Lowering of serotonin by rapid tryptophan depletion increases impulsiveness in normal individuals

Abstract Rationale. Reduced serotonergic activity has been associated with impulsive behavior; however, intervention studies have been scarce. Objectives. To examine whether induced lowering of serotonin (5-HT) levels would increase behavioral measures of impulsivity. Methods. Twenty-four healthy young males ingested a mixture of the essential amino acids except for tryptophan in a balanced, randomized, double-blind, placebo-controlled, cross-over study design. The continuous-performance test–identical pairs was administered when the plasma concentration of tryptophan was expected to be at the lowest point. The plasma concentrations of 23 amino acids were measured at baseline and 5 h after the ingestion of the amino acid mixture. Results. The intervention led to a dramatic fall in free and total plasma tryptophan, and the tryptophan/large neutral amino acids ratio. This in turn has been shown to lower the level of 5-HT in the central nervous system. The tryptophan depletion resulted in a statistically significant more impulsive- or disinhibited response style on the continuous-performance test–identical pairs when the subjects were solving verbal tasks. Depleted subjects exposed to spatial stimuli had fewer correct responses and a decreased ability to discriminate between stimuli. Conclusions. These results indicate that a rapid lowering of tryptophan increases impulsiveness and decreases discriminating ability in normal individuals. The effect of 5-HT depletion on discriminating ability in this study was similar to that previously reported in depressed patients. Electronic Publication     

Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion

Rationale Acute tryptophan depletion (ATD) is a widely used method to study the role of serotonin (5-HT) in affect and cognition. ATD results in a strong but transient decrease in plasma tryptophan and central 5-HT synthesis and availability. Although its use is widespread, the evidence that the numerous functional effects of ATD are caused by actual changes in 5-HT neuronal release is not very strong. Thus far, decreases in 5-HT efflux (thought to reflect synaptic release) were only reported after chronic tryptophan depletion or when ATD was combined with blockade of 5-HT reuptake. Objective With the current experiment, we aimed to study the validity of the method of ATD by measuring the extent to which it reduces the efflux of 5-HT (and dopamine) in the prefrontal cortex in the absence of reuptake blockage. Materials and methods We simultaneously measured in freely moving animals plasma tryptophan via a catheter in the jugular vein and 5-HT and DA efflux in the medial prefrontal cortex through microdialysis after ATD treatment. Results ATD reduced plasma tryptophan to less than 30% of control, without affecting 5-HT or DA efflux in the prefrontal cortex, indicating that even strong reductions of plasma tryptophan do not necessarily result in decreases in central 5-HT efflux. Conclusion The present experiment showed that reductions in plasma tryptophan, similar to values associated with behavioural effects, do not necessarily reduce 5-HT efflux and suggest that the cognitive and behavioural effects of ATD may not be (exclusively) due to alterations in 5-HT release.     

Emotional processing as a predictor of symptom change: An acute tryptophan depletion study in depressed patients

Acute tryptophan depletion (ATD) in currently depressed patients has no immediate effect on symptoms, but leads to transient symptom improvement or worsening the next day. In view of recent findings concerning the cognitive effects of serotonin manipulations, we used ATD in fourteen depressed patients to investigate whether cognitive effects following ATD predict symptom changes. We found that symptom improvement 24 h after ATD was associated with an improved recall of positive words and with less attentional bias and recall of negative words, 5 h after ATD. These results indicate that serotonergic alterations affect emotional processing which may subsequently lead to symptom changes.     

Effect of tryptophan depletion on the attentional salience of smoking cues

Rationale There is increasing evidence linking cigarette craving and smoking behavior to serotonergic neurotransmission. Objectives The purpose of the current study was to examine the effects of a serotonergic challenge on the attentional salience of various cues associated with cigarettes. We hypothesized that cigarette-related word cues would be more distracting after acute tryptophan depletion than after a placebo challenge. We also hypothesized that smokers vulnerable to recurrent depression would show greater attentional bias towards these cues than smokers without a history of depression. Methods Thirty-four smokers diagnosed as having (n = 15) or lacking (n = 19) a history of DSM-IV major depressive disorder (MDD) underwent acute tryptophan depletion (ATD) and placebo challenges in double-blind and counterbalanced order 1 week apart. Five hours after consumption of each mixture, subjects completed a modified Stroop task to measure attentional bias to smoking-related, positive affect, and negative affect word cues. Stroop interference was calculated as a difference score between latencies for the motivationally salient and the neutral (furniture) word lists. Results Controlling for change in dysphoric mood from baseline to 5 h, repeated measures MANOVAs showed that ATD, as compared to placebo challenge, produced greater interference for smoking word cues [F(1,29)=4.15, p = 0.05], but not for negative [F(1,29)=2.78, p = 0.11] or positive [F(1,29)=1.60, p = 0.22] affect word cues. Conclusions Acutely compromising central serotonergic neurotransmission via ATD heightens the attentional salience of cigarette-related cues, perhaps by triggering reward and motivational deficits underlying nicotine dependence.     

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers

RATIONALE: Cognitive impairment is a common feature of depressive illness. While accumulating evidence suggests that brain serotonin (5-HT) pathways play an important role in the neurobiology of depression, the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear. OBJECTIVE: The present study examined the effects of acute dietary depletion of tryptophan (TRP) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression. METHODS: We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind, placebo-controlled, crossover design. RESULTS: The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression. In particular, TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task. These deficits were not due to a global sedative effect, as planning ability was unimpaired. CONCLUSIONS: The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function, such as planning ability. These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry.     

Acute tryptophan depletion does not change somatosensory evoked magnetic fields

Rationale Serotonin is shown to regulate the activity of primary auditory cortex, but little is known about serotonin modulation of other sensory cortices.Methods We investigated somatosensory evoked magnetic fields (SEF) to left median nerve stimulation in eight healthy subjects in a double-blind, controlled, cross-over design study after acute tryptophan depletion (ATD) and control mixture. SEFs were recorded with the whole-head magnetoencephalography 6 h after ingestion of mixtures. The SEF sources and strength were estimated by a least-squares fit of a single equivalent current dipole.Results ATD decreased the total and free TPR levels by 75 and 48% and control mixture increased them by 98% and 44%. ATD had no effect on the amplitudes or latencies of SEF components. The source locations of the responses were not significantly affected by ATD.Conclusion Serotonin does not affect stimuli processing in the primary somatosensory cortex.     

Effects of tryptophan depletion on brain potential correlates of episodic memory retrieval

RATIONALE: Neuropsychological impairments in depressive illness may be secondary to proposed serotonergic abnormalities. Acute tryptophan depletion (ATD) in healthy subjects impairs episodic memory, but the mechanism of this is unclear. OBJECTIVES: To examine the effects of ATD on the neural correlates of episodic memory retrieval in healthy subjects. METHODS: Fourteen healthy men were given an amino acid cocktail drink with or without tryptophan, in a double blind, crossover design. Event related potentials (ERPs) were recorded during a well-validated episodic memory task performed 5 h after drink ingestion. Subjects listened to words spoken in a male or female voice. At test, old and new words were presented visually; subjects judged whether words were old or new, and if old, the gender of the voice at study. RESULTS: ATD led to an 84+/-5% reduction in plasma free tryptophan concentrations, and significantly impaired episodic memory recall. ERP recordings demonstrated previously reported left parietal and right frontal "old/new" differences for ERPs to items associated with accurate episodic memory retrieval versus correctly rejected new items. ATD increased ERP voltage between 500 and 1400 ms post-stimulus particularly over posterior regions of the scalp, but there was no interaction with item type. Topographical analysis of the old/new difference revealed no significant treatment by site interaction. CONCLUSIONS: ATD impairs episodic memory recall with no effect on the magnitude or topography of the neural correlates of retrieval in healthy subjects. This suggests that the effects of ATD on recall may reflect an impairment of memory encoding and/or consolidation.     

Acute tryptophan depletion and self-injurious behavior in aggressive patients and healthy volunteers

Rationale  An association between serotonin (5-HT) activity and self-injurious (i.e., self-aggressive) behavior across the spectrum of lethality (from self-mutilation through completed suicide) is a well-replicated finding. Studies to date, however, have relied on nonexperimental designs to examine this relationship, limiting the causal inferences that can be drawn about the role of 5-HT in self-aggressive behavior. Objective  Examine the effect of experimentally altered 5-HT activity (via dietary tryptophan depletion) on self-aggressive behavior among adults with and without intermittent explosive disorder (IED). Individuals with a marked history of aggression, such as those with IED, are characterized by compromised 5-HT and heightened risk for self-aggression, making this a population of interest for examining the proposed relations. Materials and methods  IED patients (n = 16) and healthy controls (n = 16) received a tryptophan depletion and a placebo drink on separate days at least 1 week apart. Self-aggressive behavior was assessed on both study days using a well-validated laboratory-based behavioral assessment with self-aggression defined as the intensity of shock self-administered. Results  Tryptophan depletion facilitated selection of more intense shocks, on average, in both groups. Patients with IED were also more self-aggressive overall than healthy volunteers. No IED by drink condition interactions were found. Conclusion  Experimentally lowered 5-HT bioavailability enhances overall self-injurious behavior irrespective of aggression history.

Effects of acute tryptophan depletion on affective processing in first-degree relatives of depressive patients and controls after exposure to uncontrollable stress

RATIONALE: Individuals with a family history of depression may be more likely to develop depression due to an innate vulnerability of their serotonergic system. However, even though serotonergic vulnerability may constitute a risk factor in the development of depression, it does not seem to be sufficient to cause a depressive episode. Based on previous data, it is suggested that stress may be a mediating factor. OBJECTIVES: This study examined the role of serotonin (5-HT) in stress coping in individuals with or without a family history of depression. MATERIALS AND METHODS: Nineteen healthy first-degree relatives of depressive patients (FH+) and 19 healthy controls without a family history of depression (FH-) were tested in a double-blind placebo-controlled design for affective processing under acute stress exposure, following acute tryptophan depletion (ATD) or placebo. RESULTS: Significant negative effects were found of stress on affective processing in FH- and FH+. In addition, FH- responded slower to positive words after stress only following ATD, whereas FH+ responded marginally slower under stress already after placebo and before stress following ATD. CONCLUSION: Acute stress exposure reduces positive affective bias; supporting the role of stress as an important predecessor in the development of depression. Furthermore, FH+ may be more susceptible than FH- to the negative effects of stress as well as to the negative effects of ATD. The results support the assumption that the 5-HT system is involved in stress resilience and may be more vulnerable in first-degree relatives of depression.     

Modulation of neural response to happy and sad faces by acute tryptophan depletion

Background Central serotonin (5HT) plays a major role in emotional processing. We used functional neuroimaging (fMRI) to investigate the effects of experimental manipulation of central 5HT levels on the regional neural response to happy and sad facial expressions. Methods Ten healthy participants (eight men and two women) were scanned during an implicit emotional processing task after receiving a tryptophan-free (acute tryptophan depletion, ATD) or a balanced amino acid drink in a double-blind design. Results ATD lowered total plasma tryptophan concentration by 80%. There was no significant effect on subjective mood ratings, on response accuracy and on reaction times. Compared to sham depletion, ATD attenuated activation in the right medial/inferior frontal gyrus, the posterior cingulate cortex, the occipital and parietal cortex bilaterally, the right hippocampus, claustrum and insula. Conversely, ATD was associated with relatively increased activation in the left inferior frontal gyrus. ATD had differential effects on activation during the processing of happy and sad faces in the right putamen and in the left superior temporal gyrus. Conclusions In both cortical and sub-cortical regions, the neural response associated with processing emotional faces is significantly modulated by 5HT manipulation resulting from ATD. Moreover, in certain areas, this effect of 5HT depends on the emotional valence of the stimulus.     

The effects of tryptophan depletion and loading on laboratory aggression in men: time course and a food-restricted control

Some studies have shown that sharp reduction of L-tryptophan (Trp) concentration in plasma results in increases in laboratory-measured aggression. Conversely, raising plasma Trp has blunted aggression. These effects are presumably due to impaired or enhanced serotonin synthesis and neurotransmission in the brain. In this study, the laboratory-measured aggressive behavior of eight men under both Trp depletion (T-) and Trp loading (T+) conditions was compared to their aggressive behavior under food-restricted control conditions (overnight fast without an amino acid beverage). Subjects were provoked by periodic subtraction of money which was attributed to a fictitious other participant, and aggression was defined as the number of retaliatory responses the subject made ostensibly to reduce the earnings of the (fictitious) other participant. Following ingestion of the T- beverage, aggressive responding was significantly elevated relative to the food-restricted control condition, and this increased aggressive behavior became more pronounced across behavioral testing sessions on a time-course which paralleled previously documented decreases in plasma Trp concentrations. In contrast, no changes were observed in aggressive responding under T+ conditions relative to food-restricted conditions. These within-subject behavioral changes under depleted plasma Trp conditions support earlier indications of a role of serotonin in regulating aggression. Received: 8 January 1998/Final version: 16 July 1998     

Acute tryptophan depletion evokes negative mood in healthy females who have previously experienced concurrent negative mood and tryptophan depletion

Introduction  The majority of individuals who suffer an episode of depression go on to experience recurrences. We have proposed, based upon the observation that reducing serotonin via acute tryptophan depletion (ATD) is more likely to induce negative mood in recovered depressed individuals than never depressed individuals, that this may be because associations form between negative mood and reduced serotonin during an episode of depression (Robinson and Sahakian, Psychol Med 38:315–318, 2008b). Such associations would mean that subsequent reductions in serotonin are more likely to provoke depressed mood and hence trigger an episode of depression. Methods  In this study, we tested this hypothesis by manipulating the mood state of healthy females undergoing ATD (or balanced placebo) on two separate testing sessions. On the first session, subjects received either negative or neutral mood induction, while on the second session all subjects received neutral mood induction. Results  Our findings demonstrate significant ATD-induced negative mood exclusively on the second visit of subjects who received both ATD and negative mood induction procedure on their first visit. Discussion  These findings may be explained by the formation of an association between the negative mood and reduced serotonin states during the first visit. As such, these findings provide preliminary support for the associative hypothesis of recurrence in depression. Conclusion  Such associations might therefore explain the discrepancy between the effects of ATD in recovered- and never-depressed individuals and may, in turn, explain why an episode of depression increases the risk of subsequent episodes.     

Differential effects of 5-HTTLPR genotypes on mood,memory, and attention bias following acute tryptophan depletion and stress exposure

Rationale  Polymorphisms of the serotonin transporter gene (5-HTTLPR) may be associated with increased vulnerability to acute tryptophan depletion (ATD) and depression vulnerability especially following stressful life events. Objective  The aim of the present study was to investigate the effects of ATD in subjects with different 5-HTTLPR profiles before and after stress exposure on affective and cognitive–attentional changes. Materials and methods  Eighteen subjects with homozygotic short alleles (S′/S′) and 17 subjects with homozygotic long alleles (L′/L′) of the 5-HTTLPR participated in a double-blind, placebo-controlled, crossover design to measure the effects of ATD on mood, memory, and attention before and after acute stress exposure. Results  ATD lowered mood in all subjects independent of genotype. In S′/S′ genotypes, mild acute stress increased depressive mood and in L′/L′ genotypes increased feelings of vigor. Furthermore, S′/S′ genotypes differed from L′/L′ genotypes on measures of attention independent of treatment and memory following ATD. Conclusions  Polymorphisms of the 5-HTTLPR differentially affect responses to mild stress and ATD, suggesting greater vulnerability of S′/S′ carriers to serotonergic manipulations and supporting increased depression vulnerability.     

Impaired recognition of fear facial expressions in 5-HTTLPR S-polymorphism carriers following tryptophan depletion

RATIONALE: Genotype at the 5' promoter region (5-HTTLPR) of the serotonin transporter has been implicated in moderating the effects of acute tryptophan depletion on neurocognitive functioning. Acute tryptophan depletion has been associated with the processing of fear-relevant cues, such as emotional expressions, but the effect of genotype at the 5-HTTLPR has not been assessed. OBJECTIVE: The present study investigated the effects of acute tryptophan depletion on the recognition of standardized facial expressions of emotions in healthy volunteers classified as ll homozygotes or s carriers. MATERIALS AND METHODS: A double-blind between-groups design was used with volunteers randomly selected to ingest capsules containing an amino acid mixture specifically lacking tryptophan, or placebo capsules containing lactose. 5 h after capsule ingestion, subjects were required to identify anger, disgust, fear, happiness, sadness, and surprise expressions that progressed from neutral to each full emotional expression in 5% steps. RESULTS: Tryptophan depletion significantly impaired the recognition of fearful facial expressions in s carriers but not ll homozygotes. This impairment was specific to fear expressions. No significant differences in the recognition of other expressions were found. Free tryptophan levels were correlated with fear recognition in s carriers but not ll homozygotes. CONCLUSIONS: The effects of acute tryptophan depletion on the processing of emotional expressions varies as a function of genotype at the 5-HTTLPR. Depletion impairs the recognition of fear in s carriers but not ll homozygotes. This finding reinforces the importance of considering genotype when assessing the behavioral effects of pharmacologic modulation.     

Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol

Rationale Sleep deprivation has a negative effect on cognitive and psychomotor performance and mood state, partially due to decreases in creatine levels in the brain. Therefore, creatine supplementation should lessen the negative effects of sleep deprivation. Objectives The objective of this study was to examine the effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Method Subjects were divided into a creatine group (n=10) and a placebo group (n=9). They took 5 g of creatine monohydrate or a placebo, dependent on their group, four times a time a day for 7 days, immediately prior to the experiment. The study was double blind. Subjects undertook tests of random movement generation (RMG), verbal and spatial recall, choice reaction time, static balance and mood state pre-test (0 h), after 6, 12 and 24 h of sleep deprivation, with intermittent exercise. They were tested for plasma concentrations of catecholamines and cortisol at 0 and 24 h. Results At 24 h, the creatine group demonstrated significantly less change in performance from 0 h (Δ) in RMG, choice reaction time, balance and mood state. There were no significant differences between groups in plasma concentrations of catecholamines and cortisol. Norepinephrine and dopamine concentrations were significantly higher at 24 h than 0 h, but cortisol were lower. Conclusions Following 24-h sleep deprivation, creatine supplementation had a positive effect on mood state and tasks that place a heavy stress on the prefrontal cortex.     

The effect of tryptophan depletion and enhancement on subjective and behavioural aggression in normal male subjects

In order to investigate the link between aggression and 5-HT, we looked at effects of changes in plasma tryptophan on healthy male subjects. Twenty-four with high trait aggression (H) and 24 with low (L) drank an amino acid mixture with (T+) or without (T–) trytophan. These caused plasma tryptophan enhancement and depletion, respectively, at 4.5 h. Group H subjects given T– became more angry, aggressive, annoyed, hostile and quarrelsome on subjective measures, whereas those given T+ responded in the opposite way. On a behavioural measure of aggression, group H subjects responded more aggressively after T– than T+. In contrast, there was no consistent effect on subjective or behavioural aggression in group L subjects. Feelings of well-being in group H were decreased by T– and increased by T+. In group L, T+ reduced feelings of well-being, possibly due to the sedative effect of tryptophan in this group, which correlated positively with plasma trytophan concentration. Changes in plasma tryptophan are probably followed by changes in central 5-HT turnover. We conclude that, in those with pre-existing aggressive traits, acute falls in central 5-HT can cause increased subjective and objective aggression, while rises can have the opposite effect. The absence of changes in a low aggressive group suggests that the primary effect may be on impulsivity, possibly mediated by 5-HT_1a receptors, expressing underlying aggressive traits. The findings on mood changes provide support for earlier reports of a lowering of mood with tryptophan depletion.     

A preliminary report on dopamine system reactivity in PKU: acute effects of haloperidol on neuropsychological, physiological, and neuroendocrine functions

Background Classic phenylketonuria (PKU) is due to an inborn error of metabolism resulting in an inability to metabolize the amino acid phenylalanine. To avoid mental retardation, affected individuals observe a phenylalanine-restricted diet. When dietary control is poor, deficits in prefrontally mediated cognitive functions have been observed. It has been suggested that these deficits are due to disruptions in the mesocortical dopamine system that projects to the prefrontal cortex.Methods In this study, dopamine system reactivity was examined in individuals with PKU, relative to age-matched controls, using the non-specific DA antagonist haloperidol, in a repeated measures placebo-controlled design. Outcome variables included neuroendocrine, physiological, and cognitive measures.Results Regardless of drug condition, PKU participants differed from control participants in their blood phenylalanine and tyrosine levels, and in their times to complete measures of attention and working memory. Also, relative to placebo, haloperidol influenced several variables irrespective of group status, including serum prolactin secretion, times to complete attention and working memory tasks, and accuracy of working memory performance. An interaction between group and drug condition was observed for the digit span task, where PKU participants exhibited greater relative impairments on haloperidol. When composite indices of impairment were derived, PKU participants demonstrated selective disruption in executive function on haloperidol relative to control subjects.Conclusions Findings are consistent with the presence of frontostriatal dysfunction in PKU but are less consistent with the notion that PFC dopamine function is specifically affected.     

A test of possible cognitive and environmental influences on the mood lowering effect of tryptophan depletion in normal males

In a previous study we found that a tryptophan-deficient amino acid mixture, designed to lower tissue tryptophan and thus brain 5-hydroxytryptamine (5HT) levels, caused a rapid (5 h) lowering of mood in normal males. Because of the importance of this evidence indicating a direct causal connection between low 5HT and low mood, we have now investigated other possible explanations for the mood lowering effect. Research strongly supports the involvement of environmental setting and cognition in the production and experience of emotions. Therefore we investigated how these factors might influence the mood-lowering effects of tryptophan depletion. In an instructional manipulation subjects were either supplied or not supplied with information designed to account for any possible peripheral sensations that might be related to depressive affect. In an environmental manipulation subjects were exposed either to a supportive and comfortable atmosphere (positive environment), or an unrewarding and unstimulating environment (negative environment). In the control group, which received a balanced amino acid mixture, the positive and negative environments had the expected effects on the scores of the Multiple Affect Adjective Checklist, thus indicating the effectiveness of these procedures. In the tryptophan depletion group neither the instructional nor the environmental manipulation had any influence on the mood lowering effect. It may be that tryptophan depletion lowers mood in normal males because low 5HT influences mood directly rather than via cognitive processes. Our data strongly support the idea that 5HT exerts an effect on mood and that low 5HT may, in some patients, be an important factor contributing to the etiology of clinical depression.     

Acute tryptophan depletion decreases intensity dependence of auditory evoked magnetic N1/P2 dipole source activity

Abstract Rationale. Intensity dependence of the N1/P2 components may be regulated by serotonergic neurons in the primary auditory cortex, where low activity leads to a high intensity dependence and vice versa. Depletion of tryptophan (TRP), a precursor for serotonin has been described to reduce serotonin content in brain of animals and humans. Objective. We investigated the intensity dependence of magnetic and electric N1/P2 components in ten subjects in a double-blind, controlled, cross-over design study after oral mixture of amino-acids leading to acute tryptophan depletion (ATD) and control. Methods. Auditory evoked magnetic fields (AEF) and potentials (AEP) were recorded with 122-channel magnetoencephalography simultaneously with 64-channel EEG 5 h after ingestion of mixtures. The AEF sources and strength were estimated by a least-squares fit of a single equivalent current dipole. The amplitudes and latencies of N1 and P2 recorded with EEG were analyzed at frontal electrode site. Results. TRP depletion decreased the total and free TRP levels by 76 and 45% and control mixture increased it by 48 and 28%. ANOVA showed that ATD had a significant main effect on the N1m/P2m dipole moments at the contralateral (P=0.02), but failed significantly to influence the ipsilateral responses. A significant mixture ingestion-by-stimulus intensity interaction was observed on the N1m/P2m dipole moments at the contralateral hemisphere (P=0.01). The N1/P2 slope for intensity dependence function was decreased following ATD compared with the control experiment (P=0.01) at the contralateral hemisphere. For EEG, a significant mixture ingestion-by-stimulus intensity interaction on the N1 latencies at the Fz electrode position was observed (P=0.01). Conclusion. ATD decreased the intensity dependence of N1m/P2m source dipole moments in the primary auditory cortex at the hemisphere contralateral to the ear stimulated. These results suggest that serotonin participates in the regulation of intensity of auditory stimulation. Electronic Publication     

Specificity of the tryptophan depletion method

Thirteen healthy subjects were subjected to tryptophan (TRP) depletion, lysine (LYS) depletion, and a placebo condition in a double blind cross-over study. The aim of the study was to test the specificity of psychological effects induced by TRP depletion. Subjects ingested a 100 g amino acid mixture with or without TRP or LYS. Six hours later, plasma TRP levels had decreased by 77% in the TRP depletion test and LYS levels by 51% in the LYS depletion condition. After 6 h of TRP depletion, subjects reported significantly more tiredness and lowering of mood, compared to subjects in the placebo group, and memory performance declined. After 6 h of LYS depletion, no significant differences in mood and memory compared to placebo were found. We conclude that the effects of TRP depletion on mood and memory are specific for the depletion of TRP and are not caused by the depletion of an amino acid per se. This supports the hypothesis that TRP depletion affects brain serotonin metabolism and not only brain protein metabolism in general. Received: 13 February 1998/Final version: 8 July 1998