Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans

Background:

Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood.

Methods:

We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results.

Results:

Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control.

Conclusions:

The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding.     

Differential effects of acute serotonin and dopamine depletion on prepulse inhibition and p50 suppression measures of sensorimotor and sensory gating in humans.

Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal 'gating' function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.     

Effects of acute combined serotonin and dopamine depletion on cue-induced drinking intention/desire and cognitive function in patients with alcohol dependence

Background

Alcohol cues can precipitate the desire to drink and cause relapse in recovering alcohol-dependent patients. Serotonin and dopamine may play a role in alcohol cue-induced craving. Acute combined tryptophan (Trp), tyrosine (Tyr), and phenylalanine (Phe) depletion (CMD) in the diet attenuates the synthesis of serotonin and dopamine in the human brain. However, no study of the effects of acute CMD has been previously conducted. Therefore, we investigated whether the attenuation of serotonin and dopamine synthesis changes cue-induced alcohol craving in recently abstinent alcoholics.

Methods

In this double-blind, randomized, placebo-controlled, crossover design, 12 male patients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for alcohol dependence were divided into two conditions: (1) monoamine depletion (i.e., consumption of a concentrated amino acid beverage that resulted in a rapid and significant decrease in plasma-free Tyr/Phe/Trp) and (2) balanced condition (i.e., consumption of a similar beverage that contained Tyr/Phe/Trp). The participants were scheduled for two experimental sessions, with an interval of ≥7 days. The cue-induced craving test session was conducted 6 h after each amino acid beverage administration. Drinking urge, blood pressure, heart rate, working memory, and attention/psychomotor performance were assessed before and after administration.

Results

Compared with the balanced condition, the monoamine depletion condition significantly increased drinking intention/desire and diastolic blood pressure. Cognitive performance was not different between the two conditions.

Conclusions

Acute combined serotonin and dopamine depletion may increase drinking intention/desire and diastolic blood pressure without influencing cognitive function.     

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

Rationale

Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood.

Objective

This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women.

Methods

In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n?=?13) and nonuser controls (n?=?17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task.

Results

The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n?=?7), relative to controls (n?=?9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users.

Limitation

The group sizes were small, when males and females were considered separately.

Conclusions

Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.     

Is a serotonergic mechanism involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced appetite suppression in the Sprague-Dawley rat?

The major cause of TCDD-induced death in rats is a progressive voluntary feed refusal which has been correlated with reduced gluconeogenesis. Since centrally administered TCDD does not cause death or decreased feed intake in rats, the ability of TCDD to suppress appetite via peripheral mechanisms acting on the central nervous system was examined in two experimental models. First, it was found that the feed intake of rats on scheduled feeding cycles was not decreased by blood transfused from rats with TCDD-induced appetite suppression (8 days after a lethal dose of TCDD, i.p.). In contrast, a similar transfusion from normal, satiated rats did reduce feed intake of recipient rats by approximately 40%, suggesting that TCDD-treated rats are not satiated but rather that they are not hungry. In the second study tryptophan (the amino acid precursor of the neurotransmitter serotonin) was measured in the plasma and tryptophan, serotonin, norepinephrine and dopamine in the hypothalamus as well as dopamine and its metabolites in the striatum 4, 8, and 16 days after TCDD dosage (125 g/kg, i.p.). Progressive time-dependent increases in tryptophan levels in plasma and brain were paralleled by increases in brain serotonin and 5-hydroxyindoleacetic acid (the primary metabolite of serotonin) in TCDD-treated rats. No changes were observed regarding the other biogenic amines. It is suggested based on these data and on substantial evidence from the published literature that a serotonergic mechanism may be involved in TCDD-induced feed intake reduction.     

Acute serotonin and dopamine depletion improves attentional control: findings from the stroop task.

Schizophrenia is associated with impairments of attentional control on classic experimental paradigms such as the Stroop task. However, at a basic level the neurochemical mechanisms that may be responsible for such impairments are poorly understood. In this study, we sought to investigate the influence of brain monoamine function on Stroop task performance in healthy participants using the established methods of acute dietary serotonin, dopamine, and combined monoamine depletion. The study was a double-blind placebo controlled design in which 12 healthy male participants completed the Stroop task under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Decreased Stroop interference indicating improved attentional control was observed after both tryptophan depletion and tyrosine/phenylalanine depletion, while there was no significant change in interference after combined monoamine depletion. Findings suggest that reduced tonic dopamine or serotonin activity within specific neural circuits (such as the striatum, anterior cingulate, or prefrontal cortex) may play a critical role in attentional control, possibly by improving gating of information via reducing noise in monoaminergic systems. These findings enhance our understanding of the neurochemical basis of attentional control and the possible cause of attentional control deficits in schizophrenia.     

The effect of acute tryptophan depletion on the neural correlates of emotional processing in healthy volunteers.

The processing of affective material is known to be modulated by serotonin (5-HT), but few studies have used neurophysiological measures to characterize the effect of changes in 5-HT on neural responses to emotional stimuli. We used functional magnetic resonance imaging to investigate the effect of acute tryptophan depletion, which reduces central 5-HT synthesis, on neural responses to emotionally valenced verbal stimuli. Though no participants experienced significant mood change, emotional information processing was substantially modified following 5-HT depletion. A behavioral bias toward positive stimuli was attenuated following depletion, which was accompanied by increased hemodynamic responses during the processing of emotional words in several subcortical structures. Inter-individual differences in tryptophan depletion-elicited anxiety correlated positively with the caudate bias toward negative stimuli. These data suggest that 5-HT may play an important role in mediating automatic negative attentional biases in major depression, as well as resilience against negative distracting stimuli in never-depressed individuals.     

急性色氨酸、苯丙氨酸和酪氨酸剥夺对酒依赖者线索暴露诱导的饮酒迫促性的作用

目的:评价急性色氨酸、苯丙氨酸和酪氨酸剥夺(CMD)对酒依赖者线索暴露诱导的饮酒迫促性的作用。方法:采用随机双盲交叉对照的方法,选择符合ICD-10和DSM-Ⅳ诊断标准的男性酒依赖患者12名,并排除任一符合DSM-Ⅳ轴Ⅰ诊断的其他精神障碍。在签署知情同意书的情况下,每位受试者间隔至少7d分别在实验当天禁食的情况下给予含人体必需的16种氨基酸的氨基酸饮料(BLANCE)或缺失色氨酸、苯丙氨酸和酪氨酸的氨基酸饮料(CMD),实验的前一天低蛋白饮食,实验当天结束后给予高蛋白饮食。实验当天,在给予氨基酸饮料前后进行Tiffany饮酒迫促性量表、焦虑可视模拟标尺、抑郁可视模拟标尺、副反应量表测查以及血压、心率检测。给予氨基酸饮料6h后进行非酒精(纯净水)相关线索和酒精(白酒)相关线索暴露,并评价暴露前后饮酒迫促性、焦虑可视模拟标尺分、抑郁可视模拟标尺分和血压、心率的变化。结果:CMD组在非酒精相关线索和酒精相关线索暴露后饮酒意愿(Intention/desire to drinking)和舒张压均增加,差异具有显著性(P=0.0217,0.038),而BLANCE组在非酒精相关线索和酒精相关线索暴露后饮酒意愿、舒张压差异均无显著性。焦虑可视模拟标尺分、抑郁可视模拟标尺分、收缩压、心率在两组中的非酒精相关线索和酒精相关线索暴露前后的差异无显著性。在安全性方面,所有受试者中有1名出现腹泻,但是病人尚能耐受。其余少见的副反应主要有恶心、头晕、困倦等,皆为轻度或中度。结论:急性色氨酸、苯丙氨酸和酪氨酸剥夺(CMD)后酒依赖患者在非酒精和酒精相关线索暴露后的饮酒意愿增加,舒张压增高,但是对焦虑和抑郁情绪没有影响。口服氨基酸饮料的副反应少且轻微。     

Behavioral and Neural Substrates of Habit Formation in Rats Intravenously Self-Administering Nicotine

Tobacco addiction involves a transition from occasional, voluntary smoking towards habitual behavior that becomes increasingly resistant to quitting. The development of smoking habits may reflect a loss of behavioral control that can be modeled in rats. This study investigated the behavioral and neural substrates of habit formation in rats exposed to either brief (10 days) or extended (47 days) intravenous (IV) nicotine self-administration training. Following training, the first cohort of rats were exposed to a nicotine devaluation treatment, which involved repeated pairings of IV nicotine with lithium injection. They were then tested for sensitivity of responding to nicotine devaluation under extinction and reinstatement conditions. The second cohort of rats received equivalent self-administration training followed by processing of brain tissue for c-Fos immunohistochemistry. After brief training, devaluation suppressed nicotine-seeking during tests of extinction and reinstatement, confirming that responding is initially sensitive to current nicotine value, and therefore, goal directed. In contrast, after extended training, devaluation had no effect on extinction or reinstatement of responding, indicating that responding had become habitual. Complementary neuroanalysis revealed that extended nicotine self-administration was associated with increased c-Fos expression in brain regions implicated in habitual control of reward seeking, including activation of the dorsolateral striatum and substantia nigra pars compacta. These findings provide evidence of direct devaluation of an IV drug reward, that nicotine self-administration is initially goal-directed but becomes habitual with extended training, and that this behavioral transition involves activation of brain areas associated with the nigrostriatal system.     

Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward.

The therapeutic effects of chronic selective serotonin reuptake inhibitors (SSRIs) are well documented, yet the elementary behavioral processes that are affected by such treatment have not been fully investigated. We report here the effects of chronic fluoxetine treatment and genetic deletion of the serotonin transporter (SERT) on food reinforced behavior in three paradigms: the progressive ratio operant task, the concurrent choice operant task, and the Pavlovian-to-Instrumental transfer task. We consistently find that chronic pharmacological blockade or genetic deletion of SERT result in similar behavioral consequences: reduced operant responding for natural reward. This is in line with previous studies reporting declines in operant responding for drugs and intracranial self-stimulation with fluoxetine treatment, suggesting that the effect of SERT blockade can be generalized to different reward types. Detailed analyses of behavioral parameters indicate that this reduction in operant responding affect both goal-directed and non-goal-directed behaviors without affecting the Pavlovian cue-triggered excessive operant responding. In addition, both pharmacological and genetic manipulations reduce locomotor activity in the open field novel environment. Our data contrast with the effect of dopamine in increasing operant responding for natural reward specifically in goal-directed behaviors and in increasing Pavlovian cue-triggered excessive operant responding. Serotonin and dopamine have been proposed to serve opposing functions in motivational processes. Our data suggest that their interactions do not result in simple opponency. The fact that pharmacological blockade and genetic deletion of SERT have similar behavioral consequences reinforces the utility of the SERT null mice for investigation of the mechanisms underlying chronic SSRIs treatment.     

Differences in Anxiety-Like Behavior within a Batch of Wistar Rats Are Associated with Differences in Serotonergic Transmission,Enhanced by Acute SRI Administration,and Abolished By Serotonin Depletion

Background:

The anxiety-reducing effect of long-term administration of serotonin reuptake inhibitors is usually seen only in subjects with anxiety disorders, and such patients are also abnormally inclined to experience a paradoxical anxiety-enhancing effect of acute serotonin reuptake inhibition. These unique responses to serotonin reuptake inhibitors in anxiety-prone subjects suggest, as do genetic association studies, that inter-individual differences in anxiety may be associated with differences in serotonergic transmission.

Methods:

The one-third of the animals within a batch of Wistar rats most inclined to spend time on open arms in the elevated plus maze were compared with the one-third most inclined to avoid them with respect to indices of brain serotonergic transmission and how their behavior was influenced by serotonin-modulating drugs.

Results:

“Anxious” rats displayed higher expression of the tryptophan hydroxylase-2 gene and higher levels of the tryptophan hydroxylase-2 protein in raphe and also higher levels of serotonin in amygdala. Supporting these differences to be important for the behavioral differences, serotonin depletion obtained by the tryptophan hydroxylase-2 inhibitor p-chlorophenylalanine eliminated them by reducing anxiety in “anxious” but not “non-anxious” rats. Acute administration of a serotonin reuptake inhibitor, paroxetine, exerted an anxiety-enhancing effect in “anxious” but not “non-anxious” rats, which was eliminated by long-term pretreatment with another serotonin reuptake inhibitor, escitalopram.

Conclusions:

Differences in an anxiogenic impact of serotonin, which is enhanced by acute serotonin reuptake inhibitor administration, may contribute to differences in anxiety-like behavior amongst Wistar rats.     

Locomotor hyperactivity caused by dopamine infusion into the nucleus accumbens of rat brain: specificity of action

Rats selected as high-activity and low-activity responders to the hyperactivity-inducing action of peripherally administered (-)N-n-propylnorapomorphine [(-)NPA] were subject to intra-accumbens infusion of dopamine, noradrenaline, serotonin, acetylcholine and GABA (0.48 l/h, 25 g/24 h, 13 days). Locomotor activity was measured during infusion and for a minimum of 35 days thereafter. After discontinuation of infusion the animals' responsiveness to (-)NPA was also assessed and, on the 2nd day of withdrawal, sensitivity to the hyperactivity-inducing action of acute intra-accumbens dopamine was determined. Dopamine caused a biphasic pattern of hyperactivity during infusion with peaks of responding between days 2–5 and 8–12: normal values returned after withdrawal of infusion. However, 2–3 weeks after withdrawal of intra-accumbens dopamine infusion animals showed reversed responding to (-)NPA challenge, the initial low-active animals giving a high-active response and high-active animals giving low-activity. Infusions of noradrenaline, serotonin, GABA and acetylcholine produced some increase in locomotor activity towards the termination of infusion, but no treatment could replicate the first hyperactivity peak and no treatment, after withdrawal, could reverse the responsiveness to (-)NPA of high- and low-active animals. Acute injections of dopamine into the nucleus accumbens showed that the infusion of the different neurotransmitter substances caused change within that nucleus. Nevertheless, changes in locomotor behaviour following the infusion of dopamine into the nucleus accumbens are specific for dopamine.     

Comparison of the behavioral depressant effects of biogenic amine depleting and neuroleptic agents following various 6-hydroxydopamine treatments

The effects of prior catecholamine reductions produced by 6-hydroxydopamine on the behavioral depressant effects of catecholamine depleting and neuroleptic drugs were examined using a continuously reinforced bar-press response. In spite of large depletions, 6-hydroxydopamine treated rats showed no deficits in performance. Similarly, animals preferentially depleted of norepinephrine or dopamine showed no deficit in this task. When -methyltyrosine or reserpine were administered at a dose which had minimal effect on responding in control animals, the 6-hydroxydopamine group in which both amines were reduced and the group preferentially depleted of dopamine showed severe deficits in bar-press responding. Responding in rats preferentially depleted of norepinephrine was slightly reduced but not to the extent observed in animals depleted of dopamine. Administration of the dopamine--hydroxylase inhibitor, U-14,624, depressed responding but did not produce differential effects which correlated with brain norepinephrine concentration in the 6-hydroxydopamine-treated groups. Furthermore, the behavioral depression produced after treatment with chlorpromazine, haloperidol, and pimozide was not altered by any of the 6-hydroxydopamine treatments. These findings provide further evidence for the view that dopamine depletion plays a major role in the behavioral depressant effects of -methyltyrosine and reserpine, but do not eliminate a role for brain norepinephrine.     

The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels

Alterations in brain tryptophan levels cause changes in brain serotonin synthesis, and this has been used to study the implication of altered serotonin levels in humans. In the acute tryptophan depletion (ATD) technique, subjects ingest a mixture of amino acids devoid of tryptophan. This results in a transient decline in tissue tryptophan and in brain serotonin. ATD can result in lower mood and increase in irritability or aggressive responding. The magnitude of the effect varies greatly depending on the susceptibility of the subject to lowered mood or aggressivity. Unlike ATD, tryptophan can be given chronically. Tryptophan is an antidepressant in mild to moderate depression and a small body of data suggests that it can also decrease aggression. Preliminary data indicate that tryptophan also increases dominant behavior during social interactions. Overall, studies manipulating tryptophan levels support the idea that low serotonin can predispose subjects to mood and impulse control disorders. Higher levels of serotonin may help to promote more constructive social interactions by decreasing aggression and increasing dominance.     

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.     

Phosphodiesterase 2 and 5 inhibition attenuates the object memory deficit induced by acute tryptophan depletion

The underlying mechanism of short-term memory improvement after inhibition of specific phosphodiesterases (PDEs) is still poorly understood. The present study aimed to reveal the ability of PDE5 and PDE2 inhibitors, that increase cyclic guanosine monophosphate (cGMP) and both cyclic adenosine monophosphate (cAMP) and cGMP, respectively, to reverse an object recognition deficit induced by acute tryptophan depletion. Acute tryptophan depletion is a pharmacological challenge tool to lower central serotonin (5-hydroxytryptamine; 5-HT) levels by depleting the availability of its dietary precursor tryptophan. Short-term object memory was tested in male Wistar rats by exposing them to the object recognition task. First, the effects of acute tryptophan depletion upon object recognition 2 h after administration of the nutritional mixture were established. Subsequently, acute tryptophan depletion was combined with the PDE5 inhibitor vardenafil (1, 3 and 10 mg/kg) or with the PDE2 inhibitor BAY 60-7550 (0.3, 1 and 3 mg/kg), 30 min prior to testing. Acute tryptophan depletion significantly lowered plasma tryptophan levels and impaired object recognition performance. Vardenafil (3 and 10 mg/kg) and BAY 60-7550 (3 mg/kg) were able to attenuate the acute tryptophan depletion induced object recognition impairment. Thus, both PDE5 and PDE2 inhibition improved short-term object recognition performance after an acute tryptophan depletion induced deficit. The underlying mechanisms, however, remain poorly understood and further studies are needed to determine whether the present findings can be explained by a direct effect of enhanced cAMP and cGMP levels upon 5-HT activity, or even other neurotransmitter systems, and possibly an interaction with synthesis of nitric oxide or effects upon cerebral blood flow function.     

Serotonin Modulates the Effects of Pavlovian Aversive Predictions on Response Vigor

Updated theoretical accounts of the role of serotonin (5-HT) in motivation propose that 5-HT operates at the intersection of aversion and inhibition, promoting withdrawal in the face of aversive predictions. However, the specific cognitive mechanisms through which 5-HT modulates withdrawal behavior remain poorly understood. Behavioral inhibition in response to punishments reflects at least two concurrent processes: instrumental aversive predictions linking stimuli, responses, and punishments, and Pavlovian aversive predictions linking stimuli and punishments irrespective of response. In the current study, we examined to what extent 5-HT modulates the impact of instrumental vs Pavlovian aversive predictions on behavioral inhibition. We used acute tryptophan depletion to lower central 5-HT levels in healthy volunteers, and observed behavior in a novel task designed to measure the influence of Pavlovian and instrumental aversive predictions on choice (response bias) and response vigor (response latencies). After placebo treatment, participants were biased against responding on the button that led to punishment, and they were slower to respond in a punished context, relative to a non-punished context. Specifically, participants slowed their responses in the presence of stimuli predictive of punishments. Tryptophan depletion removed the bias against responding on the punished button, and abolished slowing in the presence of punished stimuli, irrespective of response. We suggest that this set of results can be explained by a role for 5-HT in Pavlovian aversive predictions. These findings suggest additional specificity for the influence of 5-HT on aversively motivated behavioral inhibition and extend recent models of the role of 5-HT in aversive predictions.     

Behavioral and neuropharmacological analysis of amphetamine and 2,5-dimethoxy-4-methylamphetamine in rats

A comparison of the behavioral pharmacology of DOM and amphetamine in rats indicated that lower doses (0.10–1.0 mg/kg) of the two agents had similar effects on schedule-controlled food-reinforced and shock-avoidance behavior. Similarities were also noted in their effects on horizontally directed motor activity when testing was preceded by a period of acclimation. However, most doses of DOM tended to decrease unacclimated motor activity, while amphetamine increased this behavior.Neuropharmacological antagonism studies indicated that brain catecholamines (CA) and serotonin (5-HT) are involved in the behavioral effects of both DOM and amphetamine. Cinanserin, a 5-HT receptor blocker, attenuated the behavioral disruptive effects of both agents on food-reinforced responding. Cinanserin attenuated the effects of all doses of DOM and those of higher doses of amphetamine on shock avoidance. When given prior to lower doses of amphetamine, there was a greater behavioral stimulation than when amphetamine was given alone. Prior depletion of brain CA with -methyltyrosine (-MT) did not affect DOM induced disruption of food-reinforced responding, while -MT attenuated the behavioral effects of all doses of DOM and amphetamine on shock avoidance. These data suggest that DOM and amphetamine share a similar component in their mechanism of action which depends on the availability of a releasable pool of brain CA.Supported in part by Grants NS-10323 from NINDS and MH-22093 from NIMH. Some of the data have been reported in abstract form elsewhere (Federation Proceedings 32, 818, 1973; The Pharmacologist 16, 205, 1974) and a portion of this work is from a thesis submitted to the Faculty of Michigan State University by W. J. M. in partial fulfillment of the requirements for the Ph. D. degree in Pharmacology.     

Acute tryptophan depletion in healthy volunteers enhances punishment prediction but does not affect reward prediction.

Central serotonin (5-HT) has been implicated in emotional and behavioral control processes for many decades, but its precise contribution is not well understood. We used the acute tryptophan depletion procedure in young healthy volunteers to test the hypothesis that central 5-HT is critical for predicting punishment. An observational reversal-learning task was employed that provided separate measures of punishment and reward prediction. Under baseline, subjects made more prediction errors for punishment-associated stimuli than for reward-associated stimuli. This bias was abolished after central 5-HT depletion, which enhanced the ability to predict punishment while not affecting reward prediction. The selective potentiation of punishment prediction concurs with recent theorizing, suggesting that central 5-HT carries a prediction error for future punishment, but not for future reward (Daw et al, 2002). Furthermore, the finding highlights the importance of central 5-HT in resilience to adversity and may have implications for a variety of neuropsychiatric disorders including depression and anxiety.     

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

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