Effects of beta-adrenoceptor blockade on components of human decision-making

Rationale Converging evidence from studies with neurological patients and brain imaging studies with healthy volunteers suggests that the capacity to make choices between actions associated with probabilistic rewards and punishments depends upon a network of cortico-limbic systems including the orbitofrontal cortex, cingulate cortex, amygdala and striatum. The involvement of such structures highlights the emotional aspects of decision-making and suggests that decision-making may be sensitive to manipulations of the catecholamine systems that innervate these structures. In this study, we investigated the possible role of noradrenaline (NA).Objective We examined the effects of a single oral 80 mg dose of the beta-adrenoceptor blocker, propranolol, on the decision-making of healthy volunteers in a double-blind, placebo-controlled, between-subjects design.Methods Seventeen volunteers ingested a placebo while 15 volunteers ingested propranolol. Visual analogue scales, and self-reported positive and negative ratings, were used to assess subjective changes and mood. Vital signs were also monitored. Seventy-five minutes after treatment, volunteers were asked to make a series of choices between two simultaneously presented gambles, differing in the magnitude of possible gains (i.e. reward), the magnitude of possible losses (i.e. punishment), and the probabilities with which these outcomes were delivered. Volunteers also chose between gambles probing identified non-cognitive biases in human decision-making, namely, risk-aversion when choosing between gains and risk-seeking when choosing between losses.Results Propranolol treatment did not result in gross changes in subjective state or mood in comparison to placebo, but did slow heart rate significantly. Propranolol produced a selective change in volunteers decision-making; namely, it significantly reduced the discrimination between large and small possible losses when the probability of winning was relatively low and the probability of losing was high.Conclusions These results suggest that NA modulates the processing of punishment signals when choosing between probabilistic rewards and punishments under conditions of increased arousal.     

The effects of low doses of delta-9 tetrahydrocannabinol on reinforcement processing in the risky decision-making of young healthy adults.

Research suggests that risky decision-making is sensitive to neuromodulatory influences acting upon corticolimbic circuitry. However, while other evidence attests to effects of delta-9 tetrahydrocannabinol (THC) on the activity of reward pathways, relatively little is known about the possible involvement of cannabinoid activity in risky choice. In this experiment, we examined the effects of a single sublingual 5 mg dose of THC on a test of risky decision-making (requiring choices between simultaneously presented gambles differing in their magnitude of gains, magnitude of losses and the probability with which these outcomes were delivered). Tests of non-normative decision-making involving risk-aversion when deciding between gains and risk-seeking choices when deciding between losses were also included. In all, 15 healthy adults were administered 5 mg THC and placebo in a double-blind, placebo-controlled, within-subject, cross-over design. THC had three principal effects relative to placebo: (i) THC reduced choice of gambles with variable gains and losses, but increased choice of gambles with zero-expected value; (ii) THC reduced participants' attention towards losses when the probability of winning was low (and the probability of losing was high); and (iii) THC speeded participants' responses to gambles with large compared to small potential gains. These results suggest that THC mediates specific motivational processes and the processing of reinforcement cues during risky choice, perhaps reflecting altered CB1 receptor or catecholamine activity within corticolimbic pathways.     

Acute effects of nicotine on visual search tasks in young adult smokers

Rationale Many studies have reported the long-term adverse effects of alcohol on executive cognitive function in chronic alcohol abusers, yet little research has investigated the acute effects of alcohol in social drinkers. Studies on acute effects report alcohol-induced deficits on tasks that require executive cognitive processes, with alcohol acting to increase preservative errors and reduce planning. Aim The present investigation examines the acute effects of a moderate dose of alcohol on a decision-making task that involves participants making a forced choice between two simultaneously presented binary-outcome gambles. Methods Alcohol (0.6 g/kg) or placebo was administered to 32 social drinkers. Participants completed the task, making a total of 80 decisions about gambles that varied in the magnitude of expected gains, losses and the probability with which these outcomes were delivered. Participants also chose between gambles probing identified non-normative biases in human decision making, namely, risk aversion for choosing between gains and risk seeking for choosing between losses. Results All participants picked the experimental gamble more frequently when the probability of winning was high vs low, when the gains were large vs small and when the losses were small vs large; the alcohol group had an impaired ability to factor in the magnitude of gains and the likelihood of winning when the losses were large. Deliberation time did not differ between the groups. Conclusion These data suggest that alcohol given acutely impairs risky decision making. In particular, alcohol impairs one's ability to alter responding in light of changing prospective rewards in order to make favourable decisions.     

Effects of tryptophan depletion on the performance of an iterated Prisoner's Dilemma game in healthy adults.

Adaptive social behavior often necessitates choosing to cooperate with others for long-term gains at the expense of noncooperative behaviors giving larger immediate gains. Although little is know about the neural substrates that support cooperative over noncooperative behaviors, recent research has shown that mutually cooperative behavior in the context of a mixed-motive game, the Prisoner's Dilemma (PD), is associated with increased neural activity within reinforcement circuitry. Other research attests to a role for serotonin in the modulation of social behavior and in reward processing. In this study, we used a within-subject, crossover, double-blind design to investigate performance of an iterated, sequential PD game for monetary reward by healthy human adult participants following ingestion of an amino-acid drink that either did (T+) or did not (T-) contain l-tryptophan. Tryptophan depletion produced significant reductions in the level of cooperation shown by participants when playing the game on the first, but not the second, study days. This effect was accompanied by a significantly diminished probability of cooperative responding given previous mutually cooperative behavior. These data suggest that serotonin plays a significant role in the acquisition of socially cooperative behavior in human adult participants, and suggest novel hypotheses concerning the serotonergic modulation of reward information in socially cooperative behavior in both health and psychiatric illness.     

Risk-Taking in Disorders of Natural and Drug Rewards: Neural Correlates and Effects of Probability,Valence, and Magnitude

Pathological behaviors toward drugs and food rewards have underlying commonalities. Risk-taking has a fourfold pattern varying as a function of probability and valence leading to the nonlinearity of probability weighting with overweighting of small probabilities and underweighting of large probabilities. Here we assess these influences on risk-taking in patients with pathological behaviors toward drug and food rewards and examine structural neural correlates of nonlinearity of probability weighting in healthy volunteers. In the anticipation of rewards, subjects with binge eating disorder show greater risk-taking, similar to substance-use disorders. Methamphetamine-dependent subjects had greater nonlinearity of probability weighting along with impaired subjective discrimination of probability and reward magnitude. Ex-smokers also had lower risk-taking to rewards compared with non-smokers. In the anticipation of losses, obesity without binge eating had a similar pattern to other substance-use disorders. Obese subjects with binge eating also have impaired discrimination of subjective value similar to that of the methamphetamine-dependent subjects. Nonlinearity of probability weighting was associated with lower gray matter volume in dorsolateral and ventromedial prefrontal cortex and orbitofrontal cortex in healthy volunteers. Our findings support a distinct subtype of binge eating disorder in obesity with similarities in risk-taking in the reward domain to substance use disorders. The results dovetail with the current approach of defining mechanistically based dimensional approaches rather than categorical approaches to psychiatric disorders. The relationship to risk probability and valence may underlie the propensity toward pathological behaviors toward different types of rewards.     

The role of 5-HTTLPR in choosing the lesser of two evils, the better of two goods: examining the impact of 5-HTTLPR genotype and tryptophan depletion in object choice

Rationale The serotonin (5-HT) system is considered important for decision-making. However, its role in reward- and punishment-based processing has not yet been clearly determined. Objectives The present study examines the effect of 5-HTTLPR genotype and tryptophan depletion on reward- and punishment-related processing, using a task that considers decision-making in situations of subtlety of choice. Thus, it considers that response choice often occurs in situations where both options are desirable (e.g., choosing between mousse au chocolat or crème caramel cheesecake from a menu) or undesirable. It also considers that response choice is easier when the reinforcements associated with the options are far apart, rather than close, in value. Materials and methods Healthy volunteers underwent acute tryptophan depletion (ATD) or control procedures and genotyping of the 5-HTTLPR for long and short allele variants. We then examined the effects and interactions of ATD and the serotonin promoter polymorphism genotype on two aspects of decision-making: (a) decision form, choosing between two objects to gain the greater reward or lesser punishment and (b) between-object reinforcement distance, the difference in reinforcements associated with two options. Results ATD and LL homozygosity had comparable interactions with decision form and between-object reinforcement distance. Specifically, both modulated the effect of between-object reinforcement distance when deciding between objects both associated with punishment. Moreover, ATD and genotype interacted with ATD disproportionately affecting the performance of the LL homozygous group. Conclusions These results suggest that serotonin is particularly associated with punishment, rather than reward-related processing, and that individual sensitivity to punishment-related information and tryptophan depletion varies with genotype.     

The effects of a branched chain amino acid mixture supplemented with tryptophan on biochemical indices of neurotransmitter function and decision-making

Rationale We have previously shown that a 60-g mixture of branched chain amino acids (BCAAs) lowers the plasma availability of the catecholamine precursors tyrosine (TYR) and phenylalanine (PHE) and produces biochemical and neuropsychological changes consistent with impaired dopamine neurotransmission. However, the BCAA mixture also lowers the ratio of tryptophan (TRP) to BCAA which could impair brain serotonin function.Objectives To determine the biochemical and neuropsychological effects of a BCAA mixture supplemented with TRP.Methods We studied 32 healthy volunteers who were randomly and blindly allocated to either a single administration of amino acid mixture (60 g BCAA and 2 g TRP) or placebo. We carried out venous sampling to measure plasma levels of amino acids and performed selected cognitive tasks sensitive to monoamine manipulation 5 h after mixture ingestion.Results Relative to placebo, the BCAA/TRP mixture substantially lowered the ratio of TYR+PHE:BCAA and increased plasma prolactin. The ratio of TRP:BCAA was also lowered but to a lesser extent. The BCAA/TRP mixture produced significant changes in a task of decision-making where volunteers showed reduced discrimination between gambles with large and small losses.Conclusions A 62 g BCAA/TRP mixture decreases the availability of TYR and PHE for brain catecholamine synthesis and increases plasma prolactin consistent with lowered brain dopamine function. Addition of 2 g TRP to the 60 g BCAA mixture does not prevent a reduction of the ratio TRP:BCAA relative to placebo. The effects of the BCAA/TRP mixture on decision-making suggest a general action of dopamine pathways on the processing of emotional information in risky choice, including punishment-related cues, consistent with suggestions that dopamine mechanisms mediate behavioural responses to aversive as well as appetitive stimuli in instrumental conditioning.     

Tryptophan depletion decreases the recognition of fear in female volunteers

Rationale. Serotonergic processes have been implicated in the modulation of fear conditioning in humans, postulated to occur at the level of the amygdala. The processing of other fear-relevant cues, such as facial expressions, has also been associated with amygdala function, but an effect of serotonin depletion on these processes has not been assessed. Objective. The present study investigated the effects of reducing serotonin function, using acute tryptophan depletion, on the recognition of basic facial expressions of emotions in healthy male and female volunteers. Methods. A double-blind between-groups design was used, with volunteers being randomly allocated to receive an amino acid drink specifically lacking tryptophan or a control mixture containing a balanced mixture of these amino acids. Participants were given a facial expression recognition task 5 h after drink administration. This task featured examples of six basic emotions (fear, anger, disgust, surprise, sadness and happiness) that had been morphed between each full emotion and neutral in 10% steps. As a control, volunteers were given a famous face classification task matched in terms of response selection and difficulty level. Results. Tryptophan depletion significantly impaired the recognition of fearful facial expressions in female, but not male, volunteers. This was specific since recognition of other basic emotions was comparable in the two groups. There was also no effect of tryptophan depletion on the classification of famous faces or on subjective state ratings of mood or anxiety. Conclusions. These results confirm a role for serotonin in the processing of fear related cues, and in line with previous findings also suggest greater effects of tryptophan depletion in female volunteers. Although acute tryptophan depletion does not typically affect mood in healthy subjects, the present results suggest that subtle changes in the processing of emotional material may occur with this manipulation of serotonin function. Electronic Publication     

Individual differences in threat sensitivity predict serotonergic modulation of amygdala response to fearful faces

RATIONALE: In this study we used functional magnetic resonance imaging (fMRI) to examine the effects of acute tryptophan depletion (ATD), a well-recognised method for inducing transient cerebral serotonin depletion, on brain activation to fearful faces. OBJECTIVES: We predicted that ATD would increase the responsiveness of the amygdala to fearful faces as a function of individual variation in threat sensitivity. METHODS: Twelve healthy male volunteers received a tryptophan depleting drink or a tryptophan balancing amino acid drink (placebo) in a double-blind crossover design. Five hours after drink ingestion participants were scanned whilst viewing fearful, happy and neutral faces. RESULTS: Consistent with previous findings, fearful faces induced significant signal change in the bilateral amygdala/hippocampus as well as the fusiform face area and the right dorsolateral prefrontal cortex. Furthermore, ATD modulated amygdala/hippocampus activation in response to fearful relative to happy faces as a function of self-reported threat sensitivity (as measured with the Behavioral Inhibition Scale; Carver CS, White TL (1994) Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: the BIS/BAS scales. J Pers Soc Psychol 67:319-333). CONCLUSION: The data support the hypothesis that individual variation in threat sensitivity interacts with manipulation of 5-HT function to bias the processing of amygdala-dependent threat-relevant stimuli.     

Acute tryptophan depletion in healthy males attenuates phasic cardiac slowing but does not affect electro-cortical response to negative feedback

RATIONALE: Recent studies have shown that serotonin might be involved in performance monitoring, although the results have been inconclusive. Inconsistent results might be related to the type of pharmacological manipulation and the used behavioral and physiological measures. OBJECTIVES: The present study aimed at further specifying the role of serotonin in performance monitoring. MATERIALS AND METHODS: The effect of serotonin on performance monitoring was studied by using acute tryptophan depletion (ATD), a well-known method to transiently lower central serotonin levels. Twenty healthy male volunteers performed a time-estimation task and their event-related brain potential (ERP), behavioral, and cardiac responses to feedback stimuli were measured. Furthermore, subjective mood and amino-acid levels were determined. RESULTS: As expected, ATD did not affect mood and lowered tryptophan levels. ATD attenuated cardiac slowing to negative feedback but did not affect responses to positive feedback, ERPs, and performance measures. CONCLUSIONS: The data point in the direction of a dissociation between cardiac and electro-cortical responses. Cardiac responses appear to be more sensitive to changes in serotonin metabolism and appear to reflect different aspects of the feedback stimulus. The phasic cardiac response appears to be an important measure that provides additional information about the impact of feedback stimuli and serotonergic functioning.     

Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning.

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.     

The impact of tryptophan depletion and 5-HTTLPR genotype on passive avoidance and response reversal instrumental learning tasks.

Transient reductions in serotonin levels during tryptophan depletion (TD) are thought to impair reward processing in healthy volunteers, while another facet of the serotonergic system, the serotonin transporter (5-HTTLPR) short allele polymorphism, is implicated in augmented processing of aversive stimuli. We examined the impact and interactions of TD and the serotonin promoter polymorphism genotype on reward and punishment via two forms of instrumental learning: passive avoidance and response reversal. In this study, healthy volunteers (n=35) underwent rapid TD or control procedures and genotyping (n=26) of the 5-HTTLPR for long and short allele variants. In the passive avoidance task, tryptophan-depleted volunteers failed to respond sufficiently to rewarded stimuli compared to the control group. Additionally, long allele homozygous individuals (n=11) were slower to learn to avoid punished stimuli compared to short allele carriers (n=15). TD alone did not produce measurable deficits in probabilistic response reversal errors. However, a significant drug group by genotype interaction was found indicating that in comparison to short allele carriers, tryptophan-depleted individuals homozygous for the long allele failed to appropriately use punishment information to guide responding. These findings extend prior reports of impaired reward processing in TD to include instrumental learning. Furthermore, they demonstrate behavioral differences in responses to punishing stimuli between long allele homozygotes and short allele carriers when serotonin levels are acutely reduced.     

Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms.

We used a novel computerized decision-making task to compare the decision-making behavior of chronic amphetamine abusers, chronic opiate abusers, and patients with focal lesions of orbital prefrontal cortex (PFC) or dorsolateral/medial PFC. We also assessed the effects of reducing central 5-hydroxytryptamine (5-HT) activity using a tryptophan-depleting amino acid drink in normal volunteers. Chronic amphetamine abusers showed suboptimal decisions (correlated with years of abuse), and deliberated for significantly longer before making their choices. The opiate abusers exhibited only the second of these behavioral changes. Importantly, both sub-optimal choices and increased deliberation times were evident in the patients with damage to orbitofrontal PFC but not other sectors of PFC. Qualitatively, the performance of the subjects with lowered plasma tryptophan was similar to that associated with amphetamine abuse, consistent with recent reports of depleted 5-HT in the orbital regions of PFC of methamphetamine abusers. Overall, these data suggest that chronic amphetamine abusers show similar decision-making deficits to those seen after focal damage to orbitofrontal PFC. These deficits may reflect altered neuromodulation of the orbitofrontal PFC and interconnected limbic-striatal systems by both the ascending 5-HT and mesocortical dopamine (DA) projections.     

Serotonin Depletion Induces ‘Waiting Impulsivity' on the Human Four-Choice Serial Reaction Time Task: Cross-Species Translational Significance

Convergent results from animal and human studies suggest that reducing serotonin neurotransmission promotes impulsive behavior. Here, serotonin depletion was induced by the dietary tryptophan depletion procedure (TD) in healthy volunteers to examine the role of serotonin in impulsive action and impulsive choice. We used a novel translational analog of a rodent 5-choice serial reaction time task (5-CSRTT)— the human 4-CSRTT—and a reward delay-discounting questionnaire to measure effects on these different forms of ‘waiting impulsivity''. There was no effect of TD on impulsive choice as indexed by the reward delay-discounting questionnaire. However, TD significantly increased 4-CSRTT premature responses (or impulsive action), which is remarkably similar to the previous findings of effect of serotonin depletion on rodent 5-CSRTT performance. Moreover, the increased premature responding in TD correlated significantly with individual differences on the motor impulsivity subscale of the Barratt Impulsivity Scale. TD also improved the accuracy of performance and speeded responding, possibly indicating enhanced attention and reward processing. The results suggest: (i) the 4-CSRTT will be a valuable addition to the tests already available to measure impulsivity in humans in a direct translational analog of a test extensively used in rodents; (ii) TD in humans produces a qualitatively similar profile of effects to those in rodents (ie, enhancing premature responding), hence supporting the conclusion that TD in humans exerts at least some of its effects on central serotonin; and (iii) this manipulation of serotonin produces dissociable effects on different measures of impulsivity, suggesting considerable specificity in its modulatory role.     

The effect of citalopram pretreatment on neuronal responses to neuropsychological tasks in normal volunteers: an FMRI study.

Changes in serotonin neurotransmission have also been implicated in the etiology and treatment of impulse control disorders, depression, and anxiety. We have investigated the effect of enhancing serotonin function on fundamental brain processes that we have proposed are abnormal in these disorders. In all, 12 male volunteers received citalopram (7.5 mg intravenously) and placebo pretreatment in a single-blind crossover design before undertaking Go/No-go, Loss/No-loss, and covert (aversive) face emotion recognition tasks during functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent responses were analyzed using Statistical Parametric Mapping (SPM2). The tasks activated prefrontal and subcortical regions generally consistent with literature with lateral orbitofrontal cortex (BA47) common to the three tasks. Citalopram pretreatment enhanced the right BA47 responses to the No-go condition, but attenuated this response to aversive faces. Attenuations were seen following citalopram in the medial orbitofrontal (BA11) responses to the No-go and No-loss (ie relative reward compared with Loss) conditions. The right amygdala response to aversive faces was attenuated by citalopram. These results support the involvement of serotonin in modulating basic processes involved in psychiatric disorders but argue for a process-specific, rather than general effect. The technique of combining drug challenge with fMRI (pharmacoMRI) has promise for investigating human psychiatric disorders.     

Effects of acute tryptophan depletion on cognitive function in euthymic bipolar patients.

Decreasing brain 5-HT levels by acute tryptophan depletion has been shown to selectively impair cognition in healthy volunteers. In bipolar disorder, ATD causes measurable neurophysiological effects without altering mood. The purpose of this study was to examine the effects of ATD on neuropsychological performance in 14 euthymic bipolar patients. Cognitive function was evaluated 4-6 h after ingestion of a control or depleting amino-acid drink. Plasma tryptophan levels fell significantly following the depleting drink, however there were no main effects on the ID/ED set-shift task, Paired Associates Learning or Vigil. A trend towards a decrease in the proportion of perfect solutions on the Tower of London task was observed when depleted. While ATD reduces 5-HT levels in the brain, it does not appear to alter neuropsychological performance on tests of sustained attention or associative learning. Effects on specific 'executive' functions are less clear, and should be the focus for future research.     

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.     

Neural mechanisms of risky decision-making and reward response in adolescent onset cannabis use disorder

Background

Neural mechanisms of decision-making and reward response in adolescent cannabis use disorder (CUD) are underexplored.

Methods

Three groups of male adolescents were studied: CUD in full remission (n = 15); controls with psychopathology without substance use disorder history (n = 23); and healthy controls (n = 18). We investigated neural processing of decision-making and reward under conditions of varying risk and uncertainty with the Decision-Reward Uncertainty Task while participants were scanned using functional magnetic resonance imaging.

Results

Abstinent adolescents with CUD compared to controls with psychopathology showed hyperactivation in one cluster that spanned left superior parietal lobule/left lateral occipital cortex/precuneus while making risky decisions that involved uncertainty, and hypoactivation in left orbitofrontal cortex to rewarded outcomes compared to no-reward after making risky decisions. Post hoc region of interest analyses revealed that both control groups significantly differed from the CUD group (but not from each other) during both the decision-making and reward outcome phase of the Decision-Reward Uncertainty Task. In the CUD group, orbitofrontal activations to reward significantly and negatively correlated with total number of individual drug classes the CUD patients experimented with prior to treatment. CUD duration significantly and negatively correlated with orbitofrontal activations to no-reward.

Conclusions

The adolescent CUD group demonstrated distinctly different activation patterns during risky decision-making and reward processing (after risky decision-making) compared to both the controls with psychopathology and healthy control groups. These findings suggest that neural differences in risky decision-making and reward processes are present in adolescent addiction, persist after remission from first CUD treatment, and may contribute to vulnerability for adolescent addiction.     

The effect of acute tryptophan depletion on probabilistic choice

Choice behaviour can be viewed as a response to reinforcement determined by an interaction between the quantities, delays and probabilities of two outcomes. The variation in the perceived value of a reinforcer with alteration of these factors (discounting) can be modelled mathematically by hyperbolic discounting functions. Making risky choices is a feature of impulsivity and has been associated with reduced serotonin (5-hydroxytryptamine, 5-HT) function. In this study, we investigated the possible role of 5-HT in modulating probability discounting using the technique of acute tryptophan (TRP) depletion in subjects undertaking an imaginary gambling task. The gambling task consisted of choosing between two 'roulette-like' dials: 'A' which provided a smaller but nearly certain 'win' and 'B' which gave a 'win' 2.5 times the amount with a probability that was systematically varied. A series of reward sizes on dial 'A' was presented ranging from 10 pence to 10,000 pounds. The probability of winning on dial 'B' at which the subjects valued the two dials equally (indifference point) was determined as a measure of willingness to take a risk. Subjects were more likely to take a risk for smaller rewards but the indifference points in the 15 subjects who received TRP depletion did not differ from 13 who had the control drink. On a surprise retesting 1 week later there was a trend (p < 0.07) for subjects to be more willing to take risks the second time, particularly in the case of small rewards. This study does not support a role for 5-HT in modulating probabilistic choice in agreement with recent evidence from experiments with animals; however, the imaginal nature of the task and modest numbers may have influenced the result.     

Acute Tryptophan Depletion Increases Translational Indices of Anxiety but not Fear: Serotonergic Modulation of the Bed Nucleus of the Stria Terminalis?

Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders.