Effects Of Acute Tryptophan Depletion Research Articles

A central serotonin regulating gene polymorphism (TPH2) determines vulnerability to acute tryptophan depletion-induced anxiety and ventromedial prefrontal threat reactivity in healthy young men

Serotonin (5-HT) has long been implicated in adaptive emotion regulation as well as the development and treatment of emotional dysregulations in mental disorders. Accumulating evidence suggests a genetic vulnerability may render some individuals at a greater risk for the detrimental effects of transient variations in 5-HT signaling. The present study aimed to investigate whether individual variations in the Tryptophan hydroxylase 2 (TPH2) genetics influence susceptibility for behavioral and neural threat reactivity dysregulations during transiently decreased 5-HT signaling. To this end, interactive effects between TPH2 (rs4570625) genotype and acute tryptophan depletion (ATD) on threat reactivity were examined in a within-subject placebo-controlled pharmacological fMRI trial (n = 51). A priori genotype stratification of extreme groups (GG vs. TT) allowed balanced sampling. While no main effects of ATD on neural reactivity to threat-related stimuli and mood state were observed in the entire sample, accounting for TPH2 genotype revealed an ATD-induced increase in subjective anxious arousal in the GG but not the TT carriers. The effects were mirrored on the neural level, such that ATD specifically reduced ventromedial prefrontal cortex reactivity towards threat-related stimuli in the GG carriers. Furthermore, the ATD-induced increase in subjective anxiety positively associated with the extent of ATD-induced changes in ventromedial prefrontal cortex activity in response to threat-related stimuli in GG carriers. Together the present findings suggest for the first time that individual variations in TPH2 genetics render individuals susceptible to the anxiogenic and neural effects of a transient decrease in 5-HT signaling.

Acute tryptophan depletion balances altered resting-state functional connectivity of the salience network in female patients recovered from anorexia nervosa.

Background:It has been suggested that individuals predisposed to or recovered from anorexia nervosa experience a hyperserotonergic state associated with anxiety that might be mitigated by restricted food intake, because diminished levels of the tryptophan precursor lower the central availability of serotonin (5-HT). At the neural level, the salience network is a system of functionally connected brain regions; it has been closely associated with 5-HT functioning and mental disorders (including anorexia nervosa). The aim of the present study was to investigate the effect on the salience network of a temporary dietary manipulation of 5-HT synthesis in patients with anorexia nervosa.Methods:In this double-blind crossover study, we obtained data on resting-state functional connectivity from 22 weight-recovered female patients with a history of anorexia nervosa, and 22 age-matched female healthy controls. The study procedure included acute tryptophan depletion (a dietary intervention that lowers the central 5-HT synthesis rate) and a sham condition.Results:We identified an interaction of group and experimental condition in resting-state functional connectivity between the salience network and the orbitofrontal cortex extending to the frontal pole (F1,42 = 12.52; pFWE = 0.026). Further analysis revealed increased resting-state functional connectivity during acute tryptophan depletion in patients recovered from anorexia nervosa, resembling that of healthy controls during the sham condition (T42 = −0.66; p = 0.51).Limitations:The effect of acute tryptophan depletion on the central availability of 5-HT can be judged only indirectly using plasma ratios of tryptophan to large neutral amino acids. Moreover, the definition of anorexia nervosa recovery varies widely across studies, limiting comparability.Conclusion:Taken together, our findings support the notion of 5-HT dysregulation in anorexia nervosa and indicate that reduced 5-HT synthesis and availability during acute tryptophan depletion (and possibly with food restriction) may balance hyperserotonergic functioning and the associated resting-state functional connectivity of the salience network.

Acute tryptophan depletion alters affective touch perception

RationaleAffiliative tactile interactions help regulate physiological arousal and confer resilience to acute and chronic stress. C-tactile afferents (CTs) are a population of unmyelinated, low threshold mechanosensitive cutaneous nerve fibres which respond optimally to a low force stimulus, moving at between 1 and 10 cm/s. As CT firing frequencies correlate positively with subjective ratings of touch pleasantness, they are hypothesised to form the first stage of encoding affiliative tactile interactions. Serotonin is a key modulator of social responses with known effects on bonding.ObjectivesThe aim of the present study was to determine the effect of acutely lowering central serotonin levels on perceptions of CT-targeted affective touch.MethodsIn a double blind, placebo-controlled design, the effect of acute tryptophan depletion (ATD) on 25 female participants’ ratings of directly and vicariously experienced touch was investigated. Psychophysical techniques were used to deliver dynamic tactile stimuli; some velocities were targeted to optimally activate CTs (1–10 cm/s), whereas other, faster and slower strokes fell outside the CT optimal range. Discriminative tactile function, cold pain threshold and tolerance were also measured.ResultsATD significantly increased pleasantness ratings of both directly and vicariously experienced affective touch, increasing discrimination of the specific hedonic value of CT targeted velocities. While ATD had no effect on either tactile or cold pain thresholds, there was a trend for reduced tolerance to cold pain.ConclusionsThese findings are consistent with previous reports that depletion of central serotonin levels modulates neural and behavioural responsiveness to appetitive sensory signals.

No effects of acute tryptophan depletion on anxiety or mood in weight-recovered female patients with anorexia nervosa

BackgroundPrevious studies have suggested that individuals recovered from anorexia nervosa (AN) are characterized by increased serotonergic (5-HT) activity that might be related to elevated levels of anxiety. Assuming these traits to be also present in individuals at risk for AN, it was further hypothesized that restricting food intake might be a means to temporarily alleviate dysphoric affective states by reducing central nervous availability of tryptophan (TRP), the sole precursor of 5-HT. One study that supported this hypothesis found anxiolytic effects in individuals with a history of AN during an experimentally induced short-term depletion of TRP supply to the brain.MethodsIn this placebo-controlled, double-blind cross-over study, 22 patients weight-recovered from AN (recAN) and 25 healthy control participants (HC) completed questionnaires assessing anxiety and momentary mood during acute tryptophan depletion (ATD), a dietary intervention that lowers central 5-HT synthesis.ResultsThe ATD procedure effectively reduced the ratio of TRP to competing for large neutral amino acids in the peripheral blood, indicating decreased TRP supply to the brain. Effects of ATD on anxiety and mood did not differ between recAN and HC. Bayesian null hypothesis testing confirmed these initial results.DiscussionOur results do not support the hypothesis that short-term depletion of TRP and its impact on the brain 5-HT reduces anxiety or improves mood in AN. As the evidence for the role of 5-HT dysfunction on affective processes in patients with AN is limited, further studies are needed to assess its relevance in the pathophysiology of AN.

Acute tryptophan depletion in healthy subjects increases preferences for negative reciprocity.

Reciprocity motivates to reward those who are kind (= positive reciprocity) and to punish those who are unkind (= negative reciprocity). The neurotransmitter serotonin (5-HT) modulates human behavior in numerous social situations, such as retaliation in response to perceived unfairness. In a placebo-controlled study, we used acute tryptophan depletion (ATD) to investigate the influence of available serotonin on choice behavior and reciprocity in the Hawk-Dove game. This game illustrates a conflict situation and incorporates two potential strategies: the cooperative Dove strategy and the uncooperative, more aggressive Hawk strategy. After strategic choices, we elicited the subjects’ expectations (= beliefs) regarding the opponent’s choices and controlled for risk preferences and current mood. We defined strategy choices as negative reciprocity when the participants opted for Hawk in response to an expected Hawk. We hypothesized that the ATD-induced reduction of 5-HT availability would increase participants’ preferences for negative reciprocity. Generalized estimating equations reveal no significant main effect of ATD on assessed belief, mood, or risk attitude. But assessment of ATD’s marginal effects over beliefs suggests that ATD significantly increases the tendency for negative reciprocity, whereas positive reciprocity (Dove in response to an expected Dove) is unaffected. We could therefore demonstrate that 5-HT availability mediates (negative) reciprocal behavior in social decision-making.

Probabilistic reversal learning under acute tryptophan depletion in healthy humans: a conventional analysis.

The involvement of serotonin in responses to negative feedback is well established. Acute serotonin reuptake inhibition has enhanced sensitivity to negative feedback (SNF), modelled by behaviour in probabilistic reversal learning (PRL) paradigms. Whilst experiments employing acute tryptophan depletion (ATD) in humans, to reduce serotonin synthesis, have shown no clear effect on SNF, sample sizes have been small. We studied a large sample of healthy volunteers, male and female, and found ATD had no effect on core behavioural measures in PRL. These results indicate that ATD effects can differ from other manipulations of serotonin expected to have a parallel or opposing action.

Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging.

SummaryMonoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

Effects of Acute Tryptophan Depletion on Repetitive Behavior in Laying Hens.

Repetitive pecking at the feather cover of other birds (FP) is one of the most important welfare problems in domestic birds. It is not only characterized by motor symptoms, but also by an innate vulnerability of the serotonergic system. Moreover, the serotonergic system influences cognitive function. Acute tryptophan depletion (ATD) is a widely used method for studying serotonergic function in mammals and has been recently validated in birds. However, a tryptophan-deficient amino acid mixture has never been tested on groups of birds to impact their social behavior, including repetitive feather pecking, nor has it been given to potentially impact their cognition and motor performance. One hundred and sixty White Leghorn laying hens consisting of two genetic lines divergently selected to perform high (H) or low (L) levels of FP, and an unselected control line (UC), were kept in 10 groups consisting of 4 H, 3 L, and 9 UC genotypes. In a counterbalanced order, half of the groups were first subjected to an ATD treatment, while the other half were first given a balanced control (BC) treatment, and vice versa, after which their feather pecking behavior was observed. The effect of ATD/BC on repetitive pecking, motor performance, and cognition was investigated in a 5-s delayed reward task in an operant chamber with 10 phenotypic feather peckers, 10 recipients of feather pecking, and 10 bystanders (who neither performed nor received feather pecks). ATD given to groups of birds induced gentle, repetitive feather pecking in all genotypes. Following ATD, phenotypic feather peckers performed more poorly during the delayed reward task, as seen by their higher number of repetitive, non-rewarded key, and non-key pecks in the operant chamber. In conclusion, ATD impacted the hens' social behavior by increasing the number of repetitive gentle feather pecks at conspecifics. Furthermore, feather peckers were more likely to peck while waiting for a reward after ATD, suggesting a role for the serotonergic system on cognition in these birds.

Effects of Dietary Acute Tryptophan Depletion (ATD) on NPY Serum Levels in Healthy Adult Humans Whilst Controlling for Methionine Supply-A Pilot Study.

Central nervous serotonin (5-HT) can influence behaviour and neuropsychiatric disorders. Evidence from animal models suggest that lowered levels of neuropeptide Y (NPY) may have similar effects, although it is currently unknown whether decreased central nervous 5-HT impact NPY concentrations. Given that the production of NPY is dependent on the essential amino acid methionine (MET), it is imperative to account for the presence of MET in such investigations. Hence, this study sought to examine the effects of acute tryptophan depletion (ATD; a dietary procedure that temporarily lowers central nervous 5-HT synthesis) on serum concentrations of NPY, whilst using the potential renal acid load indicator (PRAL) to control for levels of MET. In a double-blind repeated measures design, 24 adult humans randomly received an AA-load lacking in TRP (ATD) on one occasion, and a balanced control mixture with TRP (BAL) on a second occasion, both with a PRAL of nearly 47.3 mEq of MET. Blood samples were obtained at 90, 180, and 240 min after each of the AA challenges. ATD, and therefore, diminished substrate availability for brain 5-HT synthesis did not lead to significant changes in serum NPY concentrations over time, compared to BAL, under an acute acidotic stimulus.

5-HT modulation of pain perception in humans

IntroductionAlthough there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain.ObjectivesHere, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers.MethodsFifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session.ResultsOur investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood.ConclusionAs far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes.

Peripheral Serotonin 1B Receptor Transcription Predicts the Effect of Acute Tryptophan Depletion on Risky Decision-Making.

BackgroundThe effects of acute tryptophan depletion on human decision-making suggest that serotonin modulates the processing of rewards and punishments. However, few studies have assessed which of the many types of serotonin receptors are responsible.MethodsUsing a within-subject, double-blind, sham-controlled design in 26 subjects, we examined whether individual differences in serotonin system gene transcription, measured in peripheral blood, predicted the effect of acute tryptophan depletion on decision-making. Participants performed a task in which they chose between successive pairs of fixed, lower-stakes (control) and variable, higher-stakes (experimental) gambles, each involving wins or losses. In 21 participants, mRNA from 9 serotonin system genes was measured in whole blood prior to acute tryptophan depletion: 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, 5-HT3E, 5-HT7 (serotonin receptors), 5-HTT (the serotonin transporter), and tryptophan hydroxylase 1.ResultsAcute tryptophan depletion did not significantly influence participants’ sensitivity to probability, wins, or losses, although there was a trend for a lower tendency to choose experimental gambles overall following depletion. Significant positive correlations, which survived correction for multiple comparisons, were detected between baseline 5-HT1B mRNA levels and acute tryptophan depletion-induced increases in both the overall tendency to choose the experimental gamble and sensitivity to wins. No significant relationship was observed with any other peripheral serotonin system markers. Computational analyses of decision-making data provided results consistent with these findings.ConclusionsThese results suggest that the 5-HT1B receptor may modulate the effects of acute tryptophan depletion on risky decision-making. Peripheral levels of serotonin markers may predict response to treatments that act upon the serotonin system, such as selective serotonin reuptake inhibitors.

Effects of acute tryptophan depletion on central processing of CT-targeted and discriminatory touch in humans.

C-tactile afferents (CTs) are slowly conducting nerve fibres, present only in hairy skin. They are optimally activated by slow, gentle stroking touch, such as those experienced during a caress. CT stimulation activates affective processing brain regions, alluding to their role in affective touch perception. We tested a theory that CT-activating touch engages the pro-social functions of serotonin, by determining whether reducing serotonin, through acute tryptophan depletion, diminishes subjective pleasantness and affective brain responses to gentle touch. A tryptophan depleting amino acid drink was administered to 16 healthy females, with a further 14 receiving a control drink. After 4h, participants underwent an fMRI scan, during which time CT-innervated forearm skin and CT non-innervated finger skin was stroked with three brushes of differing texture, at CT-optimal force and velocity. Pleasantness ratings were obtained post scanning. The control group showed a greater response in ipsilateral orbitofrontal cortex to CT-activating forearm touch compared to touch to the finger where CTs are absent. This differential response was not present in the tryptophan depleted group. This interaction effect was significant. In addition, control participants showed a differential primary somatosensory cortex response to brush texture applied to the finger, a purely discriminatory touch response, which was not observed in the tryptophan depleted group. This interaction effect was also significant. Pleasantness ratings were similar across treatment groups. These results implicate serotonin in the differentiation between CT-activating and purely discriminatory touch responses. Such effects could contribute to some of the social abnormalities seen in psychiatric disorders associated with abnormal serotonin function.

The effects of acute tryptophan depletion on speech and behavioural mimicry in individuals at familial risk for depression.

Major depressive disorder (MDD) has been associated with abnormalities in speech and behavioural mimicry. These abnormalities may contribute to the impairments in interpersonal functioning that are often seen in MDD patients. MDD has also been associated with disturbances in the brain serotonin system, but the extent to which serotonin regulates speech and behavioural mimicry remains unclear. In a randomized, double-blind, crossover study, we induced acute tryptophan depletion (ATD) in individuals with or without a family history of MDD. Five hours afterwards, participants engaged in two behavioural-mimicry experiments in which speech and behaviour were recorded. ATD reduced the time participants waited before speaking, which might indicate increased impulsivity. However, ATD did not significantly alter speech otherwise, nor did it affect mimicry. This suggests that a brief lowering of brain serotonin has limited effects on verbal and non-verbal social behaviour. The null findings may be due to low test sensitivity, but they otherwise suggest that low serotonin has little effect on social interaction quality in never-depressed individuals. It remains possible that recovered MDD patients are more strongly affected.

Empathic accuracy and oxytocin after tryptophan depletion in adults at risk for depression.

RationaleMajor depressive disorder (MDD) has been associated with disturbances in social functioning and in the brain serotonin system. Reduced levels of serotonin may negatively influence social functioning, for example by impairing the recognition of facial emotion expressions.ObjectivesThe present study investigated the effect of acute tryptophan depletion (ATD), which reduces brain serotonin, on a related component of social functioning, empathic accuracy (EA), and oxytocin levels.MethodsIndividuals with (FH+) and without (FH−) a family history of MDD participated in a randomized, double-blind, crossover study. On two separate test days, participants ingested tryptophan-deficient and nutritionally balanced amino acid mixtures. Six hours later, they performed an EA task, which involved watching videos of people recounting autobiographical emotional events. While watching, participants continuously rated how these people felt during the recounting. Mood state was repeatedly assessed using the Positive Affect and Negative Affect Schedule and a series of visual analogue scales. Blood samples obtained at baseline and 5 h after mixture ingestion were assessed for tryptophan and oxytocin levels.ResultsATD decreased circulating levels of tryptophan and oxytocin. Nevertheless, there were no significant effects of ATD on EA or mood in either FH group.ConclusionsWhile previous studies have shown that acute reductions in brain serotonin alter the recognition of facial emotion expressions in never-depressed individuals, the present study suggests that empathic abilities may remain unaffected.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-015-4093-9) contains supplementary material, which is available to authorized users.

Effects of acute tryptophan depletion on raphé functional connectivity in depression

Depression remains a great societal burden and a major treatment challenge. Most antidepressant medications target serotonergic raphé nuclei. Acute tryptophan depletion (ATD) modulates serotonin function. To better understand the raphé's role in mood networks, we studied raphé functional connectivity in depression. Fifteen depressed patients were treated with sertraline for 12 weeks and scanned during ATD and sham conditions. Based on our previous findings in a separate cohort, resting state MRI functional connectivity between raphé and other depression-related regions (ROIs) was analyzed in narrow frequency bands. ATD decreased raphé functional connectivity with the bilateral thalamus within 0.025–0.05Hz, and also decreased raphé functional connectivity with the right pregenual anterior cingulate cortex within 0.05–0.1Hz. Using the control broadband filter 0.01–0.1Hz, no significant differences in raphé-ROI functional connectivity were observed. Post-hoc analysis by remission status suggested increased raphé functional connectivity with left pregenual anterior cingulate cortex in remitters (n=10) and decreased raphé functional connectivity with left thalamus in non-remitters (n=5), both within 0.025–0.05Hz. Reducing serotonin function appears to alter coordination of these mood-related networks in specific, low frequency ranges. For examination of effects of reduced serotonin function on mood-related networks, specific low frequency BOLD fMRI signals can identify regions implicated in neural circuitry and may enable clinically-relevant interpretation of functional connectivity measures. The biological significance of these low frequency signals detected in the raphé merits further study.

The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications.

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.

Studying the effects of dietary body weight-adjusted acute tryptophan depletion on punishment-related behavioral inhibition

BackgroundAlterations in serotonergic (5-HT) neurotransmission are thought to play a decisive role in affective disorders and impulse control.ObjectiveThis study aims to reproduce and extend previous findings on the effects of acute tryptophan depletion (ATD) and subsequently diminished central 5-HT synthesis in a reinforced categorization task using a refined body weight–adjusted depletion protocol.DesignTwenty-four young healthy adults (12 females, mean age [SD]=25.3 [2.1] years) were subjected to a double-blind within-subject crossover design. Each subject was administered both an ATD challenge and a balanced amino acid load (BAL) in two separate sessions in randomized order. Punishment-related behavioral inhibition was assessed using a forced choice go/no-go task that incorporated a variable payoff schedule.ResultsAdministration of ATD resulted in significant reductions in TRP measured in peripheral blood samples, indicating reductions of TRP influx across the blood–brain barrier and related brain 5-HT synthesis. Overall accuracy and response time performance were improved after ATD administration. The ability to adjust behavioral responses to aversive outcome magnitudes and behavioral adjustments following error contingent punishment remained intact after decreased brain 5-HT synthesis. A previously observed dissociation effect of ATD on punishment-induced inhibition was not observed.ConclusionsOur results suggest that neurodietary challenges with ATD Moja–De have no detrimental effects on task performance and punishment-related inhibition in healthy adults.

P.1.i.017 Independent effects of acute tryptophan depletion on mood and cortical activation during working memory tasks

Coronary artery disease is prevalent with high morbidity and coronary artery bypass grafting is one of its most important treatments. Anxiety and sleep disorders after surgery are very common and need appropriate control. The current study aimed to evaluate the efficacy of Melissa officinalis L. (Lemon Balm) for managing this problem.A double-blind randomized placebo controlled clinical trial was conducted with 80 in-patients who underwent coronary artery bypass surgery. The patients were randomized into either the herbal medicine or the placebo group. Capsules containing 500 mg of Melissa officinalis L. dried leaf powder as herbal medicine or wheat starch as placebo were administered three times a day. Sleep quality and anxiety measures were the main outcomes and St Mary’s Hospital Sleep Quality and Hospital Anxiety Depression Scale were used questionnaires respectively.At baseline there were no significant differences in the anxiety scores between the two groups. After the intervention, anxiety scores were 7.15 ± 1.2 and 10.18 ± 3.1 in the herbal medicine and placebo groups respectively (P = 0.001). Moreover, the mean changes of sleep quality in the herbal medicine group was significantly higher than the placebo group; 14.40 ± 5.1 vs 7.52 ± 4.4 (P < 0.001).The results of current study showed that seven-day treatment with 1.5 g/day dried leaf powder of Melissa officinalis appeared to reduce the levels of anxiety and improve the sleep quality in patients after coronary artery bypass surgery, by 49% and 54% respectively.

Acute Tryptophan Depletion Reduces Nitric Oxide Synthase in the Rat Hippocampus

Acute tryptophan depletion (ATD) is extensively used to investigate the role of central serotonin (5-HT). However, several studies reported that ATD had no significant effect on central 5-HT concentration and some ATD-induced changes was independent of 5-HT in the rodent brain. Therefore, the potential mechanism of ATD might not be ascribed solely to changes in the central 5-HT system. In recent studies, evidence suggests that nitric oxide synthase (NOS) is closely associated with ATD-induced changes in modulation of cerebral blood flow and metabolism, cognitive, and locomotor activity. Thus, NOS is implicated to be an underlying factor contributing to ATD-induced changes. In the present study, the effect of ATD upon central NOS levels in the rat was evaluated. Male Sprague-Dawley (SD) rats were orally administered a tryptophan-free protein-carbohydrate mixture. Then, ATD effects upon affective behavior and spatial memory were assessed by the forced swimming test (FST) and Morris water maze test, respectively. Further, NOS activity and neuronal NOS (nNOS) protein levels in the hippocampus were measured after ATD. Our experimental results showed that ATD had no influence on affective behavior in the FST or spatial memory in SD rats. Interestingly, a significant reduction of both constitutive NOS activity and nNOS protein levels after ATD was found in the hippocampus. These findings demonstrate ATD does not influence affective behavior and spatial memory despite a direct effect on hippocampal NOS. Our study might provide a valuable clue for exploring earlier reported ATD-induced behavioral and neurochemical changes in rodents.

The effect of acute tryptophan depletion on mood and impulsivity in polydrug ecstasy users

Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood. This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women. In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n = 13) and nonuser controls (n = 17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task. The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n = 7), relative to controls (n = 9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users. The group sizes were small, when males and females were considered separately. Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.