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During mild stress, epinephrine output increases to about times the resting level, whereas during more severe stress, e. There are no "normal" catecholamine levels, although pathological levels can be found in association with adrenal tumours, for example. In order to reduce the influence of circadian rhythms and individual differences in baseline levels, it is recommended to express individual responses to stress in relation to a person's corresponding baseline level obtained during relaxation at the same time of the day on another day. Thus, percent change from baseline is usually a more relevant measure than absolute levels.

In stress research, like in many other research areas, most studies have been performed on men. However, in the early s, investigators in Marianne Frankenhaeuser's group in Stockholm started to compare stress responses of males and females. In these early studies of sex differences in psychophysiological stress responses, it was consistently found that women were less reactive than men in terms of epinephrine secretion during experimental stress e.

Although women performed as well or usually even better than men on the various stress tests, they did not increase their epinephrine secretion much.

However, during more intense stress such as a stressful examination Frankenhaeuser, Rauste von Wright et al. A possible explanation for these sex differences is that performance stress is less challenging to women than to men. Studies comparing men and women matched for education and occupational level show that women may respond with as much epinephrine output at work and during experimental stress as men do Lundberg, However, women's stress levels, but not men's, have been found to remain elevated even after work Frankenhaeuser et al.

Although the possible influence of biological factors such as steroid sex hormones on catecholamine responses cannot be excluded Wasilewska, Kobus and Bargiel, ; Tersman, Collins and Eneroth, , it seems as if psychological factors and gender role patterns are more important than biological factors for the sex differences in catecholamine responses. For example, oestrogen replacement therapy did not significantly influence catecholamine responses in women during experimental stress Collins et al.

In men, a significant positive correlation is usually found between perceived stress and physiological responses at work e. However, in women, physiological stress levels at work seem to spill over into non-work situations Rissler, ; Frankenhaeuser et al. This interaction between stress from paid employment and unpaid work at home is important to consider in the study of women's stress. Epinephrine levels are significantly elevated by overstimulation as well as understimulation, compared to more optimal environmental conditions Frankenhaeuser et al.

Work overload, a very fast work pace, too much responsibility and role conflicts as well as simple, monotonous and repetitive jobs or a lack of meaningful activities e. The acute response "phasic" elevation, according to Ursin et al. One example of an adequate or economic response to mental stress is presented in Fig. The subjects were able to return to their baseline level each time the stress exposure ended. Another example is shown in Fig. Despite a more than percent increase during labour and pushing, the epinephrine levels had returned to the pregnancy levels after a couple of days.

Epinephrine output of 50 women giving birth to their first child Alehagen et al. Lack of unwinding norepinephrine among female managers after a day at work compared to their male colleagues, has been found in two studies Frankenhaeuser et al. This gender difference was found mainly in women with children at home, whereas in men the presence of children at home did not influence their stress hormone levels.

Correlation between catecholamine levels at work and in the evening at home in women and men based on Frankenhaeuser et al. Rissler found that a period of overtime on Saturdays at work during a period of several weeks influenced the epinephrine levels in the evening measured on Wednesdays in female white-collar workers. Lundberg and Palm found that overtime at work was correlated with epinephrine output during the weekend at home in full-time employed mothers, but not fathers, of preschool children.

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It is of interest to note that Alfredsson et al. Whereas epinephrine output is influenced mainly by mental stress, norepinephrine is more sensitive to physical activity and body posture. Comparisons of work stress in blue and white-collar workers are consistent with experimental findings as shown in Table 3, where data from a series of real-life studies are summarized. The physical activity of the white-collar workers is probably too low to influence norepinephrine output.

Considering the various cardiovascular and metabolic functions influenced by the catecholamines, this means that blue-collar workers in general are exposed to a greater total physiological load than white-collar workers are. In addition, workers in repetitive jobs seem to have difficulties unwinding after work, i. This pattern of catecholamine responses is also consistent with the association between low SES and high catecholamine levels reported by Cohen et al. In view of traditional gender differences in responsibility for unpaid work at home Hall, ; Kahn, ; Lundberg et al.

Catecholamine responses are strongly related to the intensity of mental stress regardless of its emotional valence. This was demonstrated in early experiments by Levi , in which participants were exposed to films with contrasting emotional content, and by Lundberg et al.

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Thus, elevated catecholamine levels reflect negative stress as well as strong positive emotions. Urinary catecholamines are particularly useful in the study of occupational psychosocial stress as they reflect the mean stress levels for longer periods of time and do not cause pain or discomfort to the participants. In addition, catecholamines are linked to certain health problems such as cardiovascular disorders. Acta Physiologica Scandinavica Alehagen, S.

Catecholamine and cortisol reaction to child birth. International Journal of Behavioral Medicine, 8, Fear, pain and stress hormones during childbirth. Alfredsson, L. Type of occupation and near-future hospitalization for myocardial infarction and some other diagnoses. International Journal of Epidemiology, 14, Axelrod, J. Stress hormones: Their interaction and regulation. Science, Baum, A. Urinary catecholamines in behavioral research in stress. Ziegler Eds. Ann Arbor, Butterworths, pp. Cannon, W. American Journal of Physiology Cohen, S.

Socioeconomic status is associated with stress hormones. Psychosomatic Medicine, 68, Collins, A. Stress responses in male and female engineering students. Journal of Human Stress, 4, Psychophysiological stress responses in postmenopausal women before and after hormonal replacement therapy. Human Neurobiology, 1, Forsman, L.

Neurotransmitters Overview

Individual and group differences in psychophysiological responses to stress - with emphasis on sympathetic-adrenal medullary and pituitary-adrenal cortical responses. Consistency in cathecolamine and cortisol excretion in males and females. Frankenhaeuser, M. Journal of Human Stress 2: Women, work and health. Stress and opportunities, New York: Plenum Press. The sympathetic-adrenal and pituitary-adrenal response to challenge: comparison between the sexes.

Dembroski, T. Biobehavioral bases of coronary heart disease.

Chapter Contents

Basel, New York: Karger. Dunne, E. Sex differences in sympathetic adrenal medullary reactions induced by different stressors. Psychopharmacology, 47, Sex differences in psychoneuroendocrine reactions to examination stress. Psychosomatic Medicine, 40, Stress on and off the job as related to sex and occupational status in white-collar workers. Journal of organizational behavior, 10, Perceptual and Motor Skills Hall, E. Womens work: an inquiry into the health effects of invisible and visible labour. Doctoral Dissertation, Karolinska Institute, Stockholm.

Henry, J. Integrative Physiological and Behavioral Science, 1: Stress, Health, and the Social Environment. A Sociobiologic Approach to Medicine. Hjemdahl, P. Catecholamine measurements in urine with high-performance liquid chromatography with amperometric detection - comparison with an autoanalyser fluorescence method. Journal of Chromatography, , Johansson, G.

Ergonomics Kahn, R. Frankenhaeuser, U. Chesney Eds. Women, work, and health. Stress and opportunities. New York: Plenum Press, Karasek, R. Physiology of stress and regeneration in job related cardiovascular illness. Journal of Human Stress, 8, Krantz, G. Consistency in physiological stress responses and electromyographic activity during induced stress exposure in women and men. Integrative Physiology and Behavioral Science 39, Krantz, D. Acute psychophysiologic reactivity and risk of cardiovascular disease: A review and methodologic critique. Psychological Bulletin, 96, Levi, L.

The urinary output of adrenaline and noradrenaline during pleasant and unpleasant emotional states. Psychosomatic Medicine, 27, Ascorbic acid was dissolved to 0. Osaka, Japan , was dissolved in 0. The solution was administered to mice intraperitoneally. For examination of the acute effect of BH4, mice were sacrificed 1 h after the injection, and for that of the chronic effect, animals were injected with the drug once a day for 7 days.

Then, on the following day, they were sacrificed for biochemical and Western blot analyses. The Ptps gene was inactivated by homologous recombination in ES cells by use of a targeting vector, in which a 0. The genotype of the mice was also determined by Southern hybridization Fig. This means that mutant mice could survive in utero during embryogenesis; however, all homozygotes died within 48 h after birth.

Northern hybridization using total RNA extracted from the brain and the liver of newborn mice showed that homozygotes were null mutants, for Ptps mRNA was not detected Fig. Biochemical analysis revealed a dramatic decrease in the level of biopterin 6. There was no significant difference between heterozygotes and wild-type mice Fig.


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These results show that in vivo synthesis of catecholamines and 5HT was diminished by the lack of BH4. The phenylalanine content in both brain and liver of homozygotes was 2 times higher than that of the wild type Fig. Pteridine, monoamine, and phenylalanine contents in the tissues of newborn mice.

A , neopterin black column and biopterin hatched column. C , phenylalanine contents in their brain black column and liver white column. Genotypes are indicated below the columns. Enzyme activities in the brains of newborn knockout and wild-type mice. Next, we examined the localization of TH protein by using an immunohistochemical technique. Dopaminergic and noradrenergic neural cell bodies are located in the substantia nigra, ventral tegmental area, and locus ceruleus. Those neural cell bodies in homozygotic mutant mice as well as in wild-type ones were stained with anti-TH antibody equally Fig.

Although there was no significant difference in TH staining on cell bodies, we found a striking difference in the terminal region. In the brain of wild-type mice, nerve fibers were strongly stained with anti-TH antibody, and many positive varicosities were easily seen at higher magnification in the striatum, to which dopaminergic neurons in the substantia nigra project Fig. In the same region of the homozygotic mutant mice, nerve fibers were not stained; instead, a few unusual TH-immunopositive cells were found in the striatum Fig. In order to examine the presence of dopaminergic fibers, we stained the same sections with anti-AADC antibody.

This time nerve fibers in the striatum were positively stained in homozygotes similarly as in the wild type Fig. These results indicate that the amount of TH protein was markedly decreased only in nerve terminals, but not in cell bodies. These findings were identical to those obtained from the other homozygous mouse. Cell bodies of dopaminergic neurons in the midbrain of the homozygote mutant were stained with anti-TH antibody B to the same extent as those of the wild type A.

In the striatum of the wild-type mouse C , many neural fibers with varicosities were reactive with anti-TH antibody, which was especially evident at higher magnification E. Neural fibers were not stained with anti-TH antibody in the same region of the homozygous mutant mouse D , and unusual TH-immunopositive cells could be seen in the mutant striatum F.

Some of these are indicated by arrows. The striatum of the homozygous mutant was reactive with anti-AADC antibody H to the same extent as that of the wild type G. Asterisks in C and D indicate the portions that are shown at higher magnifications in E and F , respectively. Scale bars in B , D , and H are mm, and the one in F is 50 mm. A reduction in TH protein in the brain of homozygous newborn mice was also shown by Western blotting Fig. This Western blot analysis clearly confirmed that the reduction in TH activity was caused by decrease in the amount of the TH protein amount itself.

Western analysis using the brain homogenate of mice rescued with BH4 administration. These injections were done for 7 days. Northern blotting of TH. Genotypes are indicated at the top of the panels. Upper panel , Th ; lower panel , G3pdh. Neural cell bodies in the substantia nigra, ventral tegmental area, and locus ceruleus of homozygotes were immunopositively stained with anti-GCH antibody as in the wild type data not shown.

Serotonergic cell bodies in the dorsal raphe nucleus of the homozygous mice were also well stained with anti-TPH antibody in the Ptps -null mice as well as in the wild type data not shown. NE is a neurotransmitter of the peripheral sympathetic neurons, and NE and epinephrine are synthesized in adrenomedullary cells as hormones. Since cardiovascular function, respiratory rate, metabolism, and body temperature are regulated by both sympathetic and parasympathetic nervous systems, physical catastrophe could be caused by failure of the peripheral nervous systems as well as by dysfunction of the central nervous system in Ptps knockout mice.

So we recorded the surface electrocardiogram of newborn homozygotic mutant mice and compared their heart rates with those of their littermates. Next, with anti-TH antibody we immunostained the adrenal gland and the kidney where many terminals of sympathetic nerves exist. Adrenomedullary cells in the homozygotic mutants were immunopositive as well as those in the wild type, but sympathetic nerve terminals in the kidney of homozygotes showed less positive staining for TH compared with those of the wild-type animals Fig. These results indicate that TH protein was decreased selectively in nerve terminals and that dysfunction of peripheral nervous system could thus be involved in the cause of death for homozygous mutant mice.

Electrocardiographic analysis of the newborn mice. A , typical surface electrocardiograms of the littermates are depicted. B , heart rate calculated from the electrocardiograms. Immunostaining of TH in the adrenal gland and kidney. The adrenal medulla in the homozygous mutant mouse was positively stained with anti-TH antibody as well as the wild-type one. C and D , the kidney of wild type and homozygous mutant, respectively, at higher magnification. Sympathetic nerve terminals were well stained with anti-TH antibody in the kidney of the wild-type mouse C , whereas those of the homozygous mutant were weakly stained D.

Monoamine contents and the monoamine-synthesizing enzyme activities in their brain were analyzed and compared with those of vehicle-injected mice 0. The biopterin content in the brains of both BH4-injected wild type and homozygous mutants was 6—7 times higher than that of the ascorbic acid-injected wild-type mice Fig. This finding indicates that BH4 passed through the immature blood-brain barrier well in neonates. Despite the great elevation in the amount of BH4, the DA content in the brain was not altered at all in the wild-type mice, whereas the 5HT content was slightly increased 1.

In contrast, the increase in DA levels in the Ptps -null mice was only 1. Acute effect of intraperitoneal administration of BH4 on the brain of newborn mice. The knockout mice could survive up to postnatal day 7, although growth retardation was obvious. Effect of repeated intraperitoneal administration of BH4 and ascorbic acid on the brain biochemistry of knockout mice. By this subchronic administration of BH4, TH activity was recovered to a greater extent than the DA level in the brain.

The 5HT content in the brain of the homozygous mutants was not remarkably improved 1 day after the last injection. The mouse brains were fixed 3 h after the last injection. Strikingly, the caudate-putamen of the rescued homozygous mice was quite reactive with the anti-TH antibody as was that of the heterozygous control mice Fig. Further, we confirmed the increase in the amount of TH protein in the BH4-rescued homozygous mutant mice by Western blot analysis. As shown in Fig. The data also showed that TPH protein was not decreased in the neonatal brain, in contrast to the case for TH.

Immunohistochemical staining of TH in the striatum of mice rescued with BH4 administration. CP , caudate-putamen; Cx , cortex. For the first time, we established mice in which de novo biosynthesis of BH4 was impaired by disruption of the Ptps gene, whose product catalyzes the conversion of 7,8-dihydroneopterin triphosphate to 6-pyruvoyl-5,6,7,8-tetrahydropterin. Homozygous mutants were born nearly according to the Mendelian law, but all of them died within 48 h.

In the brain of newborn Ptps -null mutants, only a trace amount of biopterin was present in the brain, neopterin derived from 7,8-dihydroneopterin triphosphate accumulated, and catecholamine and 5HT levels were markedly reduced. The reduction of TH activity was accompanied by a decreased amount of the enzyme only at the nerve terminals. Whereas a single administration of BH4 to the null mice led to a great increase in the 5HT content, 1 h after the administration, the DA content remained low.

These results suggest differential action of BH4 between the regulation of catecholamines and that of 5HT in the brain. We observed accumulation of phenylalanine in the brain and liver of homozygous mutant mice. Most cases of hyperphenylalaninemia are caused by a genetic defect in phenylalanine hydroxylase. The present Ptps knockout mouse is an animal model for this type of atypical hyperphenylalaninemia. Despite the dramatic change in BH4 and monoamine levels in the brain, homozygous mutants were born according to the Mendelian ratio, and no gross anomaly was seen by microscopic examination of major organs including the brain.

The present result thus indicates that the Ptps knockout mouse is not an embryonically lethal. Dbh knockout mice die at embryonic day 11 or 12 if the mother was also Dbh -null. Our findings raise the possibility that a minor side pathway for BH4 biosynthesis may exist, because it was reported that BH4 hardly passed through placenta We succeeded in rescuing homozygous mutants from death for up to 7 days by intraperitoneal administration of BH4. BH4, being a hydrophilic molecule, is believed to hardly permeate into the blood-brain barrier.

However, in the neonatal stage, peripherally administered BH4 could pass through the immature blood-brain barrier well and was incorporated into cells to increase neurotransmitter levels Fig. Their increase by administration of BH4 was more remarkable in the Ptps knockout mice than in the wild-type mice. It is possible that a BH4 transporter or carrier protein to maintain the BH4 concentration constant in the cell exists. Mice lacking nNos 32 , eNos 33 , and iNos 34 were established by gene targeting.

Hypertrophy of the pyloric sphincter and the circulate muscle layer along with the lack of NADPH-diaphorase-containing neurons occurred in the nNos knockout mice Hypotension caused by endotoxin in wild-type mice was not observed in mice deficient in iNos , and antibacterial and anti-tumor activities in the latter were poor Since we did not subfractionate the brain homogenate, the NOS activity that we assayed was that of mixed types of NOS.

In the present study, the NOS activity was slightly reduced by the lack of BH4 in vitro , but no phenotype relating to NO systems was evident in vivo. We could not determine whether in vivo NO production was impaired or not, because the levels of NO metabolites such as nitrite and nitrate were too low to be quantified under the unstimulated condition. However, as the K m value 0. It is likely that depleted BH4 may affect the immune response or host defense mechanisms when iNOS induction is required.

We are currently planning an experiment to examine this possibility. Th knockout mice, which were embryonic lethal but could be rescued by administration of l -DOPA or l - threo -dihydroxyphenylserine, died apparently of cardiovascular failure as shown by congestion in the liver and vessels and by an abnormal electrocardiogram 26 , Although the cause of neonatal death in our Ptps knockout mice remains unclear, the severe decrease in catecholamine levels, bradycardia, and the marked reduction in TH immunoreactivity in sympathetic nerve terminals suggest that failure in the peripheral nervous system in addition to abnormality in the brain could be a causative factor leading to death.

BH4 could be maternally supplied in utero ; however, it would be gradually depleted after birth. This assumption is further supported by the prolonged survival period with administration of BH4. The mortality of Ptps knockout mice resembled that of Phox2a 36 or Nurr1 -deficient mice In the former, the locus ceruleus and subsets of sympathetic, parasympathetic, and sensory ganglia were absent; and in the latter, TH-positive cells in the ventral midbrain were not generated.

DA-deficient mice were reported to be hypoactive and showed a feeding disturbance after weaning However, as thinning out of littermates did not seem to be very helpful for survival of homozygous mutants of Ptps knockout mice data not shown , simple competition with their littermates was not a critical factor. The phenylalanine content in the brain of homozygous mutant neonates was only 2 times higher than that of the wild type.

The contribution of hyperphenylalaninemia to the early death seems to be low, as it is known that the symptom of human phenylketonuria is not remarkable at the neonatal stage, but becomes worse by intake of phenylalanine in the milk. Although symptoms based on dysfunction of 5HT and NO systems were not observed in human PTPS deficiency, these factors also may have contributed to the death of knockout mice.

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Interestingly, we found TH-positive cells in the striatum of the BH4-deficient mice, which cells were not detectable in the wild-type mice. AADC-positive cells were also not visible, and GCH-immunopositive cell bodies were not detected in the striatum of wild-type and homozygous mice.

However, such intrinsic TH-positive cells were also observed in the striatum of rats with 6-hydroxydopamine lesions 39 and monkeys treated with 1-methylphenyl-1,2,3,6-tetrahydropyridine a dopaminergic neurotoxin that induces parkinsonism 40 , and these cells were reported to be increased in number after the treatment. In the latter case, the cells were reported to be doubly positive when stained with anti-TH and anti-DA transporter antibodies, and they were further reactive with anti-glutamate decarboxylase GAD 67 antibodies.

The role of prefrontal catecholamines in attention and working memory

The fact that catecholaminergic, serotonergic, and NO systems were differently affected by BH4 starvation was clearly shown by our results. In the catecholaminergic system, depletion of BH4 resulted in a reduced level of TH protein accompanied by reduced TH activity at nerve terminals. A reduction in TH immunoreactivity was observed in the striatum and sympathetic nerve terminals, whereas cell bodies of catecholaminergic neurons in the substantia nigra, ventral tegmental area, and locus ceruleus, as well as adrenomedullary cells, were well stained with the anti-TH antibody.

In the serotonergic system, however, TPH activity was not affected by the severe reduction in the BH4 level. These differences were clearly reflected by responses to acute BH4 administration. In the Ptps knockout mice, the 5HT content in the brain was dramatically increased 60 min after the administration, although the DA content was only slightly elevated. These differences were also observed to a lesser extent even in normal animals, which could synthesize BH4 Fig. The BH4 concentration in the cell had been thought to be not high enough to saturate TH However, our results showed that acute administration of BH4 to the wild-type mice was not effective to increase the DA content in the brain, although the biopterin content in the brain was elevated up to 7-fold of that of the vehicle-injected mice Fig.

Instead, BH4 depletion caused a reduction in the content of TH protein. These findings suggest that BH4 regulates the catecholamine synthesis through altering the amount of TH molecules, especially at nerve terminals. We showed previously that human TH shows regulatory kinetic properties for BH4 Flatmark et al. On the other hand, TH has been reported to make a stable and inactive complex with catechol compounds An alternative possibility is that TH is carried to the terminals with or without BH4.

TH protein and mRNA levels are normal in neural cell bodies because that is where the protein is synthesized. A shortened half-life would only be revealed at nerve terminals where TH accumulates. We observed an additional immunoreactive band of small molecular size in the brain homogenate of Ptps -null mutants by Western blot analysis data not shown , which could represent degraded TH protein. Although more study is required to clarify the molecular mechanism, these data strongly suggest that the turnover of TH protein is very rapid in the absence of the biopterin cofactor.

A similar reduction in the level of TH protein only in the striatum was shown also in patients with DRD Segawa's disease. DRD is caused by disturbed BH4 synthesis Autopsied brains of patients with the disease showed a marked reduction in the content of TH protein in the striatum 48 , Our present results would explain the reason why only dysfunction of nigrostriatal dopaminergic neurons is apparent, and why serotonergic systems can function properly in the DRD patients. Because of decreased synthesis of BH4, the amount of TH protein carried to the nerve terminal is reduced. At the nerve terminal striatum , although a small amount of BH4 is present there, the ability to synthesize DA is not sufficient due to the decreased number of the TH molecules.

In the case of serotonergic neurons, the stability of the TPH protein is not affected by depletion of BH4. Thus, the number of TPH molecules at the nerve terminal is the same as the normal one, and a sufficient amount of 5HT can be synthesized, although the rate of de novo synthesis of BH4 is partly impaired. The presence of a recycling system powered by dihydropteridine reductase may help to facilitate the monoamine synthesis through re-redox of quinonoid-dihydrobiopterin, which is formed from the reaction with aromatic amino acid hydroxylases, to BH4.

Our results also showed that the reduction in the TH protein level was reversible by supplementation with BH4. This is a novel regulatory mechanism for TH protein by BH4. The low levels of 5HT and DA would be explained by the time after the last injection. There have been several reports describing the dissociation between Th mRNA levels and expression of the enzyme activity 7. For example, a transgenic mouse bearing extra copies of the human TH gene expressed the transgene mRNA in dopaminergic neurons at levels 50 times over that of the endogenous gene.

Despite this increase in the amount of mRNA, TH immunoreactivity and enzyme activity in the striatum were altered by only 2—3-fold A part of the dissociation between Th mRNA and the protein could be explained by the stabilizing effect of the cofactor. In summary, our results showed that the amount of TH protein at the nerve terminal is governed by the intracellular concentration of BH4, that transient elevation in the BH4 content increases the biosynthesis of 5HT but not that of catecholamines, and that a continuous elevated level of BH4 leads to an increase in the catecholamine levels.

We think that this paper opens a new insight into regulation of monoamines by BH4.