Steatotic Hepatocytes Release Mature VLDL Through Methionine and Tyrosine Metabolism in a Keap1-Nrf2-Dependent Manner.

BACKGROUND AND AIMS: NAFLD is a lipotoxic disease wherein hepatic steatosis and oxidative stress are key pathogenic features. However, whether free amino acids (FAAs) are associated with the oxidative stress response against lipotoxicity has yet to be determined. We hypothesized that an imbalance of FAAs aggravates hepatic steatosis by interfering with the oxidative stress sensor. APPROACH AND RESULTS: C57BL/6 mouse immortalized hepatocytes, primary hepatocytes, and organoids were employed. Steatotic hepatocytes treated with oleic acid (OA) were cultured under FAA-modifying media based on the concentrations of FAAs in the hepatic portal blood of wild-type (WT) mice. As in vivo experiments, WT hepatocyte-specific Kelch-like ECH-associated protein 1 (Keap1) knockout mice (Keap1∆hepa ) and Cre- control mice (Keap1fx/fx ) were fed high-fat (HF) diets with modified amino acid content. The correlations were analyzed between the areas of lipid droplets (LDs) around central vein and plasma OA/FAA ratio in 61 patients with NAFLD. Mice fed an HF, Met-restricted, and tyrosine (Tyr)-deficient diet showed the NAFLD-like phenotype in which the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), triglyceride-rich VLDL, and fumarate were decreased in liver, but Keap1∆hepa ameliorated these phenomena. Reactive oxygen species and LDs induced by the deprivation of Met and Tyr were prevented in hepatic organoids generated from Keap1∆hepa . Dimethyl fumarate, an Nrf2 inducer, ameliorated the steatosis and increased the hepatic fumarate reduced by the deprivation of Met and Tyr in vitro. OA/Met or Tyr ratio in peripheral blood was associated with the hepatic steatosis in patients with NAFLD. CONCLUSIONS: An imbalance between free fatty acids and Met and Tyr induces hepatic steatosis by disturbing the VLDL assembling through the Keap1-Nrf2 system.

Preliminary evidence for an association between intake of high-fat high-sugar diet, variations in peripheral dopamine precursor availability and dopamine-dependent cognition in humans.

Obesity is associated with alterations in dopaminergic transmission and cognitive function. Rodent studies suggest that diets rich in saturated fat and refined sugars (HFS), as opposed to diets diets low in saturated fat and refined sugars (LFS), change the dopamine system independent of excessive body weight. However, the impact of HFS on the human brain has not been investigated. Here, we compared the effect of dietary dopamine depletion on dopamine-dependent cognitive task performance between two groups differing in habitual intake of dietary fat and sugar. Specifically, we used a double-blind within-subject cross-over design to compare the effect of acute phenylalanine/tyrosine depletion on a reinforcement learning and a working memory task, in two groups that are on opposite ends of the spectrum of self-reported HFS intake (low vs high intake: LFS vs HFS group). We tested 31 healthy young women matched for body mass index (mostly normal weight to overweight) and IQ. Depletion of peripheral precursors of dopamine reduced the working memory specific performance on the operation span task in the LFS, but not in the HFS group (P = 0.016). Learning from positive- and negative-reinforcement (probabilistic selection task) was increased in both diet groups after dopamine depletion (P = 0.049). As a secondary exploratory research question, we measured peripheral dopamine precursor availability (pDAP) at baseline as an estimate for central dopamine levels. The HFS group had a significantly higher pDAP at baseline compared to the LFS group (P = 0.025). Our data provide the first evidence indicating that the intake of HFS is associated with changes in dopamine precursor availability, which is suggestive of changes in central dopamine levels in humans. The observed associations are present in a sample of normal to overweight participants (ie, in the absence of obesity), suggesting that the consumption of a HFS might already be associated with altered behaviours. Alternatively, the effects of HFS diet and obesity might be independent.

Dopamine depletion effects on cognitive flexibility as modulated by tDCS of the dlPFC.

BACKGROUND: Recent evidence suggests that transcranial direct current stimulation (tDCS) may interact with the dopaminergic system to affect cognitive flexibility. Objective/hypotheses: We examined whether putative reduction of dopamine levels through the acute phenylalanine/tyrosine depletion (APTD) procedure and excitatory anodal tDCS of the dorsolateral prefrontal cortex (dlPFC) are causally related to cognitive flexibility as measured by task switching and reversal learning. METHOD: A double-blind, sham-controlled, randomised trial was conducted to test the effects of combining anodal tDCS and depletion of catecholaminergic precursor tyrosine on cognitive flexibility. RESULTS: Anodal tDCS and tyrosine depletion had a significant effect on task switching, but not reversal learning. Whilst perseverative errors were significantly improved by anodal tDCS, the APTD impaired reaction times. Importantly, the combination of APTD and anodal tDCS resulted in cognitive performance which did not statistically differ to that of the control condition. CONCLUSIONS: Our results suggest that the effects of tDCS on cognitive flexibility are modulated by dopaminergic tone.

The Effects of Acute Dopamine Precursor Depletion on the Cognitive Control Functions of Performance Monitoring and Conflict Processing: An Event-Related Potential (ERP) Study.

Studies using medications and psychiatric populations implicate dopamine in cognitive control and performance monitoring processes. However, side effects associated with medication or studying psychiatric groups may confound the relationship between dopamine and cognitive control. To circumvent such possibilities, we utilized a randomized, double-blind, placebo-controlled, within-subjects design wherein participants were administered a nutritionally-balanced amino acid mixture (BAL) and an amino acid mixture deficient in the dopamine precursors tyrosine (TYR) and phenylalanine (PHE) on two separate occasions. Order of sessions was randomly assigned. Cognitive control and performance monitoring were assessed using response times (RT), error rates, the N450, an event-related potential (ERP) index of conflict monitoring, the conflict slow potential (conflict SP), an ERP index of conflict resolution, and the error-related negativity (ERN) and error positivity (Pe), ERPs associated with performance monitoring. Participants were twelve males who completed a Stroop color-word task while ERPs were collected four hours following acute PHE and TYR depletion (APTD) or balanced (BAL) mixture ingestion in two separate sessions. N450 and conflict SP ERP amplitudes significantly differentiated congruent from incongruent trials, but did not differ as a function of APTD or BAL mixture ingestion. Similarly, ERN and Pe amplitudes showed significant differences between error and correct trials that were not different between APTD and BAL conditions. Findings indicate that acute dopamine precursor depletion does not significantly alter cognitive control and performance monitoring ERPs. Current results do not preclude the role of dopamine in these processes, but suggest that multiple methods for dopamine-related hypothesis testing are needed.

Age moderates the effect of acute dopamine depletion on passive avoidance learning.

Despite extensive links between reinforcement-based learning and dopamine (DA), studies to date have not found consistent effects of acute DA reduction on reinforcement learning in both men and women. Here, we tested the effects of reducing DA on reward- and punishment-based learning using the deterministic passive avoidance learning (PAL) task. We tested 16 (5 female) adults (ages 22-40) in a randomized, cross-over design to determine whether reducing global DA by administering an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine (P/T[-]), would affect PAL task performance. We found that P/T[-] beverage effects on PAL performance were modulated by age. Specifically, we found that P/T depletion significantly improved learning from punishment with increasing participant age. Participants committed 1.49 fewer passive avoidance errors per additional year of age (95% CI, -0.71 - -2.27, r=-0.74, p=0.001). Moreover, P/T depletion improved learning from punishment in adults (ages 26-40) while it impaired learning from punishment in emerging adults (ages 22-25). We observed similar, but non-significant trends in learning from reward. While there was no overall effect of P/T-depletion on reaction time (RT), there was a relationship between the effect of P/T depletion on PAL performance and RT; those who responded more slowly on the P/T[-] beverage also made more errors on the P/T[-] beverage. When P/T-depletion slowed RT after a correct response, there was a worsening of PAL task performance; there was no similar relationship for the RT after an incorrect response and PAL task performance. Moreover, among emerging adults, changes in mood on the P/T[-] beverage negatively correlated with learning from reward on the P/T[-] beverage. Together, we found that both reward- and punishment-based learning are sensitive to central catecholamine levels, and that these effects of acute DA reduction vary with age.

Dopamine precursors depletion impairs impulse control in healthy volunteers.

The aim of the present study was to decipher the role of the dopamine system in impulse control. Impulsive actions entail (i) activation of the motor system by an impulse, which is an urge to act and (ii) a failure to suppress that impulse, when inappropriate, in order to prevent an error. These two aspects of action impulsivity can be experimentally disentangled in conflict reaction time tasks such as the Simon task, which measures susceptibility to acting on spontaneous impulses (as well as the proficiency of suppressing these impulses). In 12 healthy volunteers performing a Simon task, dopamine availability was reduced with an amino acid drink deficient in the dopamine precursors, phenylalanine and tyrosine. Classic behavioral measures were augmented with an analysis of the electromyographic activity of the response effectors. Electromyography allows one to detect covert activations undetectable with strictly behavioral measures and further reveals the participants' ability to quickly suppress covert activations before they result in an overt movement. Following dopamine depletion, compared with a placebo condition, participants displayed comparable impulse activation but were less proficient at suppressing the interference from this activation. These results provide evidence that the dopamine system is directly involved in the suppression of maladaptive response impulses.

Serotonin and dopamine differentially affect appetitive and aversive general Pavlovian-to-instrumental transfer.

RATIONALE: Human motivation and decision-making is influenced by the interaction of Pavlovian and instrumental systems. The neurotransmitters dopamine and serotonin have been suggested to play a major role in motivation and decision-making, but how they affect this interaction in humans is largely unknown. OBJECTIVE: We investigated the effect of these neurotransmitters in a general Pavlovian-to-instrumental transfer (PIT) task which measured the nonspecific effect of appetitive and aversive Pavlovian cues on instrumental responses. METHODS: For that purpose, we used selective dietary depletion of the amino acid precursors of serotonin and dopamine: tryptophan (n = 34) and tyrosine/phenylalanine (n = 35), respectively, and compared the performance of these groups to a control group (n = 34) receiving a nondepleted (balanced) amino acid drink. RESULTS: We found that PIT differed between groups: Relative to the control group that exhibited only appetitive PIT, we found reduced appetitive PIT in the tyrosine/phenylalanine-depleted group and enhanced aversive PIT in the tryptophan-depleted group. CONCLUSIONS: These results demonstrate a differential involvement of serotonin and dopamine in motivated behavior. They suggest that reductions in serotonin enhance the motivational influence of aversive stimuli on instrumental behavior and do not affect the influence of appetitive stimuli, while reductions in dopamine diminish the influence of appetitive stimuli. No conclusions could be drawn about how dopamine affects the influence of aversive stimuli. The interplay of both neurotransmitter systems allows for flexible and adaptive responses depending on the behavioral context.

Dopamine precursor depletion influences pain affect rather than pain sensation.

Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states.

Dopamine precursor depletion impairs structure and efficiency of resting state brain functional networks.

Spatial patterns of functional connectivity derived from resting brain activity may be used to elucidate the topological properties of brain networks. Such networks are amenable to study using graph theory, which shows that they possess small world properties and can be used to differentiate healthy subjects and patient populations. Of particular interest is the possibility that some of these differences are related to alterations in the dopamine system. To investigate the role of dopamine in the topological organization of brain networks at rest, we tested the effects of reducing dopamine synthesis in 13 healthy subjects undergoing functional magnetic resonance imaging. All subjects were scanned twice, in a resting state, following ingestion of one of two amino acid drinks in a randomized, double-blind manner. One drink was a nutritionally balanced amino acid mixture, and the other was tyrosine and phenylalanine deficient. Functional connectivity between 90 cortical and subcortical regions was estimated for each individual subject under each dopaminergic condition. The lowered dopamine state caused the following network changes: reduced global and local efficiency of the whole brain network, reduced regional efficiency in limbic areas, reduced modularity of brain networks, and greater connection between the normally anti-correlated task-positive and default-mode networks. We conclude that dopamine plays a role in maintaining the efficient small-world properties and high modularity of functional brain networks, and in segregating the task-positive and default-mode networks. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'.

Tyrosine-free amino acid mixtures reduce physiologically-evoked release of dopamine in a selective and activity-dependent manner.

Depletion of the catecholamine precursor tyrosine using tyrosine-free amino acid mixtures is an important tool in neuropsychological studies, and often considered dopamine selective on the basis of neuropharmacological studies. However, little is known of the effects of tyrosine depletion when catecholamine neurons are activated physiologically. Here we investigated the effect of tyrosine-free amino acid mixtures on catecholamine release evoked in vivo using a stimulation paradigm aimed to approximate the phasic firing pattern of these neurons that accompanies cognitive and behavioural change. Dopamine and noradrenaline release was monitored by microdialysis in rat medial prefrontal cortex (mPFC) and striatum (chloral hydrate anaesthesia, perfusion medium containing 1 µM cocaine). Electrical stimulation of the medial forebrain bundle (MFB) caused a short-lasting, frequency-dependent increase in dopamine and noradrenaline. A full tyrosine-free amino acid mixture reduced the release of dopamine in mPFC and striatum, across a range of stimulation frequencies, and the effect was greater as stimulation frequency increased. Similar results were obtained using a smaller tyrosine-free amino acid mixture. In the same experiments showing decreased dopamine, neither tyrosine-free mixture of amino acids significantly altered stimulation-evoked release of noradrenaline. These results show that tyrosine depletion using tyrosine-free amino acid mixtures causes a selective, activity-dependent decrease in dopamine release when dopamine neurons are driven physiologically.

Dietary tyrosine/phenylalanine depletion effects on behavioral and brain signatures of human motivational processing.

Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino-acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: (1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and (2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD.

Dietary manipulation of serotonergic and dopaminergic function in C57BL/6J mice with amino acid depletion mixtures.

Amino acid (AA) depletion techniques have been used to decrease serotonin (5-HT) and/or dopamine (DA) synthesis after administration of a tryptophan (acute tryptophan depletion, ATD) or phenylalanine/tyrosine-free (phenylalanine-tyrosine depletion, PTD) AA formula and are useful as neurochemical challenge procedures to study the impact of DA and 5-HT in patients with neuropsychiatric disorders. We recently demonstrated that the refined Moja-De ATD paradigm decreases brain 5-HT synthesis in humans and mice and lowers brain 5-HT turnover. In the present study we validated the neurochemical effects of three developed AA formulas on brain 5-HT and DA function in mice. To distinguish the direct and indirect effects of such mixtures on 5-HT and DA and to determine whether additive depletion of both could be obtained simultaneously, we compared the effects of ATD for 5-HT, PTD for DA, and a combined monoamine depletion mixture (CMD) compared to a control condition consisting of a balanced amino acid mixture. Food-deprived male C57BL/6J mice were gavaged with AA mixtures. Serum and brain samples were collected and analyzed for determination of tryptophan (Trp), tyrosine (Tyr), 5-HT, 5-HIAA, DA, DOPAC and HVA levels. ATD was the most effective at decreasing Trp, 5-HT and 5-HIAA. In contrast, PTD reduced Tyr globally but HVA only in certain brain regions. Although CMD affected both 5-HT and DA synthesis, it was less effective when compared with ATD or PTD alone. The present results demonstrate that two newly developed PTD and CMD formulas differentially impact brain 5-HT and DA synthesis relative to 5-HT-specific ATD Moja-De. Different effects on 5-HT and DA function by these mixtures suggest that the exact composition may be a critical determinant for effectiveness with respect to the administered challenge procedure.

Presynaptic regulation of extracellular dopamine levels in the medial prefrontal cortex and striatum during tyrosine depletion.

RATIONALE: Available neurochemical probes that lower brain dopamine (DA) levels in man are limited by their tolerability and efficacy. For instance, the acute lowering of brain tyrosine is well tolerated, but only modestly lowers brain DA levels. Modification of tyrosine depletion to robustly lower DA levels would provide a superior research probe. OBJECTIVES: The objective of this study was to determine whether the subthreshold stimulation of presynaptic DA receptors would potentiate tyrosine depletion-induced effects on extracellular DA levels in the medial prefrontal cortex (MPFC) and striatum of the rat. METHODS: We administered quinpirole, a predominantly DA type 2 (D2R) receptor agonist, into the MPFC and striatum by reverse dialysis. A tyrosine- and phenylalanine-free neutral amino acid mixture [NAA(-)] IP was used to lower brain tyrosine levels. DA levels in the microdialysate were measured by HPLC with electrochemical detection. RESULTS: Quinpirole dose-dependently lowered DA levels in MPFC as well as in the striatum. NAA(-) alone transiently lowered DA levels (80 % baseline) in the striatum, but had no effect in MPFC. The co-administration of NAA(-) and a subthreshold concentration of quinpirole (6.25 nM) lowered DA levels (50 % baseline) in both the MPFC and striatum. This effect was blocked by the mixed D2R/D3R antagonist haloperidol at IP doses that on their own did not affect DA levels (10.0 nmol/kg in the MPFC and 0.10 nmol/kg in the striatum). CONCLUSIONS: Pharmacological stimulation of inhibitory D2R receptors during tyrosine depletion markedly lowers the extracellular DA levels in the MPFC and striatum. The data suggest that combining tyrosine depletion with a low dose of a DA agonist should robustly lower brain regional DA levels in man.

The effect of acute tyrosine phenylalanine depletion on emotion-based decision-making in healthy adults.

Despite interest in dopamine's role in emotion-based decision-making, few reports of the effects of dopamine manipulations are available in this area in humans. This study investigates dopamine's role in emotion-based decision-making through a common measure of this construct, the Iowa Gambling Task (IGT), using Acute Tyrosine Phenylalanine Depletion (ATPD). In a between-subjects design, 40 healthy adults were randomized to receive either an ATPD beverage or a balanced amino acid beverage (a control) prior to completing the IGT, as well as pre- and post-manipulation blood draws for the neurohormone prolactin. Together with conventional IGT performance metrics, choice selections and response latencies were examined separately for good and bad choices before and after several key punishment events. Changes in response latencies were also used to predict total task performance. Prolactin levels increased significantly in the ATPD group but not in the control group. However, no significant group differences in performance metrics were detected, nor were there sex differences in outcome measures. However, the balanced group's bad deck latencies speeded up across the task, while the ATPD group's latencies remained adaptively hesitant. Additionally, modulation of latencies to the bad decks predicted total score for the ATPD group only. One interpretation is that ATPD subtly attenuated reward salience and altered the approach by which individuals achieved successful performance, without resulting in frank group differences in task performance.

Dopamine precursor depletion impairs timing in healthy volunteers by attenuating activity in putamen and supplementary motor area.

Neuropsychological investigations of patients with Parkinson's disease, schizophrenia, or attention deficit disorder converge with psychopharmacological studies in animals and healthy volunteers to implicate dopamine (DA) pathways in timing. In parallel, single-cell recording and functional neuroimaging studies have highlighted the importance of basal ganglia, prefrontal cortex, and supplementary motor area (SMA) for timing. In a placebo-controlled, within-subject design, we combined event-related functional magnetic resonance imaging with a DA manipulation (acute phenylalanine/tyrosine depletion; APTD) in healthy volunteers to pinpoint the neuroanatomical and functional substrates of the DA modulation of timing. Behaviorally, APTD selectively impaired accuracy of perceptual timing, with no effect on performance of a color-control task matched for difficulty, working memory (WM), and attentional demands. Neurally, APTD attenuated timing-specific activity in the putamen and SMA. Notably, APTD-induced decreases in brain activity were directly correlated to APTD-induced impairments in timing performance. Moreover, APTD modulated timing-specific activity selectively during initial storage of the sample duration, but had no effect during its subsequent retrieval or comparison to a probe. Our results do not simply reflect DA modulation of WM since the color task controlled for the WM updating process necessary for timing of durations in the seconds range. Moreover, preliminary evidence indicated APTD effects on putamen and SMA were greater for subsecond (540 ms) than suprasecond (1080 ms) durations, when WM demands would actually be lower. Instead, we show for the first time in healthy humans that DA manipulation perturbs timing by attenuating the activity in putamen and SMA that mediates initial storage of temporal information into WM.

Tyrosine depletion lowers in vivo DOPA synthesis in ventral hippocampus.

In vivo dopamine synthesis in the medial prefrontal cortex of the rat is sensitive to the availability of tyrosine. Whether other limbic cortical dopamine terminal regions are similarly tyrosine-dependent is not known. In this study we examined the effects of tyrosine depletion on dopamine synthesis and catecholamine levels in the ventral hippocampus. A tyrosine- and phenylalanine-free neutral amino acid mixture was used to lower brain tyrosine levels in rats undergoing in vivo microdialysis. In one group, NSD-1015 was included in perfusate to permit measurement of DOPA levels. In a second group, NSD-1015 was not included in perfusate so that catecholamine levels could be assayed. Tyrosine depletion significantly lowered DOPA levels in the NSD-1015 treated group and lowered DOPAC but not dopamine or noradrenaline levels in the group not exposed to NSD-1015. We conclude that while catecholamine synthesis in the ventral hippocampus declines when tyrosine availability is lowered, under basal conditions, compensatory mechanisms are able to maintain stable extracellular catecholamine levels.

Tyrosine impairs enzymes of energy metabolism in cerebral cortex of rats.

Tyrosine levels are abnormally elevated in tissues and physiological fluids of patients with inborn errors of tyrosine catabolism, especially in tyrosinemia type II, which is caused by deficiency of tyrosine aminotransferase and provokes eyes, skin, and central nervous system disturbances. Considering that the mechanisms of brain damage in these disorders are poorly known, in this study, we investigated the in vivo and in vitro effects of tyrosine on some parameters of energy metabolism in cerebral cortex of 14-day-old Wistar rats. We observed that 2 mM tyrosine inhibited in vitro the pyruvate kinase (PK) activity and that this inhibition was prevented by 1 mM reduced glutathione with 30, 60, and 90 min of preincubation. Moreover, administration of tyrosine methyl ester (TME) (0.5 mg/g of body weight) decreased the activity of PK and this reduction was prevented by pre-treatment with creatine (Cr). On the other hand, tyrosine did not alter adenylate kinase (AK) activity in vitro, but administration of TME enhanced AK activity not prevented by Cr pre-treatment. Finally, TME administration decreased the activity of CK from cytosolic and mitochondrial fractions and this diminution was prevented by Cr pre-treatment. The results suggest that tyrosine alters essential sulfhydryl groups necessary for CK and PK functions, possibly through oxidative stress. In case this also occurs in the patients, it is possible that energy metabolism alterations may contribute, along with other mechanisms, to the neurological dysfunction of hypertyrosinemias.

Dopamine and food reward: effects of acute tyrosine/phenylalanine depletion on appetite.

It has been suggested that obese individuals over-eat in order to compensate for deficits in the dopaminergic reward system. The current study used acute tyrosine/phenylalanine depletion (ATPD) to investigate the effect of reduced dopamine function on appetite and the reward value of food in healthy volunteers. The compensatory-eating hypothesis would predict an increase in the reward value and consumption of food following depletion by this method. In a double-blind, counterbalanced, crossover study, 17 male participants (mean age=29.2 (SEM=2.7) years; mean body mass index=24.4 (SEM=0.6) kg/m(2)) were administered with a tyrosine/phenylalanine-free mixture (TYR/PHE-free; depletion condition) and a balanced amino acid mixture (BAL; control). Plasma amino acid levels were measured at baseline and peak depletion (300 min). Appetite, willingness to pay for food, liking, desired portion size and ad libitum food intake were also assessed. The TYR/PHE-free mixture was associated with significant decreases in tyrosine, phenylalanine, and the ratio of tyrosine+phenylalanine to the other large neutral amino acids (all p<.001). There were no effects on our measures of willingness to pay for food or liking. However, in the TYR/PHE-free condition, participants reported significantly lower levels of hunger following a fixed-test meal relative to the BAL condition. In conclusion, we found no evidence for compensatory eating following ATPD. Our results also provide support for the role of dopamine in motivational components of eating.

Reliance on habits at the expense of goal-directed control following dopamine precursor depletion.

RATIONALE: Dopamine is well known to play an important role in learning and motivation. Recent animal studies have implicated dopamine in the reinforcement of stimulus-response habits, as well as in flexible, goal-directed action. However, the role of dopamine in human action control is still not well understood. OBJECTIVES: We present the first investigation of the effect of reducing dopamine function in healthy volunteers on the balance between habitual and goal-directed action control. METHODS: The dietary intervention of acute dietary phenylalanine and tyrosine depletion (APTD) was adopted to study the effects of reduced global dopamine function on action control. Participants were randomly assigned to either the APTD or placebo group (ns = 14) to allow for a between-subjects comparison of performance on a novel three-stage experimental paradigm. In the initial learning phase, participants learned to respond to different stimuli in order to gain rewarding outcomes. Subsequently, an outcome-devaluation test and a slips-of-action test were conducted to assess whether participants were able to flexibly adjust their behaviour to changes in the desirability of the outcomes. RESULTS: APTD did not prevent stimulus-response learning, nor did we find evidence for impaired response-outcome learning in the subsequent outcome-devaluation test. However, when goal-directed and habitual systems competed for control in the slips-of-action test, APTD tipped the balance towards habitual control. These findings were restricted to female volunteers. CONCLUSIONS: We provide direct evidence that the balance between goal-directed and habitual control in humans is dopamine dependent. The results are discussed in light of gender differences in dopamine function and psychopathologies.

Acute phenylalanine/tyrosine depletion reduces motivation to smoke cigarettes across stages of addiction.

The neurobiology of tobacco use is poorly understood, possibly in part because the relevant mechanisms might differ depending on past nicotine exposure and degree of addiction. In the present study we investigated whether these factors might affect the role of dopamine (DA). Using the acute phenylalanine/tyrosine depletion method (APTD), DA synthesis was transiently decreased in three groups of abstinent smokers (n=47): (1) early low-frequency smokers, who had smoked a maximum of five cigarettes per day for less than one year, (2) stable low-frequency smokers smoking at the same level as early low-frequency smokers for at least 3 years, and (3) stable high-frequency smokers, who smoked a minimum of 10 or more cigarettes per day for at least 5 years. Motivation to obtain tobacco was measured using a progressive ratio breakpoint schedule for nicotine-containing and de-nicotinized cigarettes. Compared with a nutritionally balanced control mixture, APTD decreased the self-administration of nicotine-containing cigarettes, and this occurred in all three groups of smokers. The results suggest that DA influenced the willingness to sustain effort for nicotine reward, and this was seen in participants at all three levels of cigarette addiction. In the transition from sporadic to addicted use, the role of DA in the motivation to seek drug may change less than previously proposed.