Feature Review

Molecular Psychiatry (2011) 16, 695–713; doi:10.1038/mp.2011.9; published online 22 February 2011

Mechanism of acute tryptophan depletion: is it only serotonin?

E L van Donkelaar1, A Blokland2, L Ferrington3, P A T Kelly3, H W M Steinbusch1 and J Prickaerts1

  1. 1Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
  2. 2Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
  3. 3Cerebrovascular Research Laboratory, Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, UK

Correspondence: Dr EL van Donkelaar, Department of Psychiatry and Neuropsychology, Division of Neuroscience, Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: eva.vandonkelaar@maastrichtuniversity.nl

Received 12 March 2010; Revised 4 January 2011; Accepted 19 January 2011; Published online 22 February 2011.

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Abstract

The method of acute tryptophan depletion (ATD), which reduces the availability of the essential amino acid tryptophan (TRP), the dietary serotonin (5-hydroxytryptamine (5-HT)) precursor, has been applied in many experimental studies. ATD application leads to decreased availability of TRP in the brain and its synthesis into 5-HT. It is therefore assumed that a decrease in 5-HT release and subsequent blunted neurotransmission is the underlying mechanism for the behavioural effects of ATD. However, direct evidence that ATD decreases extracellular 5-HT concentrations is lacking. Furthermore, several studies provide support for alternative underlying mechanisms of ATD. This may question the utility of the method as a selective serotonergic challenge tool. As ATD is extensively used for investigating the role of 5-HT in cognitive functions and psychiatric disorders, the potential of alternative mechanisms and possible confounding factors should be taken into account. It is suggested that caution is required when interpreting ATD effects in terms of a selective serotonergic effect.

Keywords:

acute stress; cerebral blood flow; cognitive dysfunction; depression; serotonin; tryptophan

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Introduction

Acute tryptophan depletion (ATD) currently represents the most established human challenge test to investigate the involvement of the serotonin (5-hydroxytryptamine; 5–HT) system in the pathogenesis and pathophysiology of affective disorders. The method is nontoxic and nonintrusive, thereby providing the option to repeatedly manipulate the central 5-HT system in vivo and assess the behavioural effects of reduced 5-HT metabolism in the brain.1 The reduction of brain 5-HT in a reversible manner reflects the main methodological advantage of the tool, permitting application of the same basic method in both human subjects and rodents. This is considered valuable for comparing neurophysiological changes linked to behavioural effects across species.2

As intact 5-HT neurotransmission is necessary for a wide range of physiological and functional processes, a disruption in this system can easily provoke diverse pathophysiological abnormalities, most of which are reflected in dysfunctional behavioural output. ATD-induced behavioural changes in human subjects and laboratory animals are normally attributed to decreased 5-HT release, reflecting altered 5-HT neuronal activity. However, it is not fully clear what mechanisms underlie the neurophysiological effects of ATD and to what extent changes in 5-HT neuronal activity contribute to the ATD-induced functional and behavioural alterations. Also, no convincing evidence exists for affected central 5-HT release following ATD in animals.3

The ATD method seems important in the investigation of 5-HT-related vulnerability factors implicated in the onset of depression,4 and previously the monoamine systems were considered to be primarily responsible for the onset of depressive disorders.5 However, the lack of mood-lowering effects after ATD in healthy subjects may not support a direct causal relationship between acute decreased 5-HT metabolism and major depressive disorder.6 Moreover, as will be discussed in this review, evidence exists that ATD possibly exerts its neurochemical and behavioural effects through other mechanisms that might go beyond a straightforward decrease in 5-HT metabolism. This review covers an extensive evaluation of both the methodology and the diverse neurochemical and behavioural effects of ATD, including a critical assessment of the common parameters used for indicating presumed ATD-induced changes in 5-HT functionality. Furthermore, this review aims to outline alternatives for potential underlying mechanisms of the method that might go beyond a disturbed 5-HT system and thus draw into question the utility of ATD as a serotonergic challenge tool in experimental research in general and depression research in particular.

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Methodological aspects of ATD

5-HT is synthesized in a two-step reaction (Figure 1) from the initial substrate L-tryptophan (TRP), and the bioavailability of this essential amino acid is the principal rate-limiting factor. Thus, variations in dietary intake of TRP can have profound effects upon the synthesis of this very important neurotransmitter substance and may impact upon those aspects of brain function that are influenced by serotonergic neurons. It is this fact that underpins the use of ATD as both an experimental tool and a clinical probe for depressive illness.

Figure 1.
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Central serotonin synthesis and metabolism. In the brain, tryptophan (TRP) is first hydroxylated into 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase (TPH). Aromatic L-amino-acid decarboxylase (AAAD) subsequently catalyzes the decarboxylation of 5-HTP into 5-hydroxytryptamine (5-HT). The enzymes monoamine oxidase (MAO) and aldehyde dehydrogenase (ADH) eventually break serotonin (5-HT) down into the inactive metabolite 5-hydroxyindoleacetic acid (5-HIAA).

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From plasma to brain tryptophan

Amino acids can only be transported from the blood through the capillary endothelial cells of the blood-brain barrier (BBB) into the brain by carrier-mediated transporter systems in the capillary cell plasma membranes.7 Given that the surface area of the BBB is much smaller compared with the surface area of brain cell membranes, it is this initial transport through the BBB that limits the uptake of plasma TRP into the brain.8 The branched-chain amino acids (leucine, isoleucine and valine) together with the aromatic amino acids (phenylalanine, tyrosine and TRP) are subclassified as large neutral amino acids (LNAAs). Of the nine different amino acid transport systems identified at the BBB, the so-called Transport System L is only half saturated under normal physiological conditions and mediates high-affinity, sodium-independent uptake of all LNAAs.8, 9 Consequently, in order to bind to the L-amino-acid transport carrier and subsequent transport into the brain, TRP has to compete heavily with the other LNAAs.10, 11, 12 The availability of TRP in the brain thus depends upon the ratio of TRP to the sum of the other LNAAs (TRP/ΣLNAA), and a decrease in this ratio in plasma is normally used as the best predictor of reduced availability of TRP in the brain and subsequent synthesis into 5-HT.13, 14

From bound to free plasma tryptophan: the brain influx parameter

Approximately 90% of all TRP molecules circulating in the blood are bound to serum albumin. Although positive correlations between serum free-TRP and whole brain TRP levels have been reported in rats,15, 16 the dissociation of TRP from albumin by endogenous and exogenous ligands has been shown to increase the entry of TRP into the brain, thereby enhancing central 5-HT synthesis.17, 18 This observation suggests that only free TRP is available for transport into the brain.15 As the changes in TRP-free levels can take place independently of changes in total TRP levels,19 this would make a distinction between free and bound TRP necessary for estimating its availability in the brain. However, accumulating evidence indicates that total peripheral TRP concentrations (free plus bound) more accurately reflect the rate of influx of TRP into the brain. It has been shown that TRP is only loosely bound to albumin and although albumin itself cannot cross the BBB, it appears to be a highly flexible protein undergoing reversible conformational changes.20 These conformational changes, which occur during transport of TRP from the circulating albumin-bound pool, enhance the dissociation of TRP from the albumin-binding sites within the cerebral microvasculature and appear to be highly dependent upon cerebral haemodynamics.21 Low cerebral blood flow (CBF) is likely to increase the interaction between the albumin-bound TRP complex and the glycocalyx of the BBB, thereby causing more TRP to dissociate from albumin.21, 22 This implies that temporally dynamic or spatial differences in local CBF may influence the rate of central TRP uptake in general and even within specific brain areas.23 Thus, although only free TRP can eventually cross the BBB, the amount of albumin-bound TRP in plasma must also be taken into account to calculate the availability of TRP in the brain, as TRP can easily dissociate from albumin near the BBB, thereby increasing the TRP-free pool and subsequent uptake into the brain (see also Figure 2).

Figure 2.
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Overview of tryptophan metabolism from food intake to brain uptake and the differential effects of carbohydrates and protein upon the availability of tryptophan (TRP) in plasma for uptake into the brain. In order to obtain the amino-acid TRP, its inclusion in the diet is essential. The majority of TRP is bound to plasma albumin and only free TRP will eventually cross the blood-brain barrier (BBB). Albumin-bound TRP, however, easily dissociates from albumin near the cerebrovasculature under the influence of haemodynamic changes, thereby increasing the TRP-free fraction available for uptake into the brain. The amount of TRP in plasma eventually crossing the BBB also depends upon the presence of other large neutral amino acids (LNAAs) that all compete for the same amino acid transport system L at the BBB. Because of this competition of TRP with leucine (LEU), isoleucine (ILE), valine (VAL), phenylalaline (PHE) and tyrosine (TYR), the ratio of TRP to the sum of the other LNAAs (TRP/ΣLNAA) in plasma better reflects the amount of central TRP available for synthesis into 5-hydroxytryptamine (5-HT). Dietary carbohydrates increase the uptake of the LNAAs into peripheral tissue, thereby decreasing their levels in plasma. Together with an increase in total TRP levels, the TRP/ΣLNAA ratio changes in favour of TRP and increases its availability for transport across the BBB. As little as 2.5% of additional proteins counteracts the effects of carbohydrates, as the protein ingestion-induced increase in the levels of all amino acids is much higher than the decrease by carbohydrates. When a TRP-free diet is administrated (acute tryptophan depletion), all amino acids are elevated except for TRP, thereby decreasing the TRP/ΣLNAA ratio and thus TRP uptake into the brain.

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Solugel

In most studies, pure amino-acid mixtures without TRP have been used to reduce plasma TRP levels. However, one disadvantage of the amino-acid mixture is that differences in the distinct amino acids were found between the control condition (TRP+) and a condition in which animals were treated with saline.2, 24 In that case, the control condition is not an optimal and representative control condition. An alternative manner to reduce central 5-HT concentrations by lowering the levels of its dietary precursor TRP in plasma can be achieved by administration of specific TRP-free nutritional mixtures.

Besides the TRP-free or TRP-low balanced diets and pure amino-acid mixtures without TRP, a more advanced technique is the oral administration of a gelatin-based protein–carbohydrate mixture.2 By adding a specific amount of TRP to the control mixture, the effects of peripheral TRP suppletion, as often observed with traditional amino-acid mixtures in humans,25, 26 are avoided and thus do not cause misinterpretation of the ATD effects.2, 27, 28 Gelatin is derived from the selective hydrolysis of collagen protein, which is easily digestible and naturally lacks the essential amino-acid TRP.29 The gelatin hydrolysate used for the nutritional mixture is gelatin in an enzymatic hydrolyzed form, commercially available as Solugel (PB Gelatins, Tessenderlo, Belgium). Solugel no longer consists of a combination of a few selective amino acids, but comprises a broad range of amino acids in the form of peptides, which makes it comparable with standard diets. Moreover, it is water dispensable and unique for its gel-forming ability.24 In addition, a specific amount of carbohydrate is mixed with the Solugel, which adds an essential caloric value, thereby making the nutritional mixture even more similar to conventional food intake. Moreover, mixing proteins with carbohydrates avoids any unwanted effects upon amino-acid availability in the blood (see below and Figure 2) as is normally found with unbalanced diets containing high amounts of carbohydrate or protein only.30, 31, 32

Carbohydrate and dietary protein

Various metabolic processes are triggered when a protein/carbohydrate meal, as is the case with ATD methods, is ingested. These processes can have effects on plasma TRP levels too. After the intake of carbohydrates, blood glucose levels raise, thereby stimulating the pancreas to release the anabolic hormone insulin. The secretion of insulin stimulates glucose to be taken up by the cells for subsequent normalization of glucose levels in the blood. Concomitantly with the insulin-induced drop in blood glucose levels, plasma TRP levels increase whereas the concentration of most other amino acids in plasma decreases.33 When a carbohydrate-rich meal contains no additional protein, activation of the insulin response increases protein synthesis, thereby stimulating the uptake of almost all amino acids (mainly the branched-chain amino acids) into muscle tissue. Most of the TRP in plasma is bound to serum albumin and thus is not available for uptake into peripheral tissues, and hence the effect of insulin upon TRP is much less compared with the other LNAAs. Moreover, insulin increases the affinity of serum albumin for TRP and increases the ratio of bound to free plasma TRP, as more albumin is available because of the insulin-induced uptake of fatty acids, which were bound to albumin. Thus, because TRP is the only amino acid that binds to albumin, it is the only one that is very well prevented from being taken out of the bloodstream and up into peripheral tissue. This is even more the case when the binding to albumin increases because of insulin secretion. Taken together, after the ingestion of carbohydrate the plasma ratio of LNAAs changes in favour of total TRP, which eventually leads to an increased availability of TRP in the brain to be synthesized into 5-HT.33, 34 Yet, as little as 2.5% of additional protein is sufficient for the substantial increase of plasma LNAAs to counteract the effect of carbohydrate and the subsequent insulin-induced fall in LNAAs.32, 35 This is the case with the TRP-free protein–carbohydrate nutritional mixture (see also Figure 2).

Protein synthesis

The administration of a diet devoid of TRP depletes plasma TRP acutely by inducing hepatic protein synthesis.36 This results in an extracellular TRP removal that is because of an increased incorporation of TRP into proteins in the liver and other tissue.12, 15 The ATD-induced depletion of plasma TRP can be dose dependently blocked by administration of the protein synthesis inhibitor cycloheximide together with a TRP-free diet.37, 38 Thus, protein synthesis, and not the inhibition of TRP transportation into the brain, seems to be the important initial mechanism underlying ATD-induced decreased 5-HT in the brain.

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Central versus peripheral effects of ATD

The effects of ATD on affective behaviour (for example, depression) and various cognitive functions (for example, memory, attention and impulsivity) have been studied in human subjects and laboratory animals, and several theories regarding its underlying serotonergic mechanism and its implication for psychiatry in general have been widely explored and reviewed over the past 20 years.39, 40, 41, 42, 43 In this section we will give an overview of the peripheral and central effects after ATD in human subjects and rodents.

ATD: revealing vulnerability to depression

Many neurophysiological processes are known to be regulated by the 5-HT system, including mood and cognition, which are most prominently impaired in clinical depression.44, 45, 46 5-HT cell bodies are clustered in the brainstem raphe nuclei sending out projections throughout the entire central nervous system with ascending pathways innervating anatomically and functionally diverse regions of the cerebral cortex, including the limbic system, the basal ganglia and structures within the diencephalon.47 Because of this anatomy, the neurotransmitter influences all regions of the neuraxis, thereby modulating an extensive range of physiological and behavioural functions. Besides mood and cognition, appetite, emesis, endocrine function, gastrointestinal function, motor function, neurotrophism, perception, sensory function, pain sensitivity, sex, sleep and even vascular function are all under the control of the 5-HT system. Consequently, disrupted 5-HT synthesis and subsequent abnormal 5-HT function can lead to a diverse range of behavioural disturbances also implicated in clinical depression. Consistent findings in this respect specifically include decreased peripheral TRP levels48 and lower levels of the inactive 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF), which all reflect diminished 5-HT metabolism.49, 50 The effectiveness of serotonergic drugs used in the treatment of depression is also suggestive of an important role of disrupted function of specific pre- and post-synaptic receptors underlying impaired 5-HT neurotransmission and linked to specific depressive symptoms.51, 52

Human subjects with genetic, pre-existing 5-HT dysfunction may lack endogenous compensatory capacity to deal with an acute decrease in 5-HT metabolism, thereby exhibiting higher behavioural sensitivity to ATD.4, 26 This implies that a predisposition of so-called serotonergic vulnerability only results in direct overt psychiatric symptoms when these are triggered, as with ATD, by challenging the already vulnerable 5-HT system4 up to a certain threshold.26 In line with this hypothesis, ATD-induced transient mild mood-lowering effects, as reflected by lower mood ratings, have been reported in carriers of the ‘short’ allelic polymorphism in the promoter of the 5-HT transporter gene 5-HTTLPR (serotonin-transporter-linked promoter region)53 and in healthy subjects with a family history of depression.54 Similarly, a higher behavioural response to ATD has been observed in women,55, 56 who are presumably predisposed to a lower 5-HT synthesis rate compared with men.57 Moreover, ATD provokes a relapse of depressive symptoms in healthy subjects with a history of depression.58, 59 However, this effect is only in those subjects who were previously treated successfully with selective serotonin re-uptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs). Remitted, medication-free depressed patients with a positive treatment response history to antidepressants that primarily interact with systems other than 5-HT (for example, tricyclic antidepressants or selective norepinephrine reuptake inhibitors) appear not to be affected by ATD.60, 61, 62

ATD in healthy human subjects: inducing cognitive deficits

As mentioned above, it is generally believed and accepted that ATD does not induce considerable mood-lowering effects in healthy human subjects.59, 63, 64 Nevertheless, acute decreased peripheral TRP levels and diminished 5-HIAA concentrations in CSF are consistently reported after ATD and appear to be similar in all subpopulations, that is, in both healthy and the so-called serotonergic vulnerable subjects.54, 65, 66, 67, 68, 69 Interestingly, both healthy and vulnerable subjects display cognitive dysfunctional behaviour after ATD as reported consistently between studies.27, 28, 70, 71, 72, 73, 74, 75 It might therefore be suggested that an acute decrease in peripheral TRP levels directly interferes with mechanisms implicated in cognitive processing that depend less upon 5-HT functioning. Altered cognitive processing has been reported with impairments in long-term memory formation (in particular, consolidation processes74), decision making, reversal learning and working memory.

Effects of ATD in rodents: affect and/or cognition?

Animal models enable direct investigation of the relationships between brain and behaviour with the aim of gaining insight into human behaviour and its underlying neuronal and neuroendocrinological processes.76 Therefore, the direct consequences of ATD upon brain parameters like TRP and 5-HT in the rat are generally used for interpretation of the alterations in behavioural output in accordance with the underlying neurochemical mechanism of the method. A large body of preclinical literature provides evidence that ATD in rats significantly depletes the levels of TRP in plasma, thereby reducing 5-HT metabolism, as is suggested by the lower TRP and 5-HT levels in the rat brain tissue.24, 77, 78, 79, 80 In rats, however, the levels of peripheral and central TRP reductions, as well as brain 5-HT concentrations, have not been consistently reported, and other ATD-induced neurophysiological effects, as discussed below, have been observed in the absence of central TRP or 5-HT reductions.81, 82 Similarly and in line with the ATD effects in healthy human subjects, ATD-induced alterations in affective behavioural parameters in the rat appear controversial between studies.77, 83, 84, 85 Object memory performance is the only parameter consistently reported as impaired after ATD79, 83, 85, 86, 87, 88 and seems even more pronounced in rats with pre-existing abnormal 5-HT function.80 Table 1 provides an overview of the peripheral and central neurochemical effects and other neurophysiological changes, as well as cognitive and affective behavioural alterations after ATD induced in rodents, mainly rats, through administration of nutritional mixtures completely devoid of TRP.


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Methodological considerations: do we actually measure central effects?

It is generally assumed that the mood-lowering and cognitive dysfunctional effects of ATD are mediated by decreases in 5-HT neuronal activity. Yet, as described below, most parameters used to indicate reduced 5-HT synthesis or release appear to merely estimate decreases in 5-HT metabolism and neuronal activity, respectively, thereby remaining rather speculative.

The TRP/ΣLNAA ratio in plasma

The effects of ATD treatment upon 5-HT levels in the brain cannot be directly investigated in humans. In general therefore, the ratio TRP/ΣLNAA in plasma is used to estimate the amount of TRP available in the brain for synthesis into 5-HT. In most cases, total peripheral TRP levels (free plus albumin bound) are used for calculating the ratio to the sum of the other LNAAs. Although only the relatively small fraction of free TRP eventually crosses the BBB, TRP can easily dissociate from albumin near the BBB, thereby increasing the TRP-free pool and subsequent uptake into the brain. Thus, the direct effect of physiological factors such as hormones, exercise or mild stressors upon the rate of dissociation of TRP from albumin can only be taken into account if both total and free TRP levels are actually measured,89 which is usually not done. Therefore, based upon total peripheral TRP levels alone, the TRP/ΣLNAA ratio in plasma is probably a distorted estimation of the rate of influx of TRP into the brain.

A decrease in the TRP/ΣLNAA ratio suggests that less TRP will be available to the brain for synthesis into 5-HT. This has been confirmed by the ATD-induced decrease in the uptake of central α-methyl-L-tryptophan (α-M-TRP) as measured by positron emission tomography in humans.57 Although this finding supports the concept that ATD exerts central effects, α-M-TRP uptake does not reveal anything specific about 5-HT release,39, 67 despite the fact that it is considered a reliable indicator of 5-HT synthesis.

Finally, other LNAAs such as methionine and threonine are generally not included in the ratio as active competitors of plasma TRP. However, evidence exists that together with the branched-chain amino acids and the aromatic amino acids, methionine and threonine share the same L-amino-acid transport carrier at the BBB.8, 9, 90 Thus, calculating the TRP/ΣLNAA ratio without taking into account all competitive amino acids is most likely to result in an overestimation of brain TRP influx and subsequent dissociation from brain TRP levels and 5-HT synthesis.

The 5-HIAA/5-HT ratio in the brain

In humans subjected to ATD, a decrease in the concentration of 5-HIAA in CSF suggests that less 5-HT has been catabolyzed, which normally takes place after release, that is, after neuronal firing. Therefore, a decrease in the amount of 5-HIAA is thought to reflect decreased 5-HT metabolism, as lower intracellular 5-HT availability is presumed to result in reduced 5-HT release. However, numerous other peripheral factors seem to influence both the amount of 5-HIAA produced and its transport into and out of the CSF (see ref. 52). Moreover, 5-HT release and neuronal firing seem not to correlate necessarily with 5-HT metabolism,91, 92 and thus the amount of 5-HIAA in CSF seems not to be a valid index of changes in 5-HT release.92, 93

In contrast to human subjects, animal models offer the possibility to directly measure changes in TRP, 5-HT and 5-HIAA concentration in distinct brain areas. Significantly lower tissue levels of TRP and 5-HT have been reported after ATD compared with TRP+ control conditions in animals.24, 79, 80, 85 The 5-HIAA/5-HT ratio is normally used to calculate the 5-HT turnover rate and estimate changes in 5-HT release, reflecting neuronal activity. However, this seems to apply only under normal physiological conditions when the rate of 5-HT synthesis remains constant.94 An increase in 5-HIAA levels would then increase the 5-HIAA/5-HT ratio and allow accurate estimation of an increase in 5-HT neuronal activity, as it is assumed that more 5-HT has been released. Conversely, a decrease in 5-HIAA levels under a constant rate of 5-HT synthesis would decrease the 5-HIAA/5-HT ratio. Yet, ATD is applied to induce a decrease in 5-HT synthesis. As a decrease in intracellular 5-HT availability most likely results in a reduction of the amount of 5-HT available for release, less extracellular 5-HT will then be available to be catabolyzed into 5-HIAA. Thus, ATD is likely to decrease both 5-HT and 5-HIAA, thereby maintaining the 5-HIAA/5-HT ratio constant. In line with this, no changes in the 5-HIAA/5-HT ratio were found 3h after ATD, whereas both 5-HT (−23%) and 5-HIAA (−39%) levels appeared to be significantly decreased in rat hippocampus.84 A decrease in this ratio after ATD would only occur if significantly less 5-HIAA is produced compared with the already reduced amount of 5-HT synthesized.

As described previously, the conversion of TRP into the 5-HTP intermediate by the TPH2 (tryptophan hydroxylase 2) isoform is the first and rate-limiting step in the biosynthesis of 5-HT. In the brain, this enzyme is only 50% saturated and, therefore, the rate at which 5-HT is synthesized is limited only by substrate (that is, TRP) availability.95 However, it seems difficult to directly attribute an ATD-induced decrease in the 5-HIAA/5-HT ratio to a reduction in TRP availability. Brain measurements are generally taken at only one specific time point that impedes a comparison of the central parameters with baseline values. Thus, a decrease in 5-HIAA levels and in the 5-HIAA/5-HT ratio after ATD is normally interpreted as evidence for an ATD-induced reduction in 5-HT metabolism.

However, one animal study showed that 5-HT levels might not have changed compared with TRP+ treatment.82 Furthermore, information upon baseline 5-HT values is generally lacking. Although reductions of the 5-HIAA/5-HT ratio have been repeatedly reported after ATD in rats,85, 96, 97 between the studies, the concomitant changes in 5-HIAA or 5-HT in specific brain areas do not seem to be in accordance with each other. In general, it appears that ATD-induced absolute changes in central 5-HT or 5-HIAA concentrations and potential underlying mechanisms require further examination.

A decrease in the 5-HIAA/5-HT ratio after ATD in rats seems more likely to be caused by factors influencing the catabolism of 5-HT, such as fluctuations in the activity of the MAO enzyme.98 An acute decrease in MAO activity would reduce the absolute amount of 5-HIAA produced, thereby producing a relative increase in 5-HT levels. This would eventually lower the 5-HIAA/5-HT ratio independent of a reduction in precursor availability per se or the subsequent decrease in 5-HT synthesis and as such does not reflect a decrease in 5-HT release. It could be hypothesized that an acute change in MAO activity implies a compensatory mechanism activated upon the acute decrease in peripheral TRP levels.

Several rat studies, all of similar experimental design, have directly reported ATD-induced decreased central 5-HT levels after administration of the same TRP-free nutritional mixture.24, 80, 85, 99 This is generally thought to reflect an ATD-induced decrease in 5-HT synthesis. However, as mentioned previously, the decrease in 5-HT after TRP treatment at one specific time point is normally only compared with the control TRP+ treatment group and not with its own baseline concentrations. Thus, without these baseline values before treatment, the extent to which the significant difference in 5-HT levels between the experimental (TRP–) and control (TRP+) treatment group actually imply a reduction in 5-HT release (that is, activity) after ATD remains unclear. In addition, no direct evidence exists that ATD affects central 5-HT release (see next section).

5-HT neuronal release

Alterations in neuronal activity can be measured by in vivo microdialysis. With this technique, changes in extracellular 5-HT concentrations can be measured that are indicative of changes in neuronal release. Actual reductions of basal 5-HT release after ATD have only been reported in combination with 5-HT reuptake inhibitors.1, 100, 101 A blockade after 5-HT reuptake seems necessary to raise 5-HT to optimal levels for detection (see ref. 67). Yet, without the initial systemic increase in extracellular 5-HT concentrations, basal 5-HT release in the prefrontal cortex of rats appeared not to be affected by ATD.99 This might suggest that in the absence of de novo synthesis, 5-HT function can largely be maintained from transmitter being recycled into the presynaptic cell from the synaptic cleft. A possible decrease in 5-HT might then reflect a decrease in the storage pool of 5-HT without affecting 5-HT release.102 In line with this, decreased levels in whole-brain 5-HT levels at 2h after the consumption of a TRP-free diet in cats did not parallel changes in the functional activity of 5-HTcontaining dorsal raphe cells throughout the 4h after ingestion.102 Only recently, the lack of evidence for ATD-induced alterations in 5-HT release and neuronal activity was first critically outlined by Feenstra et al.3

Taken together, not only the parameters used to calculate reductions in brain TRP availability and 5-HT metabolism may be somewhat inaccurate, but also no direct evidence exists that the ATD-induced reductions in central 5-HT levels correlate with parallel changes in 5-HT neuronal activity under normal physiological conditions. In general, therefore, ATD-induced behavioural alterations cannot easily be directly attributed to changes in 5-HT neuronal activity. Nevertheless, ATD consistently induces cognitive impairment in both animals and humans and triggers lowering of mood especially in healthy subjects with a vulnerable 5-HT system. ATD does not directly or indirectly affect other monoaminergic systems in rats24, 82, 84, 85, 96 and no behavioural changes have been observed after depletion of other plasma amino acids.72 Moreover, administration of a TRP-free AA mixture in primates decreased TRP and 5-HIAA concentrations in CSF without affecting catecholamine metabolites, suggesting that the catecholamine system is not influenced by ATD.103

ATD-induced functional changes thus seem specific for the peripheral depletion of the essential amino acid TRP, but are more likely 5-HT mediated than 5-HT induced. Moreover, the effects of changes in TRP availability upon 5-HT synthesis rate are generally not measured under normal physiological circumstances, that is, in the absence of any other regulatory changes. Therefore, changes other than substrate availability that interfere with normal 5-HT regulation or disruptions in substrate availability itself might act as potential confounding factors for the ATD-induced neurochemical effects as expected under normal circumstances.104 Thus, the exact underlying mechanism might go beyond a straightforward alteration in the central 5-HT system itself.

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Potential alternative mechanisms underlying the effects of ATD

Decreased nitric oxide synthase (NOS) activity

The enzyme NOS is suggested to play an important role in long-term potentiation (LTP) processes and consequently in learning and memory.105, 106 As described below, several findings suggest that ATD may affect the activity of this enzyme. NOS catalyzes the conversion of the amino acid arginine (ARG) into citrulline (CIT) and nitric oxide (NO;107). Thus, NOS inhibition results in less conversion of ARG into CIT and NO. Therefore, the amount of NO synthesis might be directly related to the levels of ARG and CIT. Two independent studies reported significant lower CIT levels in the rat hippocampus after ATD.24, 81 This decrease in CIT appeared to be independent of changes in its precursor ARG. On the basis of the suggested interdependency of CIT and ARG, this finding suggests that ATD might directly affect the activity of NOS, and that decreased CIT concentrations most likely parallel decreases in NO. Endogenous NO can modulate neuronal function through interference with the release of several neurotransmitters,108 yet its precise interaction with the 5-HT system seems rather complex. Whereas slight increases in NO concentrations most likely enhance 5-HT release, moderate increases appear to decrease 5-HT release.109 The modulation of 5-HT release by NO might therefore depend on pre-existing NO concentrations and the effects might be differently regulated in distinct brain areas.105

A decrease in the activity of NOS and subsequent decreased synthesis of NO after ATD could underlie the ATD-induced object memory impairments106 as hippocampal inhibition of NOS is known to impair object recognition performance in rats.106, 110 As the ATD-induced decrease in brain CIT levels is seemingly caused by an interruption in NOS activity, this same decrease in NOS activity presumably also decreases the synthesis of NO, which could explain the ATD-induced object recognition impairments that are consistently reported in rodents.79, 80, 83, 85, 87, 88, 111

The second messenger molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) have an important role in intracellular signalling and are highly involved in learning and memory processes.110, 112, 113, 114 Both cAMP and cGMP are selectively hydrolyzed by phosphodiesterase (PDE) enzymes, and inhibition of PDE appears to be a reliable method for improving memory processes by increasing the levels of either cAMP, cGMP or both.115 Administration of the PDE2 inhibitor, BAY 60-7550, and the PDE5 inhibitor, zaprinast, have shown to increase NOS activity in rat hippocampus and striatum, and improve object recognition performance.116 Thus, besides directly increasing presynaptic cGMP levels, the enhancing effects of PDE5 and PDE2 inhibition upon memory performance might also be mediated by activation of NOS postsynaptically.116 As NO can freely diffuse back into the presynapse, it can increase cGMP levels by stimulating the synthesis of soluble guanylyl cyclase.117 An increase in NOS activity increases NO concentrations, which might underlie the improvement of the ATD-induced memory impairment by PDE inhibitors.87, 88 See also Figure 3 for an overview of how decreased NOS activity might explain ATD-induced object memory impairment and its attenuation through PDE inhibition.

Figure 3.
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Potential underlying mechanism of acute tryptophan (TRP) depletion-induced rat object memory impairment and its attenuation through phosphodiesterase inhibition. A decrease in the ratio of TRP to the sum of other large neutral amino acids (ΣLNAA) induced by acute tryptophan depletion (ATD) potentially directly affects (−) the activity of nitric oxide synthase (NOS), thereby decreasing central citrulline (CIT) levels without affecting its precursor arginine (ARG). A decrease in CIT most likely parallels a reduction in nitric oxide (NO) that subsequently affects local cerebral blood flow (CBF) in brain areas highly implicated in object memory processes. Indicated with (+) is the possible mechanisms behind the improvement of object memory deficits by inhibition of either the phosphodiesterase (PDE) enzyme type 5 (PDE5-I) or type 2 (PDE2-I), thereby directly increasing the levels of cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), respectively, or type 4 (PDE4-I) increasing cAMP only. Both second messenger molecules are highly implicated in learning and memory processes. Inhibition of PDE5 and PDE2 also directly activates NOS, thereby increasing NO levels that stimulate the synthesis of soluble guanylyl cyclase (sGC) and cGMP presynaptically. The vasodilating properties of the PDE inhibitors might additionally attenuate ATD-induced decreases in CBF. (−) Inhibition or decrease; (+) stimulation or increase.

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Cerebrovascular abnormalities

Although not completely clear at present, ATD also appears to affect local cerebral blood dynamics that may explain behavioural ATD effects. Under normal physiological conditions, the cerebral metabolic rate of glucose (CMRG) provides an index of changes in regional neuronal activity, and changes in glucose metabolism are found to be closely coupled to changes in CBF.118, 119 On this basis, abnormalities in either of these closely linked neurophysiological parameters in depressive subjects are thought to reflect changes in serotonergic neurotransmission in brain areas that can be functionally linked to the complexity of depressive symptomatology displayed.120, 121, 122, 123 However, the 5-HT neurotransmitter is a powerful vasoconstrictor124 and serotonergic fibres innervating cerebral arteries, arterioles and veins have been identified.47 Thus, if depression is represented by decreased central 5-HT neurotransmitter concentrations, an increase in CBF would seem more likely. Similarly, the ATD-induced reduction in 5-HT synthesis would decrease vasoconstrictor tone, thereby most likely increasing CBF due to vasodilatation. Surprisingly, a decrease in local CBF following ATD has been reported in human subjects125 and was also observed in rats.81 In the latter, the acute decrease of peripheral TRP levels resulted in a downward resetting of the cerebral flow–metabolism coupling relationship independently of changes in central TRP or 5-HT. This parallels preliminary findings of an uncoupling of flow from metabolism in unipolar depressed patients compared with bipolar patients and healthy controls.126 Although controversy exists about the exact location and direction of the neurophysiological abnormalities in depressive subjects,120, 127 depressive illness is generally characterized by decreases in CBF and CMRG in prefrontal cortex structures. However, it seems unlikely that a decrease in 5–HT alone accounts for the specific decreases in haemodynamic regulation.

In addition, low CBF most likely increases the interaction between the albumin-bound TRP complex and the glycocalyx of the BBB, thereby causing more TRP to dissociate from albumin.21, 22 This might provide an explanation for the fact that ATD-induced peripheral depletion of total TRP levels does not result in a significant decrease in brain TRP availability. Although it remains unclear how changes in peripheral TRP concentrations can interfere with the dynamic regulation of CBF, the findings support the notion that the underlying mechanisms of ATD might go beyond a straightforward 5-HT-mediated mechanism (see also Figure 3).

In general, decreased local CBF is best explained by a loss of dilator tone. Besides the effect of 5-HT on vasodilation, decreased local CBF has also been reported after direct inhibition of endothelial or neuronal NOS.128, 129 As mentioned previously, direct inhibition of NOS in the hippocampus is known to impair object memory performance.106, 110 Together, these findings support the suggestion that the ATD-induced impairments in object memory performance of rats could be related to one common mechanism, that is, a decrease in NO. The involvement of NO can be explained by the ATD-induced changes in brain levels of CIT as described earlier. All the findings together suggest that ATD-induced object memory impairments are most likely caused by a decrease in NO that reduces local CBF in hippocampal areas highly implicated in memory processing. Additionally, this is in line with the fact that PDE2 and PDE5 inhibition have been found to increase NOS activity in the hippocampus, which explains their potential to attenuate the ATD-induced object memory impairments. In addition, PDE inhibitors increase central cAMP and cGMP concentrations, which are both well-known vasodilators.130 Their strong vasodilating properties possibly contribute to the improvement of object memory performance through attenuation of the ATD-induced cerebrovascular effects (see also Figure 3). Interestingly, low-dose PDE4 or PDE5 inhibition did not directly affect cerebrovascular dynamics 30min after administration.131 However, this parallels the failure of the specific low-dosing regimes to reverse an object memory impairment in rodents.87, 88

Decreased brain-derived neurotrophic factor (BDNF)

BDNF could also be considered as a possible factor that is influenced by ATD. There are indications that an ATD effect on BDNF is indirect as ATD itself did not have a direct effect on peripheral and central BDNF levels.82, 97 Disruption of BDNF regulation has been implicated in both depressive symptomatology and cognitive dysfunction. Also, there are coregulating mechanisms between BDNF and the 5-HT system in general.132 The highest levels of BDNF mRNA have been reported in the dentate gyrus and hippocampal CA3 and CA2 layers.133, 134 Interestingly, another study81 showed an ATD-induced decrease in local CBF in similar areas (dentate PO, CA3 and CA2 region of the hippocampus). Regional changes in BDNF protein levels have been found after brief cerebrovascular events,135 consistent with the fact that BDNF has an important neuroprotective role.136, 137 Therefore, it can be suggested that ATD, cerebrovascular effects and BDNF could be interlinked.

In addition, BDNF has been implicated as having an important role in neuronal plasticity, including LTP.138 As LTP is assumed to be the underlying substrate of learning and memory processes,139 BDNF is thought to be a potential mediator of memory formation in general, and is known to be required specifically for memory consolidation.140 ATD in human subjects selectively impairs memory consolidation,74 which has been suggested to be caused by lower 5-HT levels in hippocampal areas.73 However, in rats, the ATD-induced cerebrovascular changes were independent of changes in central 5-HT levels.81 This suggests that decreased CBF in brain regions normally high in BDNF levels could also be considered underlying BDNF-mediated alterations in learning and memory processing after ATD.

Kynurenine (KYN) metabolites

Under normal physiological conditions, only 1 to 2% of the amount of ingested TRP is used by the body for the synthesis of 5-HT.19 The majority of total ingested TRP is catabolyzed into KYN by induction of tryptophan pyrrolase in the liver.141 Induction of pyrrolase by the enzymes IDO (indolamine 2,3-dioxygenase) and TDO (tryptophan 2,3-dioxygenase) in the liver reduces TRP availability142 and therefore 5-HT synthesis is also influenced by IDO and TDO activity.143, 144 Stimulation of these enzymes by proinflammatory cytokines, in particular interferon-γ,145 enhances the catabolism of TRP,142 thereby decreasing the amount of TRP eventually available for 5-HT synthesis in the brain. Moreover, TDO activity can also be induced by corticoids.146

Tryptophan pyrrolase is the first rate-limiting enzyme of the KYN pathway and KYN is the major degradation product of TRP.144 KYN is further converted into potentially neuroactive metabolites such as kynurenine acid and quinolinic acid.147 Independently of each other, both metabolites exert specific effects upon N-methyl-D-aspartate (NMDA) receptors,148 which have an important role in LTP and memory formation.149, 150 NMDA receptor antagonists have been shown to inhibit LTP and selectively impair learning and memory,151 but antagonists can also have a neuroprotective effect.152 Kynurenine acid has an antagonistic effect on the NMDA receptor and has been shown to have neuroprotective effects.153 Conversely, quinolinic acid depolarizes neurons by activating NMDA receptors.153 As a result, quinolinic acid can lead to neurotoxicity, similar to that found in hypoxia and ischaemia.154, 155, 156 Thus, an ATD-induced change in the amount of KYN metabolites could provide an explanation for the observed cerebral oligaemia paralleling decreased peripheral TRP levels,81 and as such KYN metabolites have already been suggested to additionally account for the consistently reported memory impairments after ATD.2

Confounding stress effects

ATD application-related procedures might produce stress, which might interfere with TRP metabolism, and subsequent 5-HT synthesis as brain 5-HT, together with other monoamines, is critically involved in the mediation of the central response to stressors and subsequent behavioural adaptation.157 Acute stressors stimulate hypothalamic–pituitary–adrenal axis activity, thereby increasing central 5-HT necessary for stress coping.158 In rodents, overnight food deprivation, repeated oral administrations by gavage, blood sampling and the immobilization necessary for applying the former are well-known stressors.159, 160, 161, 162 Yet, these experimental procedures are inevitably implicated in the application of the ATD method in rats and mice. In rats, both acute and repeated exposure to stressful stimuli have been shown to increase glucocorticoid levels and alter 5-HT turnover and release in both the hippocampus and frontal cortex.163 Thus, ATD application-related procedures in animals might interfere with normal brain TRP metabolism and subsequent 5-HT synthesis, thereby acting as confounding stress factors for the pharmacokinetic and behavioural effects of ATD.

Stress-induced changes in the breakdown of fat stored in fat cells (lipolysis) may also alter brain TRP concentrations. In the same way that insulin stimulates the uptake of albumin-bound fatty acids by fat cells, thereby decreasing the fraction of free TRP in plasma, stress can result in the reverse; stress increases lipolysis and thus the amount of plasma free-fatty acids.164 This increases the affinity of albumin for fatty acids, thereby displacing TRP from its albumin-binding sites. The resultant increase in the fraction of free TRP in plasma might increase the availability of TRP for uptake into the brain (see Figure 4). In a recent study with mice it was found that oral treatment by gavage combined with blood sampling and food deprivation, which are the standard experimental procedures, increased the TRP/ΣLNAA ratio in plasma within 20min.165 Thus, acute stress effects might explain the moderate depletion effects after ATD as a failure to considerably reduce central 5-HT levels eventually. Furthermore, it could be suggested that comparing TRP– (ATD) and TRP+ (control) conditions may not compare normal versus low levels of TRP, but instead compare moderate versus elevated TRP levels.

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Potential confounding stress effects of acute tryptophan (TRP) depletion application-related procedures. The method of acute TRP depletion (ATD) requires several highly stressful procedures, such as overnight food deprivation, repeated blood sampling, oral administrations by gavage and immobilization. Acute stress stimulates lipolysis, thereby increasing the amount of free-fatty acids in plasma that displace TRP from its albumin-binding sites. The resultant rise in free plasma TRP changes the ratio of TRP to the sum of the other large neutral amino acids (TRP/ΣLNAA) in favour of TRP, thereby increasing the amount of TRP available for uptake into the brain and its subsequent synthesis into 5-hydroxytryptamine (5-HT). Stress stimulates the secretion of corticosterone (CORT) that decreases brain-derived neurotrophic factor (BDNF) and 5-HT1A receptor binding. Both BDNF and 5-HT1A receptor functioning are highly implicated in learning and memory processes. The acute stress of ATD application-related procedures might thus explain the failure of ATD to considerably decrease 5-HT metabolism and its negative effect upon object memory performance through increased CORT levels.

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The effects of acute stress, including the ATD-related application procedures, upon 5-HT autoreceptor binding might additionally provide an explanation for the consistently reported ATD-induced memory dysfunction as indicated by object recognition impairment in rats.79, 83, 85, 86, 87, 88 Several 5-HT receptors, including 5-HT1A, are known to be highly involved in memory function166 and ATD has been shown to decrease 5-HT1A receptor binding.78 Also, acute corticosterone administration directly decreases 5-HT1A autoreceptor functioning.167 Thus, a more generalized stress effect of ATD application-related procedures, possibly linked to a decrease in 5-HT1A receptor function as described above, might underlie the ATD-induced impaired object recognition performance for which intact 5-HT1A receptor function seems to be crucial (see also Figure 4).

As a final note, it should be mentioned that these stress effects may be especially related to the experimental procedures used in animal research. In human research the effects of stress may be less as the procedure of the treatment is less stressful than the procedures used in animal research. Nevertheless, the intake of the amino-acid drink in humans has frequently been reported as unpleasant and some associated stress cannot be ruled out.31, 162, 163, 164

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Serotonin, depression and ATD

The 5-HT system is highly implicated in a wide range of functional processes. Whereas mood-lowering effects after ATD are only experienced in depression-free subjects predisposed to genetic 5-HT abnormalities, altered cognitive processing after ATD is observed in both healthy and genetically vulnerable subjects. Moreover, ATD-induced impaired object memory performance as measured by the object recognition task is consistently reported in rats79, 80, 83, 85, 86 even after only moderate peripheral TRP depletion or a single administration.87, 88 For adequate cognitive processing, the 5-HT system interacts highly with other neurophysiological systems that might all be interrupted after ATD.81, 82 This further supports the notion that an acute decrease in peripheral TRP levels directly interferes with mechanisms implicated in cognitive processing that presumably depend less upon 5-HT functioning per se. The potential alternative mechanisms underlying ATD effects might therefore provide an explanation for the consistently reported ATD-induced cognitive deficits across species.

Chronic exposure to stressful situations is one of the main contributing factors to the onset of depressive illness,158 and an intact 5-HT system is critical for mediating an adequate neurophysiological stress response and subsequent behavioural adaptation.157 At the level of somatodendritic 5-HT autoreceptors, adaptations to stress might be reflected by a reduction of these receptors, thereby reducing serotonergic feedback in dorsal raphe projection areas in an attempt to counteract an ATD-induced decrease in central 5-HT.78 Such an adaptive mechanism to an acute stressor might be less efficient in subjects predisposed to 5-HT dysfunction, which might account for the mood-lowering effects after ATD in these subjects.

As corticosteroid modulation of 5-HT function has a central role in mood disorders and cognitive functioning is highly impaired in clinical depression, the ATD findings reviewed in this article might have important implications regarding the mechanisms of adaptation to stress, and the implication of the 5-HT system in cognitive processing. As the 5-HT system is primarily modulatory, it is not surprising that in the clinical situation, most 5-HT-based treatments result in only a partial symptomatic improvement. The reviewed ATD findings thus support new insights for alternative treatment strategies along other pathways that interact highly with the 5-HT system. Upregulation of the cAMP and BDNF systems has already resulted in a novel model for the mechanism of action of antidepressants and new targets for the development of therapeutic targets.168

For an adequate interpretation of data resulting from application of the method in both clinical and preclinical settings, the described potential alternative mechanisms should be taken into account. Abnormal physiological conditions, including ATD application-related confounding stressors possibly interfere with the high number of cellular processes that are involved in 5-HT synthesis and metabolism, and might trigger other neurophysiological systems that generally interact with the 5-HT system. This possibly also reflects the heterogeneity of major depressive disorder in general, as all these neurophysiological processes might eventually be altered in clinical conditions and thus potentially be treated along different pharmacological pathways. In general, several findings support the fact that depression may not be caused solely by an abnormality of 5-HT function, but more likely by a dysfunction of other systems or brain regions modulated by 5-HT or interacting with its dietary precursor. Similarly, the ATD method does not seem to challenge the 5-HT system per se, but rather triggers 5-HT-mediated adverse events.

Conclusions

ATD currently represents the most established human challenge test to investigate the involvement of the 5-HT system in the pathogenesis and pathophysiology of affective disorders, including cognitive dysfunctional behaviour. However, the exact mechanism by which ATD exerts its neurophysiological effects, and to what extent changes in 5-HT neuronal activity contribute to the ATD-induced functional and behavioural alterations, remain unresolved issues. This pivotal lack of information impedes an adequate interpretation of the results arising from application of the method in both clinical and preclinical studies. As most biochemical brain values are merely indicative and thus speculative in human studies, animal models provide a better means for the exploration of ATD-induced neurobiochemical alterations. However, even in rats, challenging the 5-HT system by ATD introduces speculation because of the highly controversial results between studies on both the peripheral, central and behavioural level. Moreover, no convincing evidence exists that ATD induces alterations in central 5-HT release and subsequent neuronal activity. Several findings support the contribution of alternative mechanisms that go beyond a decreased 5-HT release, such as reduced NOS activity and cerebrovascular abnormalities. In addition, experimental procedures related to the application of the ATD method seem highly stressful and potentially interfere with TRP metabolism, thereby confounding ATD neurochemical and behavioural results, especially in rodents. As a decrease in CBF and confounding stress effects provide an explanation for both the consistently reported behavioural effects and the absent effects, it seems most likely that the underlying mechanism of the method goes beyond a disturbed 5-HT system. It is thus suggested that caution is required when interpreting ATD effects in terms of a selective serotonergic effect.

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Conflict of interest

The authors declare no conflict of interest.

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References

  1. Fadda F, Cocco S, Stancampiano R. A physiological method to selectively decrease brain serotonin release. Brain Res Brain Res Protoc 2000; 5: 219–222. | Article | PubMed |
  2. Blokland A, Lieben C, Deutz NEP, Schmitt J. Acute Tryptophan depletion: comparing the effects of an amino acid mixture with a gelatin-based protein in man and rats. Curr Top Nutraceut R 2004; 2: 1–8.
  3. Feenstra MG, van der Plasse G. Tryptophan depletion and serotonin release - a critical reappraisal. In: Muller CP, Jacobs B (eds). Handbook of the Behavioral Neurobiology of Serotonin, vol. 21. Academic Press: London, 2010, pp 249–258.
  4. Jans LA, Riedel WJ, Markus CR, Blokland A. Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Mol Psychiatry 2007; 12: 522–543. | Article | PubMed | ISI | ChemPort |
  5. Booij L, Van der Does AJ, Riedel WJ. Monoamine depletion in psychiatric and healthy populations: review. Mol Psychiatry 2003; 8: 951–973. | Article | PubMed | ISI | ChemPort |
  6. Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry 2007; 12: 331–359. | Article | PubMed | ISI | ChemPort |
  7. Oldendorf WH. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol 1971; 221: 1629–1639. | PubMed | ISI | ChemPort |
  8. Pardridge WM. Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 1998; 23: 635–644. | Article | PubMed | ISI | ChemPort |
  9. Smith QR. Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr 2000; 130(4S Suppl): 1016S–1122S. | PubMed | ISI | ChemPort |
  10. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 1971; 173: 149–152. | Article | PubMed | ISI | ChemPort |
  11. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral amino acids. Science 1972; 178: 414–416. | Article | PubMed | ISI | ChemPort |
  12. Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A. Effect of the oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism. J Neurochem 1974; 22: 869–870. | Article | PubMed | ISI |
  13. Fernstrom JD. Role of precursor availability in control of monoamine biosynthesis in brain. Physiol Rev 1983; 63: 484–546. | PubMed | ISI |
  14. Fernstrom JD. Diet-induced changes in plasma amino acid pattern: effects on the brain uptake of large neutral amino acids, and on brain serotonin synthesis. J Neural Transm Suppl 1979; 15: 55–67. | PubMed |
  15. Biggio G, Fadda F, Fanni P, Tagliamonte A, Gessa GL. Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci 1974; 14: 1321–1329. | Article | PubMed | ISI | ChemPort |
  16. Oldendorf WH, Szabo J. Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 1976; 230: 94–98. | PubMed | ISI | ChemPort |
  17. Tagliamonte A, Biggio G, Vargiu L, Gessa GL. Free tryptophan in serum controls brain tryptophan level and serotonin synthesis. Life Sci 2 1973; 12: 277–287. | Article | ISI |
  18. Gessa GL, Tagliamonte A. Possible role of free serum tryptophan in the control of brain tryptophan level and serotonin synthesis. Adv Biochem Psychopharmacol 1974; 11: 119–131. | PubMed | ChemPort |
  19. Bender DA. Biochemistry of tryptophan in health and disease. Mol Aspects Med 1983; 6: 101–197. | Article | PubMed | ISI |
  20. Reed RG, Burrington CM. The albumin receptor effect may be due to a surface-induced conformational change in albumin. J Biol Chem 1989; 264: 9867–9872. | PubMed | ISI |
  21. Pardridge WM, Fierer G. Transport of tryptophan into brain from the circulating, albumin-bound pool in rats and in rabbits. J Neurochem 1990; 54: 971–976. | Article | PubMed | ISI | ChemPort |
  22. Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 1987; 49: 1651–1658. | Article | PubMed | ISI | ChemPort |
  23. Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA. Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med 2006; 8: 1–27. | Article | PubMed |
  24. Lieben CK, Blokland A, Westerink B, Deutz NE. Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat. Neurochem Int 2004; 44: 9–16. | Article | PubMed | ISI | ChemPort |
  25. Fusar-Poli P, Allen P, McGuire P, Placentino A, Cortesi M, Perez J. Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature. Psychopharmacology (Berl) 2006; 188: 131–143. | Article | PubMed |
  26. Van der Does AJ. The mood-lowering effect of tryptophan depletion: possible explanation for discrepant findings. Arch Gen Psychiatry 2001; 58: 200–202. | Article | PubMed | ISI | ChemPort |
  27. Evers EA, Tillie DE, van der Veen FM, Lieben CK, Jolles J, Deutz NE et al. Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers. Psychopharmacology 2005; 178: 92–99. | Article | PubMed | ISI |
  28. Sambeth A, Riedel W, Tillie D, Blokland A, Postma A, Schmitt J. Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink. J Psychopharmacol 2009; 23: 56–64. | Article | PubMed | ISI |
  29. Djagny VB, Wang Z, Xu S. Gelatin: a valuable protein for food and pharmaceutical industries: review. Crit Rev Food Sci Nutr 2001; 41: 481–492. | Article | PubMed | ISI |
  30. Markus CR, Panhuysen G, Tuiten A, Koppeschaar H, Fekkes D, Peters ML. Does carbohydrate-rich, protein-poor food prevent a deterioration of mood and cognitive performance of stress-prone subjects when subjected to a stressful task? Appetite 1998; 31: 49–65. | Article | PubMed | ISI | ChemPort |
  31. Markus CR. Effects of carbohydrates on brain tryptophan availability and stress performance. Biol Psychol 2007; 76: 83–90. | Article | PubMed | ISI | ChemPort |
  32. Benton D. Carbohydrate ingestion, blood glucose and mood. Neurosci Biobehav Rev 2002; 26: 293–308. | Article | PubMed | ISI | ChemPort |
  33. Fernstrom JD, Wurtman RJ. Elevation of plasma tryptophan by insulin in rat. Metabolism 1972; 21: 337–342. | Article | PubMed | ISI | ChemPort |
  34. Fernstrom JD, Fernstrom MH, Grubb PE. Twenty-four-hour variations in rat blood and brain levels of the aromatic and branched-chain amino acids: chronic effects of dietary protein content. Metabolism 1987; 36: 643–650. | Article | PubMed | ISI |
  35. Teff KL, Young SN, Blundell JE. The effect of protein or carbohydrate breakfasts on subsequent plasma amino acid levels, satiety and nutrient selection in normal males. Pharmacol, Biochem Behav 1989; 34: 829–837. | Article | PubMed | ISI | ChemPort |
  36. Harper AE, Benevenga NJ, Wohlhueter RM. Effects of ingestion of disproportionate amounts of amino acids. Physiol Rev 1970; 50: 428–558. | PubMed | ISI | ChemPort |
  37. Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A. Tryptophan-free diet: a new means for rapidly decreasing brain tryptophan content and serotonin synthesis. Acta Vitaminol Enzymol 1975; 29: 72–78. | PubMed | ISI | ChemPort |
  38. Moja EA, Restani P, Corsini E, Stacchezzini MC, Assereto R, Galli CL. Cycloheximide blocks the fall of plasma and tissue tryptophan levels after tryptophan-free amino acid mixtures. Life Sci 1991; 49: 1121–1128. | Article | PubMed | ISI |
  39. Neumeister A. Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull 2003; 37: 99–115. | PubMed |
  40. Bell CJ, Hood SD, Nutt DJ. Acute tryptophan depletion. Part II: clinical effects and implications. Aust N Z J Psychiatry 2005; 39: 565–574. | Article | PubMed | ISI |
  41. Hood SD, Bell CJ, Nutt DJ. Acute tryptophan depletion. Part I: rationale and methodology. Aust N Z J Psychiatry 2005; 39: 558–564. | PubMed | ISI |
  42. Young SN. The use of diet and dietary components in the study of factors controlling affect in humans: a review. J Psychiatry Neurosci 1993; 18: 235–244. | PubMed | ISI |
  43. Reilly JG, McTavish SF, Young AH. Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. J Psychopharmacol 1997; 11: 381–392. | Article | PubMed | ISI | ChemPort |
  44. Leonard BE. Fundamentals of Psychopharmacology, 2nd edn. Wiley and Sons: New York, 1997.
  45. Maes M, Meltzer HY. The Serotonin Hypothesis of Major Depression. Raven Press, Ltd: New York, 1995, pp 933–944.
  46. Meltzer HY. Role of serotonin in depression. Ann NY Acad Sci 1990; 600: 486–499; discussion 499–500. | Article | PubMed | ChemPort |
  47. Steinbusch HW. Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 1981; 6: 557–618. | Article | PubMed | ISI | ChemPort |
  48. Cowen PJ, Parry-Billings M, Newsholme EA. Decreased plasma tryptophan levels in major depression. J Affect Disord 1989; 16: 27–31. | Article | PubMed | ISI | ChemPort |
  49. Asberg M, Traskman L, Thoren P. 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry 1976; 33: 1193–1197. | PubMed | ISI | ChemPort |
  50. van Praag HM, de Haan S. Central serotonin metabolism and frequency of depression. Psychiatry Res 1979; 1: 219–224. | Article | PubMed |
  51. Naughton M, Mulrooney JB, Leonard BE. A review of the role of serotonin receptors in psychiatric disorders. Hum Psychopharmacol 2000; 15: 397–415. | Article | PubMed | ISI | ChemPort |
  52. Cryan JF, Leonard BE. 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Hum Psychopharmacol 2000; 15: 113–135. | Article | PubMed | ISI |
  53. Neumeister A, Konstantinidis A, Stastny J, Schwarz MJ, Vitouch O, Willeit M et al. Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. Arch Gen Psychiatry 2002; 59: 613–620. | Article | PubMed | ISI | ChemPort |
  54. Klaassen T, Riedel WJ, van Someren A, Deutz NE, Honig A, van Praag HM. Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders. Biol Psychiatry 1999; 46: 489–497. | Article | PubMed | ISI | ChemPort |
  55. Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan. Lancet 1997; 349: 915–919. | Article | PubMed | ISI | ChemPort |
  56. Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C. Mood response to acute tryptophan depletion in healthy volunteers: sex differences and temporal stability. Neuropsychopharmacology 1996; 15: 465–474. | Article | PubMed | ISI | ChemPort |
  57. Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA 1997; 94: 5308–5313. | Article | PubMed | ChemPort |
  58. Neumeister A, Nugent AC, Waldeck T, Geraci M, Schwarz M, Bonne O et al. Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry 2004; 61: 765–773. | Article | PubMed | ISI | ChemPort |
  59. Moreno FA, Gelenberg AJ, Heninger GR, Potter RL, McKnight KM, Allen J et al. Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999; 46: 498–505. | Article | PubMed | ISI | ChemPort |
  60. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47: 411–418. | PubMed | ISI | ChemPort |
  61. Delgado PL, Price LH, Miller HL, Salomon RM, Licinio J, Krystal JH et al. Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 1991; 27: 321–330. | PubMed | ISI | ChemPort |
  62. Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, Moreno FA et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry 1999; 46: 212–220. | Article | PubMed | ISI | ChemPort |
  63. Delgado PL, Charney DS, Price LH, Landis H, Heninger GR. Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects. Life Sci 1989; 45: 2323–2332. | Article | PubMed | ISI | ChemPort |
  64. Young SN, Smith SE, Pihl RO, Ervin FR. Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology (Berl) 1985; 87: 173–177. | Article | PubMed | ChemPort |
  65. Carpenter LL, Anderson GM, Pelton GH, Gudin JA, Kirwin PD, Price LH et al. Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 1998; 19: 26–35. | Article | PubMed | ISI | ChemPort |
  66. Evers EA, van der Veen FM, Jolles J, Deutz NE, Schmitt JA. Acute tryptophan depletion improves performance and modulates the BOLD response during a Stroop task in healthy females. Neuroimage 2006; 32: 248–255. | Article | PubMed | ISI | ChemPort |
  67. Moore P, Landolt HP, Seifritz E, Clark C, Bhatti T, Kelsoe J et al. Clinical and physiological consequences of rapid tryptophan depletion. Neuropsychopharmacology 2000; 23: 601–622. | Article | PubMed | ISI | ChemPort |
  68. Williams WA, Shoaf SE, Hommer D, Rawlings R, Linnoila M. Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J Neurochem 1999; 72: 1641–1647. | Article | PubMed | ISI | ChemPort |
  69. Moreno FA, McGavin C, Malan TP, Gelenberg AJ, Heninger GR, Mathe AA et al. Tryptophan depletion selectively reduces CSF 5-HT metabolites in healthy young men: results from single lumbar puncture sampling technique. Int J Neuropsychopharmacol 2000; 3: 277–283. | Article | PubMed | ISI |
  70. Booij L, Van der Does AJ, Haffmans PM, Riedel WJ, Fekkes D, Blom MJ. The effects of high-dose and low-dose tryptophan depletion on mood and cognitive functions of remitted depressed patients. J Psychopharmacol 2005; 19: 267–275. | Article | PubMed | ISI | ChemPort |
  71. Sambeth A, Blokland A, Harmer CJ, Kilkens TO, Nathan PJ, Porter RJ et al. Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: a pooled analysis of nine studies. Neurosci Biobehav Rev 2007; 31: 516–529. | Article | PubMed | ISI | ChemPort |
  72. Klaassen T, Riedel WJ, Deutz NE, van Someren A, van Praag HM. Specificity of the tryptophan depletion method. Psychopharmacology 1999; 141: 279–286. | Article | PubMed | ISI |
  73. Riedel WJ. Cognitive changes after acute tryptophan depletion: what can they tell us? Psychol Med 2004; 34: 3–8. | Article | PubMed | ISI |
  74. Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM. Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl) 1999; 141: 362–369. | Article | PubMed |
  75. Mendelsohn D, Riedel WJ, Sambeth A. Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review. Neurosci Biobehav Rev 2009; 33: 926–952. | Article | PubMed | ISI |
  76. van der Staay FJ. Animal models of behavioral dysfunctions: basic concepts and classifications, and an evaluation strategy. Brain Res Rev 2006; 52: 131–159. | Article | PubMed | ISI |
  77. Blokland A, Lieben C, Deutz NE. Anxiogenic and depressive-like effects, but no cognitive deficits, after repeated moderate tryptophan depletion in the rat. J Psychopharmacol 2002; 16: 39–49. | Article | PubMed | ISI | ChemPort |
  78. Cahir M, Ardis T, Reynolds GP, Cooper SJ. Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT 2A receptor binding in the rat. Psychopharmacology 2007; 190: 497–506. | Article | PubMed | ISI | ChemPort |
  79. Jans LA, Lieben CK, Blokland A. Influence of sex and estrous cycle on the effects of acute tryptophan depletion induced by a gelatin-based mixture in adult Wistar rats. Neuroscience 2007; 147: 304–317. | Article | PubMed | ISI |
  80. Olivier JD, Jans LA, Korte-Bouws GA, Korte SM, Deen PM, Cools AR et al. Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats. Psychopharmacology (Berl) 2008; 200: 243–254. | Article | PubMed |
  81. van Donkelaar EL, Ferrington L, Blokland A, Steinbusch HW, Prickaerts J, Kelly PA. Acute tryptophan depletion in rats alters the relationship between cerebral blood flow and glucose metabolism independent of central serotonin. Neuroscience 2009; 163: 683–694. | Article | PubMed | ISI |
  82. van Donkelaar EL, van den Hove DL, Blokland A, Steinbusch HW, Prickaerts J. Stress-mediated decreases in brain-derived neurotrophic factor as potential confounding factor for acute tryptophan depletion-induced neurochemical effects. Eur Neuropsychopharmacol 2009; 19: 812–821. | Article | PubMed | ISI |
  83. Lieben CK, van Oorsouw K, Deutz NE, Blokland A. Acute tryptophan depletion induced by a gelatin-based mixture impairs object memory but not affective behavior and spatial learning in the rat. Behav Brain Res 2004; 151: 53–64. | Article | PubMed | ISI |
  84. Brown CM, Fletcher PJ, Coscina DV. Acute amino acid loads that deplete brain serotonin fail to alter behavior. Pharmacol Biochem Behav 1998; 59: 115–121. | Article | PubMed | ISI |
  85. Jans L, Korte-Bouws G, Korte S, Blokland A. The effects of acute tryptophan depletion on affective behaviour and cognition in Brown Norway and Sprague Dawley rats. J Psychopharmacol 2008; 24: 605–614. | Article | PubMed |
  86. Jans LA, Blokland A. Influence of chronic mild stress on the behavioural effects of acute tryptophan depletion induced by a gelatin-based mixture. Behav Pharmacol 2008; 19: 706–715. | Article | PubMed | ISI |
  87. Rutten K, Lieben C, Smits L, Blokland A. The PDE4 inhibitor rolipram reverses object memory impairment induced by acute tryptophan depletion in the rat. Psychopharmacology (Berl) 2007; 192: 275–282. | Article | PubMed | ChemPort |
  88. van Donkelaar EL, Rutten K, Blokland A, Akkerman S, Steinbusch HW, Prickaerts J. Phosphodiesterase 2 and 5 inhibition attenuates the object memory deficit induced by acute tryptophan depletion. Eur J Pharmacol 2008; 600: 98–104. | Article | PubMed | ISI | ChemPort |
  89. Badawy AB. Plasma free tryptophan revisited: what you need to know and do before measuring it. J Psychopharmacol 2010; 24: 809–815. | Article | PubMed | ISI |
  90. Oldendorf WH, Szabo J. Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 1976; 230: 94–98. | PubMed | ISI | ChemPort |
  91. Crespi F. In vivo voltammetry with micro-biosensors for analysis of neurotransmitter release and metabolism. J Neurosci Methods 1990; 34: 53–65. | Article | PubMed | ISI |
  92. Crespi F, Garratt JC, Sleight AJ, Marsden CA. In vivo evidence that 5-hydroxytryptamine (5-HT) neuronal firing and release are not necessarily correlated with 5-HT metabolism. Neuroscience 1990; 35: 139–144. | Article | PubMed | ISI |
  93. Westerink BH. Brain microdialysis and its application for the study of animal behaviour. Behav Brain Res 1995; 70: 103–124. | Article | PubMed | ISI | ChemPort |
  94. Shannon NJ, Gunnet JW, Moore KE. A comparison of biochemical indices of 5-hydroxytryptaminergic neuronal activity following electrical stimulation of the dorsal raphe nucleus. J Neurochem 1986; 47: 958–965. | Article | PubMed | ISI |
  95. Boadle-Biber MC. Regulation of serotonin synthesis. Prog Biophys Mol Biol 1993; 60: 1–15. | Article | PubMed | ChemPort |
  96. Ardis TC, Cahir M, Elliott JJ, Bell R, Reynolds GP, Cooper SJ. Effect of acute tryptophan depletion on noradrenaline and dopamine in the rat brain. J Psychopharmacol 2009; 23: 51–55. | Article | PubMed | ISI |
  97. Cahir M, Ardis TC, Elliott JJ, Kelly CB, Reynolds GP, Cooper SJ. Acute tryptophan depletion does not alter central or plasma brain-derived neurotrophic factor in the rat. Eur Neuropsychopharmacol 2008; 18: 317–322. | Article | PubMed | ISI |
  98. Fernstrom JD, Hirsch MJ. Brain serotonin synthesis: reduction in corn-malnourished rats. J Neurochem 1977; 28: 877–979. | Article | PubMed | ISI | ChemPort |
  99. van der Plasse G, Meerkerk DT, Lieben CK, Blokland A, Feenstra MG. Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion. Psychopharmacology (Berl) 2007; 195: 377–385. | Article | PubMed |
  100. Bel N, Artigas F. Reduction of serotonergic function in rat brain by tryptophan depletion: effects in control and fluvoxamine-treated rats. J Neurochem 1996; 67: 669–676. | Article | PubMed | ISI | ChemPort |
  101. Stancampiano R, Melis F, Sarais L, Cocco S, Cugusi C, Fadda F. Acute administration of a tryptophan-free amino acid mixture decreases 5-HT release in rat hippocampus in vivo. Am J Physiol 1997; 272(3 Part 2): R991–R994. | PubMed | ISI | ChemPort |
  102. Trulson ME. Dietary tryptophan does not alter the function of brain serotonin neurons. Life Sci 1985; 37: 1067–1072. | Article | PubMed | ISI |
  103. Young SN, Ervin FR, Pihl RO, Finn P. Biochemical aspects of tryptophan depletion in primates. Psychopharmacology (Berl) 1989; 98: 508–511. | Article | PubMed |
  104. Lenard NR, Dunn AJ. Mechanisms and significance of the increased brain uptake of tryptophan. Neurochem Res 2005; 30: 1543–1548. | Article | PubMed | ISI |
  105. Smith JC, Whitton PS. Nitric oxide modulates N-methyl-D-aspartate-evoked serotonin release in the raphe nuclei and frontal cortex of the freely moving rat. Neurosci Lett 2000; 291: 5–8. | Article | PubMed | ISI | ChemPort |
  106. Blokland A, Prickaerts J, Honig W, de Vente J. State-dependent impairment in object recognition after hippocampal NOS inhibition. NeuroReport 1998; 9: 4205–4208. | Article | PubMed | ISI | ChemPort |
  107. Dawson VL, Dawson TM. Nitric oxide actions in neurochemistry. Neurochem Int 1996; 29: 97–110. | Article | PubMed | ISI | ChemPort |
  108. Prast H, Philippu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol 2001; 64: 51–68. | Article | PubMed | ISI | ChemPort |
  109. Kaehler ST, Singewald N, Sinner C, Philippu A. Nitric oxide modulates the release of serotonin in the rat hypothalamus. Brain Res 1999; 835: 346–349. | Article | PubMed | ISI | ChemPort |
  110. Prickaerts J, de Vente J, Honig W, Steinbusch HW, Blokland A. cGMP, but not cAMP, in rat hippocampus is involved in early stages of object memory consolidation. Eur J Pharmacol 2002; 436: 83–87. | Article | PubMed | ISI | ChemPort |
  111. Lieben CK, Blokland A, Sik A, Sung E, van Nieuwenhuizen P, Schreiber R. The selective 5-HT6 receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat. Neuropsychopharmacology 2005; 30: 2169–2179. | Article | PubMed | ISI | ChemPort |
  112. Bernabeu R, Schmitz P, Faillace MP, Izquierdo I, Medina JH. Hippocampal cGMP and cAMP are differentially involved in memory processing of inhibitory avoidance learning. NeuroReport 1996; 7: 585–588. | Article | PubMed | ISI | ChemPort |
  113. Bernabeu R, Schroder N, Quevedo J, Cammarota M, Izquierdo I, Medina JH. Further evidence for the involvement of a hippocampal cGMP/cGMP-dependent protein kinase cascade in memory consolidation. NeuroReport 1997; 8: 2221–2224. | Article | PubMed | ISI | ChemPort |
  114. Rutten K, Prickaerts J, Hendrix M, van der Staay FJ, Sik A, Blokland A. Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 2007; 558: 107–112. | Article | PubMed | ISI | ChemPort |
  115. Blokland A, Schreiber R, Prickaerts J. Improving memory: a role for phosphodiesterases. Curr Pharm Des 2006; 12: 2511–2523. | Article | PubMed | ISI | ChemPort |
  116. Domek-Lopacinska K, Strosznajder JB. The effect of selective inhibition of cyclic GMP hydrolyzing phosphodiesterases 2 and 5 on learning and memory processes and nitric oxide synthase activity in brain during aging. Brain Res 2008; 1216: 68–77. | Article | PubMed | ISI |
  117. Murad F, Mittal CK, Arnold WP, Katsuki S, Kimura H. Guanylate cyclase: activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Adv Cyclic Nucleotide Res 1978; 9: 145–158. | PubMed | ChemPort |
  118. Kuschinsky W. Coupling of function, metabolism, and blood flow in the brain. Neurosurg Rev 1991; 14: 163–168. | Article | PubMed | ISI | ChemPort |
  119. Sokoloff L. Relationships among local functional activity, energy metabolism, and blood flow in the central nervous system. Fed Proc 1981; 40: 2311–2316. | PubMed | ISI | ChemPort |
  120. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry 2000; 48: 813–829. | Article | PubMed | ISI | ChemPort |
  121. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ et al. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999; 46: 1375–1387. | Article | PubMed | ISI | ChemPort |
  122. Drevets WC, Ongur D, Price JL. Reduced glucose metabolism in the subgenual prefrontal cortex in unipolar depression. Mol Psychiatry 1998; 3: 190–191. | Article | PubMed |
  123. Drevets WC, Ongur D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry 1998; 3: 220–226, 190–191. | Article | PubMed | ISI | ChemPort |
  124. Edvinsson L, MacKenzie ET. Amine mechanisms in the cerebral circulation. Pharmacol Rev 1976; 28: 275–348. | PubMed | ISI |
  125. Talbot PS, Cooper SJ. Anterior cingulate and subgenual prefrontal blood flow changes following tryptophan depletion in healthy males. Neuropsychopharmacology 2006; 31: 1757–1767. | Article | PubMed | ISI | ChemPort |
  126. Dunn RT, Willis MW, Benson BE, Repella JD, Kimbrell TA, Ketter TA et al. Preliminary findings of uncoupling of flow and metabolism in unipolar compared with bipolar affective illness and normal controls. Psychiatry Res 2005; 140: 181–198. | PubMed | ISI |
  127. Soares JC, Mann JJ. The functional neuroanatomy of mood disorders. J Psychiatr Res 1997; 31: 393–432. | Article | PubMed | ISI | ChemPort |
  128. Kelly PA, Ritchie IM, Arbuthnott GW. Inhibition of neuronal nitric oxide synthase by 7-nitroindazole: effects upon local cerebral blood flow and glucose use in the rat. J Cereb Blood Flow Metab 1995; 15: 766–773. | Article | PubMed | ISI | ChemPort |
  129. Kelly PA, Thomas CL, Ritchie IM, Arbuthnott GW. Cerebrovascular autoregulation in response to hypertension induced by NG-nitro-L-arginine methyl ester. Neuroscience 1994; 59: 13–20. | Article | PubMed | ISI | ChemPort |
  130. Dundore RL, Clas DM, Wheeler LT, Habeeb PG, Bode DC, Buchholz RA et al. Zaprinast increases cyclic GMP levels in plasma and in aortic tissue of rats. Eur J Pharmacol 1993; 249: 293–297. | Article | PubMed | ISI | ChemPort |
  131. Rutten K, Van Donkelaar EL, Ferrington L, Blokland A, Bollen E, Steinbusch HW et al. Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacology 2009; 34: 1914–1925. | Article | PubMed | ISI |
  132. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2004; 27: 589–594. | Article | PubMed | ISI | ChemPort |
  133. Ernfors P, Wetmore C, Olson L, Persson H. Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron 1990; 5: 511–526. | Article | PubMed | ISI | ChemPort |
  134. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995; 15(3 Part 1): 1768–1777. | PubMed | ISI | ChemPort |
  135. Kokaia Z, Nawa H, Uchino H, Elmer E, Kokaia M, Carnahan J et al. Regional brain-derived neurotrophic factor mRNA and protein levels following transient forebrain ischemia in the rat. Brain Res Mol Brain Res 1996; 38: 139–144. | Article | PubMed | ChemPort |
  136. Larsson E, Nanobashvili A, Kokaia Z, Lindvall O. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats. J Cereb Blood Flow Metab 1999; 19: 1220–1228. | Article | PubMed | ISI | ChemPort |
  137. Lindvall O, Kokaia Z, Bengzon J, Elmer E, Kokaia M. Neurotrophins and brain insults. Trends Neurosci 1994; 17: 490–496. | Article | PubMed | ISI | ChemPort |
  138. Lu Y, Christian K, Lu B. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008; 89: 312–333. | Article | PubMed | ISI | ChemPort |
  139. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361: 31–39. | Article | PubMed | ISI | ChemPort |
  140. Lee JL, Everitt BJ, Thomas KL. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 2004; 304: 839–843. | Article | PubMed | ISI | ChemPort |
  141. Stone TW, Darlington LG. Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 2002; 1: 609–620. | Article | PubMed | ISI | ChemPort |
  142. Botting NP. Chemistry and neurochemistry of the kynurenine pathway of tryptophan metabolism. Chem Soc Rev 1995; 24: 401–412. | Article | ISI |
  143. Smith SA, Pogson CI. The metabolism of L-tryptophan by isolated rat liver cells. Effect of albumin binding and amino acid competition on oxidatin of tryptophan by tryptophan 2,3-dioxygenase. Biochem J 1980; 186: 977–996. | PubMed | ISI |
  144. Moroni F. Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol 1999; 375: 87–100. | Article | PubMed | ISI |
  145. Hu B, Hissong BD, Carlin JM. Interleukin-1 enhances indoleamine 2,3-dioxygenase activity by increasing specific mRNA expression in human mononuclear phagocytes. J Interferon Cytokine Res 1995; 15: 617–624. | Article | PubMed | ISI | ChemPort |
  146. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther 2006; 109: 325–338. | Article | PubMed | ISI | ChemPort |
  147. Young SN, Leyton M. The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav 2002; 71: 857–865. | Article | PubMed | ISI | ChemPort |
  148. Stone TW. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 1993; 45: 309–379. | PubMed | ISI | ChemPort |
  149. Morris RG. Long-term potentiation and memory. Philos Trans R Soc Lond B Biol Sci 2003; 358: 643–647. | Article | PubMed |
  150. Morris RG, Davis S, Butcher SP. Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Philos Trans R Soc Lond B Biol Sci 1990; 329: 187–204. | Article | PubMed | ISI | ChemPort |
  151. Morris RG, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 1986; 319: 774–776. | Article | PubMed | ISI | ChemPort |
  152. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006; 5: 160–170. | Article | PubMed | ISI | ChemPort |
  153. Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 1981; 72: 411–412. | Article | PubMed | ISI | ChemPort |
  154. Stone TW, Forrest CM, Mackay GM, Stoy N, Darlington LG. Tryptophan, adenosine, neurodegeneration and neuroprotection. Metab Brain Dis 2007; 22: 337–352. | Article | PubMed | ISI |
  155. Stone TW. Endogenous neurotoxins from tryptophan. Toxicon 2001; 39: 61–73. | Article | PubMed | ISI | ChemPort |
  156. Schwarcz R, Whetsell Jr WO, Mangano RM. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 1983; 219: 316–318. | Article | PubMed | ISI | ChemPort |
  157. de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475. | Article | PubMed | ISI | ChemPort |
  158. van Praag HM. Can stress cause depression? Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 891–907. | Article | PubMed | ChemPort |
  159. Curzon G, Joseph MH, Knott PJ. Effects of immobilization and food deprivation on rat brain tryptophan metabolism. J Neurochem 1972; 19: 1967–1974. | Article | PubMed | ISI | ChemPort |
  160. Chamas FM, Underwood MD, Arango V, Serova L, Kassir SA, Mann JJ et al. Immobilization stress elevates tryptophan hydroxylase mRNA and protein in the rat raphe nuclei. Biol Psychiatry 2004; 55: 278–283. | Article | PubMed | ISI | ChemPort |
  161. Nakahara D, Nakamura M. Differential effect of immobilization stress on in vivo synthesis rate of monoamines in medial prefrontal cortex and nucleus accumbens of conscious rats. Synapse 1999; 32: 238–242. | Article | PubMed | ISI | ChemPort |
  162. Jahng JW, Kim JG, Kim HJ, Kim BT, Kang DW, Lee JH. Chronic food restriction in young rats results in depression- and anxiety-like behaviors with decreased expression of serotonin reuptake transporter. Brain Res 2007; 1150: 100–107. | Article | PubMed | ISI |
  163. Chaouloff F. Physiopharmacological interactions between stress hormones and central serotonergic systems. Brain Res Brain Res Rev 1993; 18: 1–32. | Article | PubMed | ChemPort |
  164. McMenamy RH. Binding of indole analogues to human serum albumin. Effects of fatty acids. J Biol Chem 1965; 240: 4235–4243. | PubMed | ISI | ChemPort |
  165. van Donkelaar EL, Blokland A, Lieben CK, Kenis G, Ferrington L, Kelly PA et al. Acute tryptophan depletion in C57BL/6 mice does not induce central serotonin reduction or affective behavioural changes. Neurochem Int 2010; 56: 21–34. | Article | PubMed | ISI |
  166. King MV, Marsden CA, Fone KC. A role for the 5-HT(1A), 5-HT(4) and 5-HT(6) receptors in learning and memory. Trends Pharmacol Sci 2008; 29: 482–492. | Article | PubMed | ISI |
  167. Laaris N, Haj-Dahmane S, Hamon M, Lanfumey L. Glucocorticoid receptor-mediated inhibition by corticosterone of 5-HT1A autoreceptor functioning in the rat dorsal raphe nucleus. Neuropharmacology 1995; 34: 1201–1210. | Article | PubMed | ISI | ChemPort |
  168. Duman RS. Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 1998; 44: 324–335. | Article | PubMed | ISI | ChemPort |
  169. Jans LA, Lieben CK, Smits LT, Blokland A. Pharmacokinetics of acute tryptophan depletion using a gelatin-based protein in male and female Wistar rats. Amino Acids 2009; 37: 349–357. | Article | PubMed | ISI |
  170. van Donkelaar EL, Kelly PA, Dawson N, Blokland A, Prickaerts J, Steinbusch HW et al. Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebrovascular hyperperfusion in adult male Wistar rats. J Neurosci Res 2010; 88: 1557–1568. | PubMed | ISI |