Brain Tyrosine Levels Research Articles

Biochemical and behavioural profile of NTBC treated Tyrosinemie type 1 mice.

Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the tyrosine catabolic pathway. Since HT1 patients are treated with NTBC, outcome improved and life expectancy greatly increased. However extensive neurocognitive and behavioural problems have been described, which might be related to treatment with NTBC, the biochemical changes induced by NTBC, or metabolites accumulating due to the enzymatic defect characterizing the disease. To study the possible pathophysiological mechanisms of brain dysfunction in HT1, we assessed blood and brain LNAA, and brain monoamine neurotransmitter metabolite levels in relation to behavioural and cognitive performance of HT1 mice. C57BL/6 littermates were divided in three different experimental groups: HT1, heterozygous and wild-type mice (n = 10; 5 male). All groups were treated with NTBC and underwent cognitive and behavioural testing. One week after behavioural testing, blood and brain material were collected to measure amino acid profiles and brain monoaminergic neurotransmitter levels. Irrespective of the genetic background, NTBC treatment resulted in a clear increase in brain tyrosine levels, whereas all other brain LNAA levels tended to be lower than their reference values. Despite these changes in blood and brain biochemistry, no significant differences in brain monoamine neurotransmitter (metabolites) were found and all mice showed normal behaviour and learning and memory. Despite the biochemical changes, NTBC and genotype of the mice were not associated with poorer behavioural and cognitive function of the mice. Further research involving dietary treatment of FAH-/- are warranted to investigate whether this reveals the cognitive impairments that have been seen in treated HT1 patients.

Curcumin-driven reprogramming of the gut microbiota and metabolome ameliorates motor deficits and neuroinflammation in a mouse model of Parkinson's disease.

BackgroundParkinson’s disease (PD) is a common neurodegenerative disorder, accompanied by motor deficits as well as gastrointestinal dysfunctions. Recent studies have proved that the disturbance of gut microbiota and metabolism contributes to the pathogenesis of PD; however, the mechanisms underlying these effects have yet to be elucidated. Curcumin (CUR) has been reported to provide neuroprotective effects on neurological disorders and modulate the gut flora in intestinal-related diseases. Therefore, it is of significant interest to investigate whether CUR could exert a protective effect on PD and whether the effect of CUR is dependent on the intestinal flora and subsequent changes in metabolites.MethodsIn this study, we investigated the neuroprotective effects of CUR on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16S rRNA sequencing was performed to explore the profile of the gut microbiota among controls, MPTP-treated mice and CUR-treated mice. Then, antibiotic treatment (ABX) and fecal microbiota transplantation (FMT) experiments were conducted to examine the role of intestinal microbes on the protective effects of CUR in PD mice. Furthermore, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics analysis was used to identify the landscape of the CUR-driven serum metabolome. Finally, Pearson’s analysis was conducted to investigate correlations between the gut flora-metabolite axis and CUR-driven neuroprotection in PD.ResultsOur results showed that CUR intervention effectively improved motor deficits, glial cell activation, and the aggregation of α-synuclein (α-syn) in MPTP-treated mice. 16S rRNA sequencing showed elevated abundances of Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae but depleted abundances of Aerococcaceae and Staphylococcaceae in CUR-treated mice when compared with MPTP mice. ABX and FMT experiments further confirmed that the gut microbiota was required for CUR-induced protection in PD mice. Serum metabolomics analysis showed that CUR notably upregulated the levels of tyrosine, methionine, sarcosine and creatine. Importantly, strong correlations were identified among crucial taxa (Aerococcaceae, Staphylococcaceae, Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae), pivotal metabolites (tyrosine, methionine, sarcosine and creatine) and the motor function and pathological results of mice. CUR treatment led to a rapid increase in the brain levels of tyrosine and levodopa (dopa) these changes were related to the abundances of Lactobacillaceae and Aerococcaceae.ConclusionsCUR exerts a protective effect on the progression of PD by modulating the gut microbiota-metabolite axis. Lactobacillaceae and Aerococcaceae, along with key metabolites such as tyrosine and dopa play a dominant role in CUR-associated neuroprotection in PD mice. Our findings offer unique insights into the pathogenesis and potential treatment of PD.

Regulation of dopamine production in the brains during sexual maturation in male honey bees

To explore the physiological mechanisms that underlie age-related dopamine increases during sexual maturation in the brains of male honey bees, we focused on the expression of genes encoding the enzymes tyrosine hydroxylase (Amth) and DOPA decarboxylase (Amddc), which are involved in dopamine biosynthesis in the brain. We hypothesized that juvenile hormone in hemolymph and tyrosine intake from food known as factors enhancing brain dopamine levels might both control the expression of genes related to dopamine production, and we tested this hypothesis in experiments. The brain levels of tyrosine and DOPA, which are precursors of dopamine, decreased as males aged, whereas the dopamine levels increased, suggesting active metabolism of dopamine precursors. The relative expression levels of Amth and Amddc were significantly higher in the brains of 4-day-old males compared with 0-day-old males, and the higher level of Amddc was maintained after 8 days. Topical application of the juvenile hormone analog methoprene enhanced the expression levels of Amth and Amddc in the brains according to the methoprene concentration. Oral intake of tyrosine enhanced the tyrosine, DOPA and dopamine levels in the brain, and activated Amddc expression in the brain, suggesting that tyrosine intake can increase both substrates and enzyme for dopamine biosynthesis. These results support our hypothesis that juvenile hormone and tyrosine intake may enhance the expression levels of genes encoding enzymes involved in dopamine biosynthesis in male honey bee brains during sexual maturation.

Dopamine production in the brain is associated with caste-specific morphology and behavior in an artificial intermediate honey bee caste.

Caste polymorphism in eusocial insects is based on morphological plasticity and linked to physiological and behavioral characteristics. To test the possibility that dopamine production in the brain is associated with the caste-specific morphology and behavior in female honey bees, an intermediate caste was produced via artificial rearing using different amounts of diet, before quantifying the dopamine levels and conducting behavioral tests. In field colonies, individual traits such as mandibular shape, number of ovarioles, diameter of spermatheca, and dopamine levels in the brain differed significantly between workers and queens. Females given 1.5 times the amount of artificial diet that control worker receives during the larval stage in the laboratory had characteristics intermediate between castes. The dopamine levels in the brain were positively correlated with the mandibular shape indexes, number of ovarioles, and spermatheca diameter among artificially reared females. The dopamine levels were significantly higher in females with mandibular notches than those without. In fighting experiments with the intermediate caste females, the winners had significantly higher dopamine levels in the brain than the losers. Brain levels of tyrosine were positively correlated with those of catecholamines but not phenolamines, thereby suggesting a strong metabolic relationship between tyrosine and dopamine. Thus, the caste-specific characteristics of the honey bee are potentially continuous in the same manner as those in primitively eusocial species. Dopamine production in the brain is associated with the continuous caste-specific morphology, as well as being linked to the amount of tyrosine taken from food, and it supports the aggressive behavior of queen-type females.

Improved Measurement of Brain Phenylalanine and Tyrosine Related to Neuropsychological Functioning in Phenylketonuria.

Researchers hypothesized that in phenylketonuria (PKU) high brain phenylalanine (Phe) levels and low brain tyrosine (Tyr) levels affect neuropsychological functioning. However, traditional magnetic resonance spectroscopy (MRS) yielded uncertain results of brain Phe and could not adequately measure brain Tyr. This pilot study examined the potential of correlated spectroscopy (COSY) to quantify these biomarkers and explain variability in neuropsychological functioning. Nine adults with early treated classic PKU received magnetic resonance imaging (MRI) with COSY and a battery of neuropsychological tests. Brain Phe and Tyr in parietal white matter (PWM) were compared to results in gray matter of the posterior cingulate gyrus (PCG). Brain Phe ranged from 101 to 182 (mean = 136.76 ± 23.77) μmol/L in PCG and 76 to 185 (mean = 130.11 ± 37.88) μmol/L in PWM. Brain Tyr ranged from 4.0 to 7.4 (mean = 5.44 ± 1.01) μmol/L in PCG and 4.1 to 8.4 (mean = 5.90 ± 1.48) μmol/L in PWM. Correlation coefficients were largest for brain Phe PWM and measures of auditory memory (rho = -0.79), anxiety (rho = 0.79), and executive functioning (rho = 0.69). Associations were in the expected direction, with higher brain Phe and lower brain Tyr related to poorer functioning. The two participants with severe structural MRI abnormalities had low brain Tyr levels in PCG and 3/5 of the participants with moderate to severe MRI abnormalities had higher than average brain Phe levels. COSY has the potential to quantify brain Phe and Tyr at low concentrations and in specific brain regions. In this pilot study, these biomarkers were associated with indices of neuropsychological functioning. Additional studies are needed to validate the COSY results.

Elevation of rat brain tyrosine levels by phenelzine is mediated by its active metabolite β-phenylethylidenehydrazine

Phenelzine, a non-selective irreversible inhibitor of monoamine oxidase (MAO), has been used in the treatment of depression and anxiety disorders for several decades. It is a unique inhibitor of MAO as it is also a substrate for MAO, with one of the metabolites being β-phenylethylidenehydrazine (PEH), and it also inhibits several transaminases (e.g. GABA transaminase) in the brain when administered i.p. to rats. Administration of either phenelzine or PEH to rats has been reported to produce dramatic increases in rat brain levels of GABA and alanine while reducing levels of glutamine; these effects are abolished for phenelzine, but not for PEH, when the animals are pre-treated with another MAO inhibitor, suggesting that they are mediated by the MAO-catalyzed formation of PEH from phenelzine. In the present report, we have found that phenelzine and E- and Z-geometric isomers of PEH significantly increased rat whole brain concentrations of L-tyrosine. In a time-response study, acute administration of phenelzine, E-PEH and Z-PEH (30 mg/kg i.p.) elevated rat whole brain L-tyrosine levels at 3 and 6h following injection, reaching approximately 265-305% of vehicle-treated controls at 3h. To determine whether the effect on L-tyrosine is MAO-dependent, animals were pre-treated with the non-selective MAO inhibitor tranylcypromine (1mg/kg i.p.) prior to administration of phenelzine, racemic PEH or vehicle controls. This pre-treatment reversed the effects of phenelzine, but not of PEH, on brain L-tyrosine levels, suggesting that the tyrosine-elevating property of phenelzine is largely the result of its active metabolite PEH. These results are discussed in relation to possible therapeutic applications of these drugs.

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

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. 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. 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. 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 (6.25nM) 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 (10.0nmol/kg in the MPFC and 0.10nmol/kg in the striatum). 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.

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.

Effect of chronic protein ingestion on tyrosine and tryptophan levels and catecholamine and serotonin synthesis in rat brain

ObjectivesPrevious studies have shown that brain tyrosine (TYR) levels and catecholamine synthesis rate increase in rats as chronic dietary protein content increases from 2 to 10% (% weight). A single protein, casein, was examined. The present study explores how TYR levels and catecholamine synthesis (and tryptophan (TRP) levels and serotonin synthesis) change when different proteins are ingested chronically over the same range of dietary protein contents.MethodsMale rats ingested for 8 days diets contain 2 or 10% protein (zein, gluten, casein, soy protein, or alpha-lactalbumin). On the last day, they were killed 2.5 hours into the dark period, 30 minutes after receiving an injection of m-hydroxybenzylhydrazine, an inhibitor of aromatic l-amino acid decarboxylase. Brain samples were analyzed for amino acids, including 5-hydroxytryptophan (index of serotonin synthesis rate) and dihydroxyphenylalanine (index of catecholamine synthesis rate), by HPLC-electrochemical detection.ResultsTYR levels and catecholamine synthesis rate in brain were unaffected by the particular protein ingested. However, TRP levels and serotonin synthesis rate varied markedly, depending on the protein ingested, with effects being most prominent in the 10% protein groups. The effect of dietary protein on brain TRP correlated very highly with its effect on serotonin synthesis.DiscussionThe results indicate that the protein ingested can chronically modify TRP levels and serotonin synthesis in brain, but not TYR levels or catecholamine synthesis, with effects most distinct at an adequate level of protein intake (10%).

Acute lithium administration selectively lowers tyrosine levels in serum and brain

Lithium exerts anti-dopaminergic behavioral effects. We examined whether some of these might be mediated by changes in brain levels of tyrosine (TYR), the precursor to dopamine. Lithium chloride (LiCl 2) 3.0 mEq/kg IP acutely lowered serum TYR and the ratio of serum TYR to other large neutral amino acids (LNAAs); it also selectively lowered striatum TYR levels as measured in tissue or in vivo. While LiCl 2 3.0 mEq/kg IP also augmented haloperidol (0.19 mg/kg SC)-induced catalepsy, this lithium effect was not attenuated by administration of TYR 100 mg/kg IP. We conclude that lithium acutely and selectively lowers brain TYR by lowering serum levels of tyrosine relative to the LNAAs that compete with it for transport across the blood–brain barrier. However, the lowering of TYR does not appear to significantly contribute to the ability of lithium to potentiate haloperidol-mediated catalepsy.

On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats

The mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonergic (5-HT) toxicity remain unclear. It has been suggested that MDMA depletes 5-HT by increasing brain tyrosine levels, which via non-enzymatic hydroxylation leads to DA-derived free radical formation. Because this hypothesis assumes the pre-existence of hydroxyl radicals, we hypothesized that MDMA metabolism into pro-oxidant compounds is the limiting step in this process. Acute hyperthermia, plasma tyrosine levels and concentrations of MDMA and its main metabolites were higher after a toxic (15 mg/kg i.p.) vs. a non-toxic dose of MDMA (7.5 mg/kg i.p.). The administration of a non-toxic dose of MDMA in combination with l-tyrosine (0.2 mmol/kg i.p.) produced a similar increase in serum tyrosine levels to those found after a toxic dose of MDMA; however, brain 5-HT content remained unchanged. The non-toxic dose of MDMA combined with a high dose of tyrosine (0.5 mmol/kg i.p.), caused long-term 5-HT depletions in rats treated at 21.5 °C but not in those treated at 15 °C, conditions known to decrease MDMA metabolism. Furthermore, striatal perfusion of MDMA (100 μM for 5 h) combined with tyrosine (0.5 mmol/kg i.p.) in hyperthermic rats did not cause 5-HT depletions. By contrast, rats treated with the non-toxic dose of MDMA under heating conditions or combined with entacapone or acivicin, which interfere with MDMA metabolism or increase brain MDMA metabolite availability respectively, showed significant reductions of brain 5-HT content. Altogether, these data indicate that although tyrosine may contribute to MDMA-induced toxicity, MDMA metabolism appears to be the limiting step.

In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels

We previously reported that depletion of brain tyrosine attenuated the acute clozapine (CLZ)-induced increase in medial prefrontal cortex (MPFC) dopamine (DA) levels. This effect was now examined after chronic CLZ treatment. Male rats received CLZ (10 mg kg(-1) day(-1)) in drinking water for 21 days. On day 18, a cannula was stereotaxically implanted over the MPFC. A microdialysis probe was inserted on day 20. On day 21 after a stable baseline was reached, rats received an acute injection of vehicle (VEH) or a tyrosine- and phenylalanine-free mixture of neutral amino acid [NAA(-)] (total 1 g kg(-1), i.p., two injections, 1 h apart) followed by CLZ (10 mg kg(-1), i.p.) or VEH. Basal tyrosine or norepinephrine (NE) levels were not different between the groups, but basal DA was higher in the group treated chronically with CLZ (p<0.05). Acute CLZ (10 mg kg(-1), i.p.) increased MPFC DA and NE levels to 370% and 510% of baseline, respectively, and similarly in rats chronically pretreated with CLZ or VEH. NAA(-) did not affect basal MPFC DA or NE levels but significantly attenuated acute CLZ-induced DA (220% of baseline) and NE (330% of baseline) levels (p<0.01) in rats pretreated chronically with CLZ or with VEH. These data demonstrate that even after chronic CLZ administration, the acute CLZ-induced increases in MPFC DA and NE levels depend on the availability of brain tyrosine. Judicious manipulation of brain tyrosine levels may provide a useful probe as well as a mechanism for enhancing psychotropic drug actions.

Effect of Acute Tyrosine Depletion in Using a Branched Chain Amino-Acid Mixture on Dopamine Neurotransmission in the Rat Brain

Central dopamine function is reduced by decreasing the availability of the catecholamine precursor, tyrosine, using a tyrosine-free amino acid mixture containing multiple large neutral as well as branched chain amino-acids, which compete with tyrosine for uptake into the brain. Current mixtures are cumbersome to make and administer, and unpalatable to patients and volunteers. Here, we investigate whether individual or limited amino-acid combinations could reduce brain tyrosine levels and hence dopamine function. Measurements of regional brain tyrosine levels, catecholamine and indoleamine synthesis (L-DOPA and 5-HTP accumulation, respectively) were used to identify an effective paradigm to test in neurochemical, behavioral and fos immunocytochemical models. Administration of leucine or isoleucine, or a mixture of leucine, isoleucine, and valine reduced tyrosine and 5-HTP, but not L-DOPA accumulation. A mixture of leucine, valine, and isoleucine supplemented with tryptophan reduced brain tyrosine and L-DOPA, but not 5-HTP. In microdialysis experiments this amino-acid mixture reduced basal and amphetamine-evoked striatal dopamine release, as well as amphetamine-induced hyperactivity. This mixture also reduced amphetamine-induced fos expression in striatal areas. In conclusion, the present study identified a small combination of amino acids that reduces brain tyrosine and dopamine function in a manner similar to mixtures of multiple amino acids. This minimal mixture may have use as a dopamine reducing paradigm in patient and volunteer studies.

Clozapine-induced dopamine release in the medial prefrontal cortex is augmented by a moderate concentration of locally administered tyrosine but attenuated by high tyrosine concentrations or by tyrosine depletion

Tyrosine availability can affect indices of dopamine (DA) release in activated central DA systems. There are, however, inconsistencies between studies. One possibility is that the relationship between tyrosine availability and DA release is non-linear. This study aimed to determine how tyrosine depletion as well as a range of administered tyrosine concentrations affect antipsychotic drug-induced extracellular DA levels in the MPFC or striatum. A guide cannula was implanted over the medial prefrontal cortex or striatum of adult male rats. After a 24-h recovery period, a microdialysis probe was inserted. Microdialysate collection began on the following day. Some rats received vehicle or a tyrosine- and phenylalanine-free neutral amino acid solution NAA(-) (IP) prior to clozapine (CLZ 10 mg/kg IP). Others received vehicle, CLZ (10 mg/kg IP) or haloperidol (HAL) (1 mg/kg IP) while the probe was perfused with artificial cerebrospinal fluid containing tyrosine 0-200 mug/ml. NAA(-) reduced tyrosine levels in MPFC dialysate by 35%. This reduction did not affect basal MPFC DA levels but attenuated the peak of CLZ-induced MPFC DA levels. The NAA(-) effect could be reversed by administration of tyrosine. Infused tyrosine 12.5-200 mug/ml did not affect basal DA levels either in MPFC or striatum. Within the MPFC, tyrosine 50.0 mug/ml significantly increased CLZ-induced DA levels. Within the striatum, tyrosine 25.0 mug/ml significantly increased while 150.0 mug/ml significantly decreased HAL-induced DA levels. Basal extracellular levels of DA in the MPFC and striatum are not affected by wide changes in tyrosine availability. However, modestly increased brain tyrosine levels can augment CLZ-induced MPFC and HAL-induced DA levels. Very high tyrosine concentrations attenuate HAL-induced striatal DA levels. These data may explain inconsistencies in the literature and suggest that tyrosine availability could be exploited to modulate psychotropic drug-induced DA levels in the brain.

Brain tyrosine depletion attenuates haloperidol-induced striatal dopamine release in vivo and augments haloperidol-induced catalepsy in the rat.

There are conflicting reports as to whether alterations in tyrosine levels affect functional indices of striatal dopamine (DA) transmission. Since the DA antagonist haloperidol (HAL) increases striatal DA release and induces catalepsy through its actions on striatal DA systems, it provides a useful paradigm to assess both neurochemical and behavioral effects of lowering brain tyrosine levels. To determine how brain tyrosine depletion affects HAL-induced catalepsy and striatal DA release in awake, freely moving rats. In male rats, a control or tyrosine- and phenylalanine-free neutral amino acid solution NAA(-) (IP) was administered 30-60 min prior to HAL (IP). In one cohort, striatal microdialysate was assayed for DA levels. In a parallel cohort, catalepsy was measured using the bar test. NAA (-) reduced striatal tyrosine levels by 60%. The latter did not affect basal striatal DA release, but consistently delayed the attainment of maximal HAL-induced (0.19 mg/kg and 0.25 mg/kg SC) striatal DA release; the latter was abolished by administration of tyrosine. NAA(-) also potentiated HAL-induced catalepsy. Acute brain tyrosine depletion attenuates HAL-induced striatal DA release and potentiates haloperidol-induced catalepsy. Both effects can be reversed by administration of tyrosine. Overall, the data indicate that tyrosine depletion affects both neurochemical and behavioral indices of striatal DA release.

Relationship between myelin production and dopamine synthesis in the PKU mouse brain.

Phenylketonuria is caused by specific mutations in the phenylalanine hydroxylase gene and is characterized by elevated blood phenylalanine levels, hypomyelination in forebrain structures, reduced dopamine levels, and cognitive difficulties. To determine whether brain tyrosine levels and/or myelination play a role in the up-regulation of dopamine, phenylketonuric mice were placed on a low phenylalanine diet for 4 weeks and as blood phenylalanine levels dropped to normal, the relationships between phenylalanine, tyrosine, dopamine, myelin proteins, and axonal proteins in frontal cortex and striatum were determined using gas chromatography mass spectrometry, histology, and western blotting techniques. Blood phenylalanine rapidly decreased from an eight-fold elevation to near control levels, and blood tyrosine gradually rose from about 50% to near normal values. In frontal cortex and striatum, phenylalanine levels dropped to 2- and 1.5-fold elevations above control, respectively, and tyrosine levels increased but remained less than 70% of control in both structures. In frontal cortex, increases in dopamine and myelin basic protein occurred in a similar biphasic pattern, reaching near normal levels by week 4. In striatum, dopamine and MBP dramatically increased to near normal levels in the first week. Myelination was confirmed histologically and by western blot quantification of phosphorylated neurofilaments. In summary, our results showed: (i) an increase in dopamine despite low brain tyrosine levels and (ii) similar recovery patterns for myelination and dopamine. Since myelin/axonal interactions trigger signaling pathways that result in axonal maturation, we speculate that this interaction also may trigger signals that up-regulate neurotransmitter synthesis.

Mesoprefrontal dopaminergic neurons: Can tyrosine availability influence their functions?

The dopamine (DA) neurons projecting to the prefrontal cortex (PFC) are thought to be involved in working memory, stress response, and the pathogenesis of schizophrenia. In this commentary, we review the current evidence supporting a precursor tyrosine dependence of these mesoprefrondal DN neurons. Several studies in rats employing different experimental paradigms [i.e. experimental diabetes and early-treated phenylketonuria (PKU) model]have shown that reduced tyrosine levels in brain can affect markedly the physiology and functions of these DA neurons. However, supplemental tyrosine is effective in enhancing functional transmitter outflow from mesoprefrontal DA neurons only under conditions where their physiological activity is enhanced and DA synthesis and release are uncoupled from intrinsic regulatory controls. Recent studies in Humans have also suggested that variations in brain tyrosine levels can affect significantly higher cortical functions subserved by the PFC. In early-treated PKU patients with mildly reduced tyrosine levels, marked impairments in cognitive functions dependent on the dorsolateral PFC could be detected. In drugtreated schizophrenic patients, supplemental tyrosine was shown to have a disruptive effects on the smoothpursuit eye movement performance task. Furthermore, tyrosine administration was effective in restoring impaired working memory in humans following a cold stress paradigm, as assessed by a computer-based delayed matchingto-sample memory task. These human studies, together with the current evidence obtained from animal experiments, suggest that the functions of the mesoprefrontal DA neurons can, under certain circumstances, be readily influenced by the availability of the precursor tyrosine.

A possible mechanism for the increase in brain tyrosine levels induced by cyanide in mice

Subcutaneous administration of cyanide significantly increased blood tyrosine levels of mice in a dose dependent manner. Tyrosine aminotransferase activity in liver of mice was significantly decreased in the presence of cyanide (8, 10, 20, 40, 50, 65, 80 and 100 μ M), also in a concentration-dependent manner, with a positive correlation between the percentage increase of blood tyrosine levels and the percentage decrease of hepatic tyrosine aminotransferase activity. These results suggest that the increased tyrosine levels induced in blood by cyanide may be related to its inhibition of tyrosine aminotransferase activity in the liver. Cyanide decreased hepatic ATP content and increased blood ammonia levels and brain tyrosine in a dose-dependent manner. As it is known that hyperammonaemia increases the uptake of neutral amino acids such as tyrosine into the brain from blood, the mechanism by which tyrosine levels increase in the brain may be based on increases of both tyrosine and ammonia levels in blood.

Twenty-four-hour variations in rat blood and brain levels of the aromatic and branched-chain amino acids: Chronic effects of dietary protein content

Groups of young adult, male rats were given free access for 12 weeks to a single diet containing either 12%, 24%, or 40% protein (dry weight). At the end of this time, six rats from each diet group were killed every four hours throughout a single 24-hour period, and blood samples and brains were obtained for quantitation of several of the large neutral amino acids (LNAAs). The blood level of each LNAA varied significantly as a function of time of day (tending to be lower during the day than at night) and as a function of dietary protein content (typically rising as protein intake increased). Except for tyrosine and valine, the serum concentration ratio of each LNAA to the sum of the other LNAA (previously reported to be a good predictor of the competitive uptake of each LNAA into brain) and the brain level of each LNAA showed unremarkable variations with time of day and dietary protein content. In contrast, the serum ratios and brain levels of tyrosine and valine did show notable variations at night as a function of dietary protein intake. Together, the results show that within a chronic physiologic range of protein intakes, the serum ratios and brain levels of several large neutral amino acids, particularly tryptophan, bear no relationship to dietary protein level. Though good correlations between these parameters and protein intake were obtained for valine and tyrosine, their physiologic/metabolic significance, if any, is unknown. In general, the data do not support the broad, unvalidated use of serum LNAA ratios in chronic settings as predictors of brain LNAA levels.

Observations on predicted brain influx rates of neurotransmitter precursors. Effects of tumor, operative stress with tumor removal, and postoperative TPN of varying amino acid compositions.

Effects of tumor, operative stress and tumor removal, and postoperative TPN of varying amino acid compositions on brain levels of tryptophan or tyrosine as predicted by their brain influx rates were studied in normals and in malnourished cancer patients. Concentrations of the large neutral amino acids (LNAA) were determined in patients before and after tumor removal, and in postoperative patients before and after receiving either a standard TPN solution (STD-TPN), or a branched-chain amino acid solution (BCAA-TPN). The LNAA were altered in all groups versus normals. Brain influx rates showed the following: in preoperative patients, predicted brain tryptophan levels were below normal (P less than 0.001), whereas tyrosine levels were within or above normal; no significant differences between pre- and postoperative tryptophan or tyrosine levels; postoperative STD-TPN did not change predicted brain tryptophan concentration from preinfusion values, but BCAA-TPN decreased it (P less than 0.001), underscoring the common transport carrier; and preinfusion predicted brain tyrosine levels were decreased (P less than 0.001) by both types of TPN solutions. These results imply low substrate levels for brain serotonin and catecholamine synthesis, possibly affecting functions dependent on their control.