 'biased agonism', using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT 1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT 1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT 1A biased agonists., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT 2A receptor agonist positron emission tomography (PET) radioligand [ 11 C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [ 11 C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression., Methods: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [ 11 C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT 2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region., Results: Following d-amphetamine administration, frontal nondisplaceable binding potential (BP ND ) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBP ND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041)., Conclusions: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE., (Copyright © 2022. Published by Elsevier Inc.)

It has been over 50 years since the original serotonin hypothesis was proposed by the British Psychiatrist Alec Coppen. Recently, some authors have questioned the validity of the hypothesis. In this narrative review, we summarise the evidence for the serotonin hypothesis of depression, focusing on psychopharmacology and molecular imaging, as well as systems-level neuroscience.

Cognitive deficits commonly accompany psychiatric disorders but are often underrecognised, and difficult to treat. The 5-HT 4 receptor is a promising potential treatment target for cognitive impairment because in animal studies 5-HT 4 receptor agonists enhance hippocampal-dependent memory processes. To date, there has been little work translating these effects to humans. We tested whether short-term administration of the 5-HT 4 partial agonist, prucalopride, modified behavioural and neural (fMRI) memory processing in 44 healthy human volunteers using an experimental medicine model. We found that participants who had received six days of prucalopride treatment were significantly better at recalling previously seen neutral images and distinguishing them from new images. At a neural level, prucalopride bilaterally increased hippocampal activity and activity in the right angular gyrus compared with placebo. Taken together, these findings demonstrate the potential of 5-HT 4 -receptor activation for cognitive enhancement in humans, and support the potential of this receptor as a treatment target for cognitive impairment., (© 2021. The Author(s).)

How do people sustain resources for the benefit of individuals and communities and avoid the tragedy of the commons, in which shared resources become exhausted? In the present study, we examined the role of serotonin activity and social norms in the management of depletable resources. Healthy adults, alongside social partners, completed a multiplayer resource-dilemma game in which they repeatedly harvested from a partially replenishable monetary resource. Dietary tryptophan depletion, leading to reduced serotonin activity, was associated with aggressive harvesting strategies and disrupted use of the social norms given by distributions of other players' harvests. Tryptophan-depleted participants more frequently exhausted the resource completely and also accumulated fewer rewards than participants who were not tryptophan depleted. Our findings show that rank-based social comparisons are crucial to the management of depletable resources, and that serotonin mediates responses to social norms., (© The Author(s) 2014.)

The ability to match individual patients to tailored treatments has the potential to greatly improve outcomes for individuals suffering from major depression. In particular, while the vast majority of antidepressant treatments affect either serotonin or noradrenaline or a combination of these two neurotransmitters, it is not known whether there are particular patients or symptom profiles which respond preferentially to the potentiation of serotonin over noradrenaline or vice versa. Experimental medicine models suggest that the primary mode of action of these treatments may be to remediate negative biases in emotional processing. Such models may provide a useful framework for interrogating the specific actions of antidepressants. Here, we therefore review evidence from studies examining the effects of drugs which potentiate serotonin, noradrenaline or a combination of both neurotransmitters on emotional processing. These results suggest that antidepressants targeting serotonin and noradrenaline may have some specific actions on emotion and reward processing which could be used to improve tailoring of treatment or to understand the effects of dual-reuptake inhibition. Specifically, serotonin may be particularly important in alleviating distress symptoms, while noradrenaline may be especially relevant to anhedonia. The data reviewed here also suggest that noradrenergic-based treatments may have earlier effects on emotional memory that those which affect serotonin.

Background: Close supportive relationships protect against psychological disorders and also facilitate recovery. However, little is known about the neurochemical mechanisms that mediate these effects. Variation in serotonin function influences affiliative behavior in humans and nonhuman primates. Here, we used tryptophan depletion in healthy adults to investigate the role of serotonin in the cognitive appraisal of close personal relationships., Methods: Twenty-two healthy adults drank an amino acid drink without tryptophan, and 19 healthy adults drank an amino acid drink containing tryptophan. Participants were presented with color photographs of heterosexual "couples" standing apart or making affiliative touch gestures and rated the couples for descriptors that capture qualities of close personal relationships. Trait attachment style and state affect of participants were also measured., Results: Tryptophan depletion reduced the judged intimacy and romance of photographed couples. Tryptophan-depleted women rated men as more dominant in relationships and touching couples as more able to resolve their conflicts, when compared with nondepleted women. These effects were not due to changes in mood and remained statistically reliable when the marked impact of attachment style upon relationship judgments was statistically controlled., Conclusions: Our results suggest that central serotonin activity influences the appraisal of close intimate partnerships, raising the possibility that serotonergic dysfunction contributes to altered cognitions about relationships in psychiatric illnesses., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Mood disorders such as major depression are common illnesses with considerable morbidity and significant mortality. A long-standing theory is that a breakdown in brain serotonin (5-hydroxytryptamine; 5-HT) signalling is critically involved in the symptoms and drug treatment of clinical depression. However, the nature of this 5-HT defect has proved to be frustratingly elusive, and it remains unclear how the 5-HT signalling effects of antidepressant drugs might alter neuropsychological mechanisms to bring about relief of depressed mood. This article highlights recent discoveries that advance our understanding of how 5-HT-evoked changes at molecular, cellular and neuropsychological levels might interact to alleviate the symptoms of clinical depression., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Risky decision-making involves weighing good and bad outcomes against their probabilities in order to determine the relative values of candidate actions. Although human decision-making sometimes conforms to rational models of how this weighting is achieved, irrational (or nonnormative) patterns of risky choice, including shifts between risk-averse and risk-seeking choices involving equivalent-value gambles (the "reflection effect"), are frequently observed. In the present experiment, we investigated the role of serotonin in decision-making under conditions of uncertainty. Fifteen healthy adult volunteers received a treatment of 3 g per day of the serotonin precursor, tryptophan, in the form of dietary supplements over a 14-day period, whereas 15 age- and IQ-matched control volunteers received a matched placebo substance. At test, all participants completed a risky decision-making task involving a series of choices between two simultaneously presented gambles, differing in the magnitude of their possible gains, the magnitude of their possible losses, and the probabilities with which these outcomes were delivered. Tryptophan supplements were associated with alterations in the weighting of gains and small losses perhaps reflecting reduced loss-aversion, and a marked and significant diminution of the reflection effect. We conclude that serotonin activity plays a significant role in nonnormative risky decision-making under conditions of uncertainty.

The notion that impaired serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial. Some have argued that the 5-HT hypothesis has been misused by the pharmaceutical industry to promote a simplistic biological model of depression to market selective serotonin reuptake inhibitors (SSRIs) to medical practitioners and the public. By contrast, there is now substantial evidence that unmedicated depressed patients have abnormalities in brain 5-HT function; however, the relation of these abnormalities to the clinical syndrome is unclear. The best evidence that 5-HT contributes to the pathophysiology of depression comes from studies of tryptophan depletion, which show that lowering brain 5-HT levels can induce acute symptomatic relapse in recovered depressed patients. Clarification of the mechanism of this effect will enable an understanding of how impaired 5-HT activity contributes to the subjective experience of depression.

Acute oral administration of selective serotonin re-uptake inhibitors (SSRIs) increases plasma cortisol by facilitating brain serotonin activity. Recently, salivary cortisol sampling has grown in popularity as a noninvasive means of assessing HPA axis activity. The aim of the present study was to find out whether acute oral administration of the SSRI, citalopram, increases salivary cortisol in healthy volunteers and whether the increase produced by an equivalent dose of its active isomer, escitalopram, is greater. A total of 15 healthy subjects were tested on three occasions receiving either oral citalopram (20 mg), escitalopram (10 mg), or placebo in a double-blind, randomized, crossover design. Salivary cortisol and plasma cortisol and prolactin were measured for 240 min after each treatment. Relative to placebo, both citalopram and escitalopram increased salivary and plasma cortisol levels with no evidence of consistent differences between them. Plasma prolactin concentration was not altered by either active treatment. Plasma and salivary cortisol responses after citalopram but not escitalopram correlated significantly. The present study does not support an enhanced effect of escitalopram on 5-HT-mediated neuroendocrine responses.

Background: Recent formulations of the pathophysiology of major depression suggest that stress-induced cortisol secretion may lower brain serotonin (5-HT) function, thereby precipitating depressive symptomatology. This implies that people who develop depression after stressful life events may be particularly vulnerable to the effect of cortisol on brain 5-HT activity. We therefore assessed the effect of a single dose of hydrocortisone on 5-HT-mediated growth hormone (GH) release in healthy volunteers and euthymic subjects recovered from at least two episodes of major depression., Methods: Eleven recovered depressed patients and 20 healthy controls received intravenous tryptophan (TRP) 10.5 h after placebo and hydrocortisone (50 mg orally) in a double-blind, cross-over design. Plasma GH levels were sampled for 90 min after TRP infusion., Results: The GH response to TRP was significantly lower in the recovered depressed patients than controls after hydrocortisone., Limitations: The number of recovered depressed subjects studied was small and the effect of hydrocortisone on TRP-induced GH release was different to that observed in a previous study., Conclusions: These findings are consistent with other evidence suggesting abnormal regulation of 5-HT neurotransmission in people vulnerable to recurrent depression.

Background: Neuroendocrine studies of brain serotonin (5-HT) function in depression generally show evidence of impaired 5-HT function but it is disputed whether or not this impairment resolves with clinical recovery., Aims: To use the endocrine response to the selective 5-HT reuptake inhibitor, citalopram, to study brain 5-HT function in acute and recovered depressed subjects relative to healthy controls., Method: We used a double-blind, placebo-controlled design to measure the prolactin and cortisol responses to citalopram (10 mg intravenously) in patients with major depression, in unmedicated subjects recovered from depression and in healthy controls., Results: The prolactin responses to citalopram were blunted similarly in both acutely depressed and recovered subjects. The cortisol responses were blunted in the acutely depressed patients but not in the recovered subjects., Conclusions: Our data support the proposal that some aspects of impaired 5-HT neurotransmission may be trait markers of vulnerability to depression. The recovery of the cortisol response to citalopram may indicate resolution of hypothalamic-pituitary-adrenal axis dysfunction.

Abnormal serotonergic function is implicated in the pathogenesis of affective disorders. We induced transient depressive relapses in volunteer patients by rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT), and measured neural activity during different cognitive tasks using positron emission tomography (PET). Neural activity in several 5-HT-related brain areas, e.g., dorsal raphé, habenula, septal region, amygdala, and orbitofrontal cortex, covaried significantly with plasma levels of tryptophan and ratings of depressed mood. Task-specific responses in left amygdala and left anterior cingulate were attenuated by tryptophan depletion. We used these PET data to test the hypothesis that projections from the habenula modulate dorsal raphé activity and that this modulation is enhanced in patients experiencing a profound mood change following serotonergic challenge. A strong linear correlation (r(2) > 0.5) between habenula and raphé activity was observed in subjects with postdepletion ratings >/=10 on a modified Hamilton depression scale, whereas subjects experiencing milder changes in mood had weaker habenula-raphé coupling (r(2) < 0.5). These data support a model of the serotonergic system in which the habenula projection to the raphé represents a convergent feedback pathway that controls the release of 5-HT throughout the brain. In our experiment we were able to engage this system in patients who were sensitive to tryptophan depletion., (Copyright 1999 Academic Press.)

The antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) might be enhanced by co-administration of 5-HT1A receptor antagonists. Thus, we have recently shown that the selective 5-HT1A receptor antagonist, WAY 100635, blocks the inhibitory effect of an SSRI on 5-HT cell firing, and enhances its ability to elevate extracellular 5-HT in the forebrain. Here we determined whether the beta-adrenoceptor/5-HT1A receptor ligands (+/-)-pindolol, (-)-tertatolol and (-)-penbutolol, interact with paroxetine in a similar manner. Both (-)-tertatolol (2.4 mg kg(-1) i.v.) and (-)-penbutolol (2.4 mg kg(-1) i.v.) enhanced the effect of paroxetine (0.8 mg kg(-1) i.v.) on extracellular 5-HT in the frontal cortex, whilst (+/-)-pindolol (4 mg kg(-1) i.v.) did not. (-)-Tertatolol (2.4 mg kg(-1) i.v.) alone caused a slight increase in 5-HT however, (-)-penbutolol (2.4 mg kg(-1) i.v.) alone had no effect. In electrophysiological studies (-)-tertatolol (2.4 mg kg(-1) i.v.) alone had no effect on 5-HT cell firing but blocked the inhibitory effect of paroxetine. In contrast, (-)-penbutolol (0.1-0.8 mg kg(-1) i.v.) itself inhibited 5-HT cell firing, and this effect was reversed by WAY 100635 (0.1 mg kg(-1) i.v.). We have recently shown that (+/-)-pindolol inhibits 5-HT cell firing via a WAY 100635-sensitive mechanism. Our data suggest that (-)-tertatolol enhances the effect of paroxetine on forebrain 5-HT via blockade of 5-HT1A autoreceptors which mediate paroxetine-induced inhibition of 5-HT cell firing. In comparison, the mechanisms by which (-)-penbutolol enhances the effect of paroxetine on extracellular 5-HT is unclear, since (-)-penbutolol itself appears to have agonist properties at the 5-HT1A autoreceptor. Indeed, the agonist action of (+/-)-pindolol at 5-HT1A autoreceptors probably explains its inability to enhance the effect of paroxetine on 5-HT in the frontal cortex. Overall, our data suggest that both (-)-tertatolol and (-)-penbutolol are superior to (+/-)-pindolol in terms of enhancing the effect of an SSRI on extracellular 5-HT. Both (-)-tertatolol and (-)-penbutolol are worthy of investigation for use as adjuncts to SSRIs in the treatment of major depression.

Background: Preclinical and clinical studies suggest that lowered brain serotonin neurotransmission may contribute to the pathophysiology of bulimia nervosa (BN). The aim of our study was to test this hypothesis by examining the psychological effects of a dietary-induced impairment in serotonin activity in subjects known to be at risk for manifestation of the clinical syndrome of BN., Methods: An 85.8 g amino acid mixture lacking the serotonin precursor tryptophan and a balanced mixture were administered to 10 clinically recovered, medication-free female subjects with a history of BN in a double-blind, crossover design. Twelve healthy female subjects with no history of psychiatric disorder were studied as a comparison group. Observer and self-rated measures of mood and eating disorder cognitions were made for the 7 hours following administration of each amino acid mixture., Results: Compared with healthy controls, subjects with a history of BN had significant lowering of mood, increases in ratings of body image concern, and subjective loss of control of eating following the tryptophan-free mixture., Conclusions: Our results suggest that diminished serotonin activity may trigger some of the cognitive and mood disturbances associated with BN. Our findings support suggestions that chronic depletion of plasma tryptophan may be one of the mechanisms whereby persistent dieting can lead to the development of eating disorders in vulnerable individuals.

Dieting is a common behaviour which may trigger eating disorders such as bulimia nervosa in predisposed subjects. We found that in healthy women moderate dieting for 3 weeks lowered plasma concentrations of the 5-HT precursor, L-tryptophan (TRP) and impaired brain 5-HT neurotransmission as judged by 5-HT neuroendocrine tests. In recovered female subjects with a history of bulimia nervosa we found that TRP depletion produced by an amino acid mixture lacking TRP caused a temporary return of depressive symptoms together with concerns about weight and shape and fear of loss of control of eating. Taken together the data suggest that dieting-induced decreases in TRP availability may trigger the development of bulimia nervosa is susceptible individuals.

Background: Animal experimental studies suggest that repeated administration of selective serotonin reuptake inhibitors (SSRIs) produces complex adaptive changes in brain serotonin (5-HT) pathways. The effect of these adaptive changes on different aspects of brain 5-HT neurotransmission and their clinical consequences are not well understood., Method: We studied the effect of repeated administration of the SSRI, paroxetine (20 mg daily), on the cortisol responses to the 5-HT precursor, 5-hydroxytryptophan (5-HTP), in healthy subjects and depressed patients., Results: In healthy subjects, following one week of paroxetine treatment there was a large increase in the cortisol response to 5-HTP. This increase had all but disappeared following 3 weeks treatment. In contrast, in depressed patients treated with paroxetine for 8 weeks, the cortisol response to 5-HTP was significantly increased., Conclusions: SSRI treatment in depressed patients produces a persistent increase in the cortisol response to 5-HTP, a probable measure of neurotransmission at central 5-HT2 receptors. Potentiation of 5-HT2 neurotransmission is unlikely to account for the efficacy of SSRIs in major depression but might underlie their actions in obsessive-compulsive disorder and also perhaps certain of their adverse effects, notably sexual dysfunction.

Background: Drugs that potentiate brain serotonin (5-HT) neurotransmission are effective in the treatment of obsessive-compulsive disorder (OCD), but it is unclear whether disturbances in brain 5-HT function play a role in the pathophysiology of OCD., Method: We studied the prolactin response to the selective 5-HT releasing agent d-fenfluramine in 14 non-depressed, drug-free OCD patients, and 14 healthy controls matched for age and gender., Results: The prolactin response to d-fenfluramine was significantly increased in OCD patients compared with controls., Conclusions: The disparate results of studies of 5-HT neuroendocrine function in OCD make it unlikely that disturbances of brain 5-HT function play a central role in the pathophysiology of OCD. Increased brain 5-HT neurotransmission in non-depressed OCD subjects may represent an adaptive neurobehavioural mechanism which can be amplified to therapeutic advantage by treatment with 5-HT potentiating drugs.

Background: Major depression is a common disorder but the pathophysiology is poorly understood. Current hypotheses implicate deficient function of brain serotonin pathways because drugs that selectively increase brain serotonin activity are effective antidepressants. However, there is no direct evidence that lowered serotonin function causes major depression. We aimed to assess whether lowering of brain serotonin activity by depletion of its amino acid precursor, tryptophan, could provoke a short-term relapse of clinically significant symptoms in women vulnerable to major depressive disorder., Methods: We studied 15 women who had suffered recurrent episodes of major depression but had recovered and were no longer on drug treatment. Patients received two amino acid mixtures in a double-blind crossover design. One of the mixtures was nutritionally balanced and contained tryptophan and the other was identical except it contained no tryptophan. Participants were scored on the Hamilton rating scale for depression (HAMD) before and 7 h after drinking each mixture. They also completed hourly self-rated measures of mood during this period. Blood samples were also taken at baseline and 7 h for measurement of plasma tryptophan., Findings: The tryptophan-free mixture produced a 75% reduction in plasma tryptophan concentration. After drinking the tryptophan-free mixture, ten of the 15 women experienced temporary but clinically significant depressive symptoms. The mean difference in total HAMD scores (7 h minus baseline) were significantly higher after the tryptophan-free mixture than after the nutritionally balanced mixture (7.3 vs 0.15 [95% CI 4.5-9.9]; p < 0.001). No changes in mood were seen after taking the nutritionally balanced mixture., Interpretation: We conclude that rapid lowering of brain serotonin function can precipitate clinical depressive symptoms in well, untreated individuals who are vulnerable to major depressive disorder. The findings support a key role for deficient serotonin function in the aetiology of depression.

Background: Animal experimental studies suggest that the amino acid valine may decrease brain serotonin (5-HT) function by inhibiting the transport of the 5-HT precursor, L-tryptophan, across the blood barrier. The aim of the present study was to assess whether valine could decrease brain 5-HT function in healthy subjects and provoke symptomatic relapse in recently remitted depressed patients taking antidepressant drug treatment., Method: We studied the effect of valine (30 g) on the prolactin (PRL) response to the 5-HT releasing agent, D-fenfluramine, in healthy male subjects and on the mood of 12 remitted depressed patients taking either selective serotonin re-uptake inhibitors (n = 10) or lithium and amitriptyline (n = 2)., Results: Valine significantly lowered the PRL response to D-fenfluramine in healthy subjects. In the remitted depressives, valine caused a mild but detectable lowering of mood on a number of measures but only one patient experienced a significant relapse in mood., Conclusions: Valine administration may decrease brain 5-HT neurotransmission in humans. This effect could explain the mild increase in depressive symptoms in patients taking 5-HT-potentiating drugs.

We studied the effect of 3 weeks of moderate calorie restriction on 5-HT-mediated prolactin (PRL) release in healthy volunteers using the 5-HT-releasing agent d-fenfluramine. In women, dieting significantly lowered plasma total and free tryptophan (TRP) and increased the PRL response to d-fenfluramine. None of these measures were altered in men who dieted. These findings add to the data indicating that dieting alters brain 5-HT function in women, perhaps as a consequence of reducing the availability of plasma TRP.

Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA and d-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect of d-fenfluramine might also be sensitive to lesions produced by PCA, MDMA and d-fenfluramine itself. Basal and 5-HT release evoked by d-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA, d-fenfluramine, or vehicle. In frontal cortex of vehicle controls, d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reduced d-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg x 8) and d-fenfluramine (1.25 mg/kg x 8) pretreatment reduced d-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked by d-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA and d-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data from d-fenfluramine challenge tests is discussed.

The effects of hydrocortisone administration (20 mg, orally, twice daily) on the sensitivity of brain 5-HT1A receptors in healthy volunteers were studied using a buspirone challenge paradigm. The effects of hydrocortisone administration on sleep architecture were also studied. Hydrocortisone treatment significantly attenuated the hypothermic and cortisol responses to buspirone; however, the prolactin and growth hormone responses were unchanged. Hydrocortisone also decreased the amount of rapid eye movement sleep (REM). The ability of hydrocortisone to attenuate 5-HT1A receptor mediated hypothermia and decrease REM sleep is shared by certain antidepressant treatments and may be related to the effects of corticosteroids on mood.

We studied the effect of the tricyclic antidepressant lofepramine (140-210 mg daily for 16 days) on 5-hydroxytryptamine 1A (5-HT1A) receptor sensitivity in healthy volunteers, using a buspirone neuroendocrine challenge paradigm (30 mg orally). We also studied the effect of lofepramine on platelet 5-HT content and sleep architecture. Lofepramine treatment did not alter the hypothermic, endocrine or amnesic effects of buspirone but significantly lowered platelet 5-HT content and decreased rapid eye movement sleep. Our findings suggest that at clinically used doses, lofepramine inhibits the uptake of 5-HT and produces changes in sleep architecture characteristic of tricyclic antidepressants. However, lofepramine does not appear to alter the sensitivity of 5-HT1A receptors.

Serotonin (5-HT) neuroendocrine tests are a valid and acceptable means of measuring 5-HT neurotransmission in humans. Recently, the availability of selective 5-HT receptor ligands has allowed the assessment of specific 5-HT receptor subtype function using neuroendocrine methods. Studies with selective antagonists have shown that the endocrine responses to the 5-HT precursor L-tryptophan (LTP) are mediated via postsynaptic 5-HT1A receptors, whereas endocrine responses produced by the 5-HT-releasing agent d-fenfluramine involve postsynaptic 5-HT2/1C receptors. Endocrine responses to both LTP and fenfluramine are consistently decreased in depressive illness. In contrast, endocrine responses to direct 5-HT1A and 5-HT2/1C receptor agonists are not consistently attenuated in depressed patients. The current data suggest that depressive illness is associated with an impairment of 5-HT neurotransmission that involves decreased 5-HT release rather than altered sensitivity of postsynaptic 5-HT receptors.

The prolactin response to intravenous clomipramine, a 5-HT uptake inhibitor, was significantly attenuated in 12 patients with major depression. In contrast, in a further 12 depressed patients, the PRL responses to thyrotropin-releasing hormone, which acts directly on the pituitary to release PRL, were not reduced. These findings suggest that the reduction in 5-HT-mediated PRL release seen in depressed patients is due to an impairment of brain 5-HT function rather than a pituitary abnormality.

The effect of systemic administration of the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP) on the release of 5-HT in the lateral hypothalamus of the chloral hydrate-anaesthetized rat in vivo was examined using brain microdialysis. Administration of 5-HTP caused an immediate increase of 5-HT in dialysates, which was long lasting (greater than or equal to 140 min) and dose-dependent (30-100 mg/kg i.p.). When calcium was omitted from the perfusion medium, thereby limiting exocytosis, levels of basal 5-HT were significantly decreased and the 5-HTP-induced response of 5-HT was markedly attenuated. Administration of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (0.25 mg/kg i.p.), which selectively inhibits serotoninergic neuronal activity by activation of the somatodendritic 5-HT autoreceptor, significantly decreased basal levels of 5-HT and markedly attenuated the 5-HTP-induced increase in 5-HT. The data demonstrate that systemic administration of 5-HTP caused an increase in the release of 5-HT in the hypothalamus. Furthermore, this release occurred by a calcium-dependent mechanism (probably exocytosis), was dependent on serotoninergic neuronal activity and predominantly derived from 5-HT neurones. The findings are discussed in relation to the behavioral and neuroendocrine effects of increasing availability of the 5-HT precursor.

L-Valine competes with tryptophan for transport into the brain and has previously been shown to decrease brain 5-HT synthesis. In the present study, the effect of L-valine on electrically evoked hippocampal 5-HT release was determined in the anaesthetized rat using microdialysis. In control animals two electrical stimulations of the dorsal raphe nucleus 120 min apart (S1 and S2, respectively) released similar amounts of 5-HT. In contrast, in animals which received L-valine (200 mg/kg) between stimulations, S2 released a significantly smaller amount of 5-HT than did S1, although basal 5-HT release was unchanged. The data demonstrate that L-valine decreases the electrically-evoked release of 5-HT in hippocampus in vivo.

A three week low calorie diet significantly reduced both total plasma tryptophan and the ratio of tryptophan to competing amino acids in a group of 15 healthy volunteers. Despite a similar percentage weight loss the reduction in plasma tryptophan was greater in women than men. In addition, only in women was dieting associated with increased prolactin secretion following intravenous tryptophan, a measure of brain 5-hydroxytryptamine (5-HT) function. These results suggest that dieting reduces the availability of circulating tryptophan for brain 5-HT synthesis. Women appear more vulnerable than men both to this effect and to its consequences for brain 5-HT function. Altered brain 5-HT function may play a part in some of the psychological consequences of dieting, including the development of clinical eating disorders.

Increasing brain 5-hydroxytryptamine (5-HT) function in humans raises plasma concentrations of prolactin, growth hormone and ACTH. Measurement of these hormonal responses provides an index of the functional activity of brain 5-HT pathways. More recent strategies have included the use of directly-acting 5-HT receptor agonists to probe the function of specific receptor subtypes; at present these studies are limited by the questionable selectivity of the agonists employed. Using 5-HT neuroendocrine testing it can be shown that lithium specifically increases the prolactin release mediated by 5-HT pathways. Further studies are needed to determine if this effect is caused by an enhanced sensitivity of post-synaptic 5-HT1A receptors.

There is increasing evidence that neuroendocrine and temperature responses in humans can be employed to study the functional sensitivity of different 5-HT receptor subtypes. The evidence suggests that the PRL response to LTP is mediated by 5-HT1 receptors, perhaps the 5-HT1A subtype, though further studies are needed to confirm this effect. It is uncertain whether the PRL responses to other 'presynaptic' challenges of 5-HT function, for example, fenfluramine, are mediated by the same post-synaptic 5-HT receptor subtype as that for LTP. Conversely it seems likely that agonists which stimulate 5-HT2/1C receptors increase both plasma PRL and ACTH in humans. There is also evidence that 5-HT1A receptors can increase ACTH secretion. This suggests that in humans as in animals both the 5-HT1A and 5HT2/1C receptors can facilitate ACTH release, though the significance of this dual control is not understood. It is also possible that both 5-HT1A and 5-HT2/1C receptors stimulate PRL release, but 5-HT1A receptors may have a more prominent role in GH secretion. In both human and animal studies 5-HT1A and 5-HT2 receptor agonists may produce opposite effects on body temperature. These recent developments in 5-HT neuroendocrinology have been of great interest, but much is still uncertain. Progress in this field will be considerably advanced by the availability of new selective 5-HT receptor ligands, particularly selective receptor antagonists.

Administration of antidepressant drugs to rodents appears to decrease 5-HT2 receptor function while transmission through postsynaptic 5-HT1 receptor synapses may be enhanced. Antidepressant drugs also alter 5-HT mechanisms in humans; some of these changes are congruent with effects noted in animal studies. Thus certain 5-HT-mediated neuroendocrine responses are enhanced by tricyclic antidepressants and monoamine oxidase inhibitors, and it seems likely that tricyclics may act as 5-HT2 receptor antagonists in the human brain. However, there is presently no firm evidence that any of these changes are necessary for the clinical efficacy of antidepressant drugs. The best evidence that 5-HT neurons may be involved in mediating antidepressant effects is the antidepressant activity of selective 5-HT uptake blockers.

The effect of lithium on serotonin (5-HT)-mediated responses in the brain was assessed by measuring changes in the prolactin (PRL) and growth hormone (GH) responses to L-tryptophan (LTP) in eight normal subjects. On the 4th day of lithium treatment the PRL responses were significantly enhanced, and this enhancement was still apparent after 20 days' treatment. In contrast, GH responses to LTP were not altered. Lithium had no effect on platelet 5-HT content, platelet imipramine binding and platelet 5-HT receptor binding. The ability of lithium to enhance some aspects of brain 5-HT function may be important in its mode of action in manic-depressive illness and may be particularly relevant to its potentiation of the antidepressant effect of tricyclic antidepressants.

Intravenous infusion of L-tryptophan (LTP) in 18 normal subjects produced a significant increase in plasma prolactin (PRL), growth hormone (GH), and self-ratings of drowsiness. There was no correlation between the PRL and GH responses, or between the hormonal responses and drowsiness. Saline infusion did not result in endocrine or psychological changes. The effect of LTP on both PRL and GH was dose-related in that LTP 7.5 g produced greater endocrine responses than 5.0 g. It was not significantly decreased by cyproheptadine, a 5-HT receptor antagonist. Schizophrenic patients receiving neuroleptics had increased PRL response to LTP, possibly because of the drug-induced disinhibition of PRL release. Their GH response to LTP was markedly decreased. The mechanism of this effect requires further investigation.