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

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

Auditory evoked potentials reflect serotonergic neuronal activity--a study in behaving cats administered drugs acting on 5-HT1A autoreceptors in the dorsal raphe nucleus.

A valid indicator of central serotonergic neurotransmission would be useful for various diagnostic and psychopharmacological purposes in psychiatry. However, known peripheral serotonergic measures only partially reflect serotonergic function in the brain. Previous findings suggest that the intensity dependence of auditory evoked potentials (AEPs) is closely related to central serotonergic activity. The present study examines the effects of microinjection of a 5-HT1A agonist (8-OH-DPAT) and a 5-HT1A antagonist (spiperone) into the dorsal raphe nucleus (DRN) on AEP recorded epidurally from the primary and secondary auditory cortex in behaving cats. We found a stronger intensity dependence only of AEP from the primary auditory cortex after 8-OH-DPAT, which inhibits the firing rate of serotonergic DRN neurons, and a weaker intensity dependence after spiperone, which increases serotonergic cell firing, as compared to baseline measurements. These results demonstrate that the intensity dependence of AEP is inversely related to serotonergic neuronal activity and that it may be a promising tool for assessing central serotonergic function in humans (e.g., identifying patients with low serotonergic neurotransmission).     

The loudness dependency of the auditory evoked N1/P2-component as a predictor of the acute SSRI response in depression

Rationale: A serotonergic dysfunction is supposed to play a pathogenetic role in depression, but there is a considerable number of non-responders in the acute treatment of depression with serotonergic agents like SSRI. Thus, an indicator of central serotonergic activity could lead to a more specific pharmacological treatment of depression. In animal and human data there is a growing amount of evidence that a strong loudness dependency of late auditory evoked potentials (LDAEP) is an indicator of low serotonergic activity and vice versa. Objective: In 29 depressive inpatients (DSM-III-R diagnosis 296.x in 28 patients, 300.4 in one patient), the hypothesis was tested that a strong LDAEP prior to treatment can predict a better clinical outcome under SSRI treatment over 4 weeks. Results: Patients with a strong pre-treatment LDAEP had a significantly greater decrease of depressive symptoms (Hamilton Scale for Depression) after 4 weeks than patients with a flat LDAEP. Significantly more responders fell into the group with a high LDAEP. Contrary to what might be expected, a second recording in a subsample of 19 patients after 4 weeks of treatment failed to show changes in the LDAEP. Conclusion: Our finding confirms the hypothesis that a strong LDAEP, indicating a low serotonergic activity, is related to a favorable response to acute SSRI treatment in depression. The LDAEP is a promising tool for the prediction of response to serotonin agonists in depression and it seems to be of clinical importance. Received: 11 June 1999 / Final version: 27 October 1999     

Effect of tryptophan depletion on the attentional salience of smoking cues

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

Peripheral correlates of serotonergically-influenced behaviors in vervet monkeys (Cercopithecus aethiops sabaeus)

The associations among twelve behaviors and three potential peripheral markers of central serotonergic activity were investigated in vervet monkeys (Cercopithecus aethiops sabaeus). The behaviors monitored included approach, heterogroom, rest, eat, avoid, be solitary, be vigilant, huddle, initiate aggress, receive aggress, and engage in sexual behavior. The biochemical parameters measured were whole blood serotonin, plasma free tryptophan, and plasma total tryptophan. Throughout the study period, intraindividual variability in both the behavioral and the biochemical measures was small, although there was substantial interindividual variability in both sets of measures. Free and total tryptophan correlated positively with approach, heterogroom, and eat, and inversely with avoid and be solitary. Whole blood serotonin correlated inversely with avoid and be solitary. These data are compatible with previously reported observations on the behavioral consequences of manipulating serotonergic systems in vervet monkeys and suggest that in normal, drug naive monkeys, free and total tryptophan are better correlates of the central serotonergic activity influencing behavior than is whole blood serotonin.     

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

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

Is the loudness dependence of auditory evoked potentials modulated by the selective serotonin reuptake inhibitor citalopram in healthy subjects?

The loudness dependence of auditory evoked potentials (LDAEP) has been discussed as a non-invasive in vivo marker of central serotonergic function. Evidence for this has been found in animal studies, but studies in humans provide less consistent results. In this study, the relationship between LDAEP and directly modulated central serotonergic activity in healthy subjects was investigated. In a single-blind cross-over design, the LDAEP of female participants (age: 24.0 +/- 2.3 years) was measured under two conditions: (1) infusion of 20 mg citalopram diluted in 250 ml 0.9% saline and (2) infusion of 250 ml 0.9% saline as placebo. LDAEP was measured at five different time points before, during and up to 60 min after drug/placebo administration and dipole source analysis was performed. The increase of the central serotonin activity in response to citalopram was not accompanied by a significant change of the LDAEP compared to the placebo condition. The result underlines that the acceptance of LDAEP as a marker of central serotonergic function still needs further discussion.     

Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation

Serotonin (5-hydroxytryptamine; 5-HT) circuits may play a role in cognitive performance, particularly in learning and memory. Cognitive impairment is often seen in depressed patients, in whom 5-HT turnover in the brain is thought to be lowered. A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects. In this study, the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion. Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan, according to a double-blind, cross-over design. Tryptophan depletion specifically impaired long-term memory performance in all subjects: delayed recall performance, recognition sensitivity, and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo. Short-term memory and perceptual and psychomotor functions were unchanged. There were no differences between groups with a positive and a negative family history for depression. On the basis of these results, it is concluded that tryptophan depletion specifically impairs long-term memory formation, presumably as a result of an acute decrease in 5-HT turnover in the brain. Received: 13 February 1998 / Final version: 8 July 1998     

Blockade of muscarinic, rather than nicotinic, receptors impairs attention, but does not interact with serotonin depletion

Rationale: The cholinergic system is considered to be essential for attention and the degeneration of the cholinergic system in Alzheimer’s disease (AD) correlates with the cognitive decline seen in AD patients. The serotonergic system also degenerates in AD, but its role in the modulation of cognitive functions, especially attention, is somewhat unclear. Objectives: The present study investigated possible differences between cholinergic muscarinic and nicotinic receptor mediated mechanisms, the role of serotonin (5-HT) and the interaction between the cholinergic and serotonergic systems in the modulation of attention and response control. Methods: The influences of cholinergic receptor blockade and 5-HT lesions on the performance of rats in the five-choice serial reaction time task were assessed. The 5-HT lesions were neurochemically verified. Results: The neurochemical analysis indicated that the levels of 5-HT and 5-hydroxyindoleacetic acid were reduced quite specifically in the hippocampi, parieto-occipital and frontal cortices, and in the striatum of both p-chloroamphetamine (pCA) and 5,7-dihydroxytryptamine (5,7-DHT) lesioned rats. The behavioural results showed that the pCA lesion caused a transient increase in impulsivity whereas the 5,7-DHT lesion temporarily reduced the motor activity and slightly impaired choice accuracy. Furthermore, the blockade of central muscarinic receptors by scopolamine (0.075 and 0.150 mg/kg), but not nicotinic receptors by mecamylamine (1.0 or 3.0 mg/kg), impaired the choice accuracy, whereas the blockade of both muscarinic and nicotinic receptors interfered with motor activity, though possibly via peripheral mechanisms. Interestingly, mecamylamine (3.0 mg/kg) reduced impulsivity, whereas scopolamine slightly increased it. Serotonergic lesions did not make the rats more susceptible to the effects of cholinolytics on choice accuracy. Conclusions: 5-HT system is not essential for the modulation of attention, but it is important in the modulation of response control. Central muscarinic receptors are important in the modulation of attention, whereas central nicotinic receptors may be more essential in response control. The results do not support there being an interaction between the serotonergic and the cholinergic systems in the modulation of attention. Received: 31 August 1998 / Final version: 16 August 1999     

Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature

Rationale There is a growing psychopharmacological literature on the use of Acute Tryptophan Depletion (ATD) for experimental modulation of the serotonergic system. To date, no systematic review has been undertaken assessing the neurophysiological effects following this acute central 5-HT manipulation.Materials and methods A comprehensive MEDLINE, EMBASE, PsycINFO search was performed for reports on neural substrates of Acute Tryptophan Depletion in healthy individuals and in clinical population.Results Twenty-eight placebo-controlled studies were included in the review. Although tryptophan depletion reduced plasma serotonin levels in all studies, significant effects on mood were only observed in studies with recovered depressed patients. In functional neuroimaging studies ATD was consistently found to modulate cortical activity in prefrontal areas implicated in mnemonic and executive functions and in orbitofrontal, cingulate, and subcortical regions associated with emotional processing. Electrophysiological studies indicated that ATD has a significant effect on both “selective” and “involuntary” attention.Conclusions The combination of ATD with modern brain imaging techniques allows the investigation of the neurophysiological effects of reduced 5-HT synthesis on global brain activity, executive functions, memory, attention, and affect.     

Behavioural effects of acute tryptophan depletion in healthy male volunteers

Acute tryptophan depletion (ATD) studies have been used to assess the role of the serotonergic system in various aspects of human behaviour. Changes in mood have already been described in selected groups of individuals submitted to ATD. The present study was a randomized, double-blind, cross-over trial designed to evaluate the effects of ATD on mood, memory, attention and induced anxiety in normal male volunteers. Twelve healthy male volunteers were submitted to two separate sessions of ATD, 1 week apart. Drinks containing either a balanced mixture of amino acids (B) or a similar mixture devoid of tryptophan (T-) were administered in each session. Mood was assessed using self-rating scales. Attention and memory were assessed using a battery of psychological tests. Anxiety induction was carried out using a simulation of public speaking. Blood levels of tryptophan were assessed before and after the B and T- drinks. Results showed that ATD markedly decreased plasma tryptophan (p < 0.0001). Mood ratings, memory and attention were not changed by the T- drink. There was no difference among the anxiety levels measured under T- or B mixtures. These data supports the notion that ATD does not change mood and cognitive function in healthy subjects.     

An effective dietary method for chronic tryptophan depletion in two mouse strains illuminates a role for 5-HT in nesting behaviour

Physiological depletion of tryptophan, the precursor to serotonin has been shown to alter mood and cognition in both humans and rodents. Few studies have investigated the neurochemical and behavioural effects associated with tryptophan depletion in mice. Given that BALB/c and C57BL/6J mice differ in tryptophan hydroxylase (TPH) functionality, serotonin levels and behavioural phenotype, we hypothesised that a differential strain response to chronic dietary tryptophan manipulations would be observed. Therefore, the effects of four chronic dietary tryptophan manipulations were investigated, the diets include a depleted diet (0% tryptophan, TRP(-)), a deficient diet (0.25% tryptophan, TRP(-/+)), an enhanced diet (1.25% tryptophan, TRP(+)) and a control diet (0.7%). Diet-induced alterations in peripheral and central tryptophan levels and brain serotonin turnover were determined by high performance liquid chromatography. In addition, dietary-induced alterations in behaviour were assessed in several commonly used tasks. Peripheral and central tryptophan levels and consequently central serotonergic turnover were significantly decreased by the TRP(-) diet in both strains, however, no effect of tryptophan supplementation was observed on tryptophan or serotonin levels. Dietary tryptophan manipulation induced pronounced behavioural effects, particularly in nesting behaviour where a reduction in nesting was observed following depletion and an increase in nesting behaviour was observed with enhanced tryptophan in both strains. Additionally, depletion produces an anxiolytic-like effect and did not impede locomotion. This study demonstrates significant alterations in the levels of tryptophan, serotonin turnover and behaviour following chronic dietary tryptophan depletion.     

The serotonergic hypothesis for depression in Parkinson's disease: an experimental approach.

The serotonergic hypothesis for depression in Parkinson's disease (PD) states that the reduced cerebral serotonergic activity that occurs in PD constitutes a biological risk factor for depression. The aim of our study was to assess the serotonergic hypothesis of depression in PD patients using an experimental approach. In a double-blind, randomized order, placebo-controlled crossover design, the response on the Profile of Mood States (POMS) questionnaire to acute tryptophan depletion (ATD) was studied in 15 PD nondepressed patients and 15 control subjects, without a prior personal or family history of depression. PD patients had lower (worse) baseline scores on the sadness, fatigue and vigor subscales of the POMS, in both ATD and the placebo condition, but not on the tension and anger subscales. There was however neither a significance between group effect, nor significance within-group effect due to ATD. We could find no evidence of a specific serotonergic vulnerability of PD patients for depression. Therefore, our results do not support the serotonergic hypothesis for depression in PD.     

Acute tryptophan depletion does not alter central or plasma brain-derived neurotrophic factor in the rat.

Dietary induced acute tryptophan depletion (ATD) is used to reduce central serotonergic function and to investigate the role of serotonin (5-HT) in psychiatric illness. In healthy volunteers ATD produces working memory deficits and decreases mood in some studies. Brain-derived neurotrophic factor (BDNF) plays a role in both cognition and in the regulation of mood; however, the possible contribution of central BDNF changes to the effects of ATD has not been examined. Therefore, using a rat model we have examined the effect of amino acid mixture-induced ATD on plasma and central BDNF protein levels. ATD significantly reduced free-plasma TRP by 79% and central hippocampal 5-HT by 35% when compared to controls. However, plasma or central BDNF protein levels in the hippocampus and midbrain were not significantly altered by ATD. These results suggest that changes in central BDNF do not contribute to the cognitive or mood effects of ATD.     

The effects of acute tryptophan depletion on neuropsychological function

Serotonin (5-HT, 5-hydroxytryptamine) may have an important role in the maintenance of normal neuropsychological functioning. The method of acute tryptophan depletion (ATD) provides a pharmacological challenge by which central 5-HT levels can be temporarily decreased and effects on learning, memory and mood examined. Twenty healthy male volunteers were recruited to take part in this within-subject, double-blind, crossover study. Neuropsychological function was evaluated 4-6 h after ingestion of a control or 52 g tryptophan (TRP) depleting amino-acid drink. ATD significantly lowered levels of plasma total and free TRP (p < 0.001), but this did not affect mood or performance on tests of verbal and visuo-spatial learning and memory, attention or executive function. These results contradict previous findings; however, the degree of disruption of central 5-HT levels resulting from the use of the 52 g amino-acid protocol may be an important factor in explaining the lack of effect. By utilizing more specific probes of individual 5-HT receptor subtypes, future studies can fully explore the role of 5-HT in neuropsychological functioning and may elucidate the factors determining vulnerability to the effects of serotonergic dysfunction.     

Acute dietary tryptophan depletion impairs maintenance of "affective set" and delayed visual recognition in healthy volunteers

RATIONALE: Altered serotonergic transmission in affective disorders and Alzheimer's disease has prompted research aimed at defining the precise cognitive effects of depleting central serotonin in humans, using acute dietary tryptophan depletion. OBJECTIVE: We examined the effects of tryptophan depletion on mood and cognition in healthy volunteers. Cognitive tests of memory and attentional processing were employed to test hypotheses of central 5-hydroxytryptamine (5-HT) function related to cortical processing. METHODS: A double-blind, parallel design, placebo control study was employed with 15 subjects in each group. Mood rating scales were performed at the start and 5 h after ingestion of the drink. Cognitive tests were also performed at 5 h, after completion of the subjective rating scales. RESULTS: A robust reduction in total tryptophan was achieved in the test group. Subjects receiving the placebo drink showed the expected effect of shift on the affective shifting task, that is, more errors in the more difficult shift versus the non-shift condition. The tryptophan-depleted group made a similar number of errors in the shift trials but failed to reduce the number of errors in the non-shift trials. The tryptophan-depleted group showed a significant impairment on the delayed pattern recognition task. No significant effects on the subjective mood measures were found. CONCLUSIONS: Tryptophan depletion abolished the normal tendency to improve error scores on non-shift trials in response to affective cues on a go/no-go task. We suggest that this inability to "maintain set" in the non-shift condition may be due to a disruption of semantic retrieval processes concerned with affect. The novel finding of impairment on a delayed visual pattern recognition task confirms and extends previous studies where selective effects on memory and learning have been found following acute tryptophan depletion.     

Kinetics of tryptophan accumulation into synaptosomes of various regions of rat brain

The kinetics of synaptosomal tryptophan accumulation has been determined in five regions of the rat brain. For tryptophan concentrations ranging from 2.5–20 M, we found an active uptake in all the structures studied, i.e.: Corpus striatum, midbrain, brainstem, hypothalamus and cerebral cortex + hippocampus. The Vm of tryptophan uptake was highest in the cortex, followed in descending order by corpus striatum, hypothalamus, midbrain and brainstem, while the Km was highest in the cortex, then in descending order corpus striatum, brainstem, midbrain and hypothalamus. In spite of the possible nonspecific high affinity tryptophan uptake into serotoninergic neurons, we found a correlation between the Vm of tryptophan uptake and the different results in the literature concerning uptake and release of serotonin. These observations might indicate a correlation between the Vm of tryptophan uptake and the functional activity of serotonergic neurons.This research was supported by INSERM(FRA 5) and CNRS(ERA 560)     

Prostaglandin D2 Inhibits Pentylenetetrazole-Induced Convulsions in Rats by a Serotonin-Mediated Mechanism

Prostaglandins (PGs) of the E series are known to exert anticonvulsant action in experimental animals. Earlier studies from this laboratory have indicated that PGE₁ inhibits pentylenetetrazole (PTZ)-induced convulsions in rats through a serotonin-mediated mechanism. PGD₂, the major PG in the rodent brain, shares a number of central pharmacological actions of the PGEs, and like the latter it potentiates the anticonvulsant action of phenobarbitone and phenytoin in rats. The present study was undertaken to investigate the putative anticonvulsant action of PGD₂ against PTZ-induced convulsions in rats and to evaluate the role of serotonin in the anticonvulsant action of PGD₂. PGD₂ (5, 10, and 20 µg, icv) produced a dose-related inhibition of PTZ-induced clonic convulsions in rats. The anticonvulsant action of PGD₂ (20 µg, icv) was significantly attenuated following pretreatment of the rats with pharmacologic agents known to reduce central serotonergic activity, including 5,6-dihydroxytryptamine, a selective neurotoxin for serotonergic neurons, p-chlorophenylalanine, a specific inhibitor of serotonin biosynthesis, metergoline, a serotonin postsynaptic receptor antagonist, and quipazine, which is known to inhibit neuronal release of serotonin. These findings, in conjunction with an earlier study from this laboratory indicating that PGD₂ augments rat brain serotonergic activity, suggest that the anticonvulsant activity of PGD₂ against PTZ-induced convulsions in rats is mediated through a serotonergic mechanism.     

Corticosteroid-serotonin interactions in depression: a review of the human evidence

Rationale It has been suggested that corticosteroid-serotonin interactions are central to the pathophysiology of depression. These interactions have been investigated in healthy and depressed humans, primarily using neuroendocrine techniques.Objectives To review the evidence regarding the nature of these interactions in healthy and depressed humans.Methods Electronic searches were performed for relevant papers, employing MEDLINE and Web of Science. To focus the review, we selected only those articles involving (i) assessment of serotonergic function following experimental manipulation of the HPA axis in healthy volunteers; and (ii) assessment of both serotonergic and HPA axis function in clinically depressed subjects.Results Pre-treatment with hydrocortisone, both acutely and sub-acutely attenuates the GH response to GHRH in healthy subjects. This complicates the interpretation of 5-HT neuroendocrine studies employing GH output as a measure. In depression there is evidence that reduced availability of l-tryptophan impairs HPA axis feedback. There is also evidence that depressed and healthy subjects may adapt differently both to low tryptophan and hypercortisolaemic challenges. There is no consistent evidence of a simple relationship between HPA axis function and 5-HT function in depression.Conclusions The putative reduction in central 5-HT function has not been shown to be a direct consequence of hypercortisolaemia. Rather, the 5-HT system and HPA axis have complex inter-relationships. Challenges to either system, such as stress or reduced dietary tryptophan, may perturb the other and subjects vulnerable to depression may fail to adapt to such challenges.     

Designing modulators of 5-hydroxytryptamine signaling to treat abuse disorders

Introduction: There are currently no treatments approved by the FDA to effectively treat cocaine dependence. Research of recent years has gradually revealed the importance of 5-hydroxytryptamine (5-HT) in the reinforcing and rewarding effects of cocaine and the potential for relapse. Brain-derived neurotropic factor (BDNF) is an important modulator of the serotonergic system and 5-HT modulates BDNF expression. Their reciprocal interaction is of crucial importance for synaptic plasticity during long-term cocaine intake. Thus, agents modifying BDNF–5-HT interactions might have therapeutic potential for cocaine dependence by reversing the altered brain structure that underlies relapse after cocaine withdrawal.

Areas covered: On the basis of the available literature, the authors propose an interaction between BDNF and the serotonergic system in the response to cocaine and during cocaine intake. Furthermore, they discuss putative therapies that are based on 5-HT and BDNF.

Expert opinion: Recent studies are beginning to elucidate the role of 5-HT and BDNF in cocaine addiction. Additionally, animal studies modeling addiction-like drug intake will only further help to gain a better understanding of how to treat cocaine addiction. Based on the current evidence, the authors believe that BDNF, as a modulator of the serotonergic pathway, or 5-HT, as a modulator of the BDNF system, represent a valuable target to treat drug addiction, which may yield novel therapeutics in the future.