Objective: To establish reference intervals for urinary excretion of biogenic amines from birth to adulthood.  Design and methods: 865 outpatients were categorized into nine groups ranging from birthday to 25 years. Free catecholamines, total metanephrines, vanillylmandelic and homovanillic acids were determined in urine samples by HPLC with amperometric detection.  Results: The ratio of each analyte-to-creatinine declined gradually from birth to 15–18 years reaching adults values. No difference was observed by sex except a lower excretion of epinephrine and metanephrine in girls than in boys below 1 year.  Conclusion: Our data provide age-appropriate reference ranges for the diagnosis of tumors from neural crest in children.

11.  S. Winterkamp, M.D., M. Weidenhiller, M.D., P. Otte, M.D., J. Stolper, M.D., D. Schwab, M.D.  Urinary Excretion of N-Methylhistamine as a Marker of Disease Activity in Inflammatory Bowel Disease.  The American Journal of Gastroenterology, Vol. 97, (12): 3071–3077, 2002.

OBJECTIVE: Mast cells are thought to participate in the pathogenesis of inflammatory bowel disease (IBD). In this study, urinary excretion of N-methylhistamine (UMH), a stable metabolite of the mast cell mediator histamine, was evaluated as an indicator of disease activity in patients with IBD. Urinary excretion of UMH was found to be significantly elevated in IBD. Patients with active Crohn’s disease (7.1 _ 4.2, p _ 0.002 vs controls) and active ulcerative colitis (8.1 _ 4.8, p _ 0.02 vs controls) had higher rates of UMH excretion than patients in remission (6.3 _ 3.8 and 5.2 _ 2.3, respectively) or controls (4.6 _1.9). In Crohn’s disease and ulcerative colitis, a significant correlation of UMH excretion with clinical disease activity was obtained (Crohn’s Disease Activity Index r2 _ 0.58, Clinical Activity Index r2 _ 0.57, p _ 0.0001). Serologically, orosomucoid showed the best positive correlation with disease activity (Crohn’s Disease Activity Index r2 _ 0.80, Clinical Activity Index r2 _ 0.86, p _ 0.0001), but UMH excretion was found to reflect disease activity more accurately than C-reactive protein (Crohn’s Disease Activity Index r2 _ 0.46, Clinical Activity Index r2 _ 0.42, p _ 0.0001). No association between UMH excretion and disease type or localization could be found in Crohn’s disease. However, UMH excretion correlated strongly with endoscopic severity of inflammation in Crohn’s disease (Crohn’s Disease Endoscopic Index of Severity r2 _ 0.70, p _ 0.0001) or disease extent in ulcerative colitis. CONCLUSIONS: Urinary excretion of the histamine metabolite UMH is enhanced in IBD. It appears to represent an integrative parameter to monitor clinical and endoscopic disease activity in IBD, which appears to be influenced most likely by mediators released from histamine-containing cells, such as intestinal mast cell subtypes.

12. Rouveix, M.; Duclos, M.; Gouarne, C.; Beauvieux, M.C. The 24 h Urinary Cortisol/Cortisone Ratio and Epinephrine/Norepinephrine Ratio for Monitoring Training in Young Female Tennis Players.Int J Sports Med, 27: 856-863, 2005.

The effect of training variations on the 24 h urinary cortisol/cortisone (C/Cn) ratio and the epinephrine/norepinephrine (E/NE) ratio in relation with mood (evaluated using the Brunel Mood Scale: BRUMS) and performance was investigated in seven trained young female tennis players (12.8 ± 1.7 years). Like the proposed model in adults, the monitoring of hormonal and mood parameters could be a useful index in training follow-up in young sportswomen. Assessment of nutritional intake, nitrogen excretion rate and nitrogen balance were also determined to measure the dietary practice of these athletes. Nitrogen balance was calculated from the mean daily protein intake and the urinary nitrogen excretion. Data were collected after a 1-month rest (September, T1), 3 months after T1 (after technical and endurance training: December, T2) and 7 months after T1 (after 4 months of increasing-volume/high-intensity training: March, T3). A significant increase in C/Cn ratio (+ 30%, p < 0.05) were noted from T1 to T3. In the same time, urinary NE concentrations decreased significantly. The E/NE ratio increased from T1 to T2 and decreased at T3 (T1 vs. T3: – 30%, p < 0.05). The BRUMS inventory at T3 reflected changes in specific mood states with a significant increase in fatigue and anger scores, while vigor scores decreased significantly compared to T1. This period also corresponded with the lowest percentage of matches won and with the highest training load. Energy intake was about 16% lower than the French recommendations for girls of the same age. However, a positive nitrogen balance was observed from a mean intake of 1.0 g·kg–1 ·day–1.  Our results reveal that an increase of overnight urinary C/Cn ratio and a decrease of E/NE ratio  are concomitant with alterations in mood state and performance, all these parameters being associated with physical and psychological stress.

13.  Ayelet B. Snow, A. Khalyfa, Laura D. Serpero, O. Capdevila, Jinkwan Kim, M.O. Buazza, and David Gozal.  Catecholamine Alterations in Pediatric Obstructive Sleep Apnea: Effect of Obesity.  Pediatric Pulmonology, 44: 559-567, 2009. 

Summary. Study Objectives: Obstructive sleep apnea (OSA) elicits increased sympathetic activity in adults and increased urinary catecholamines. Moreover, urinary catecholamine excretion is altered in obese patients. We hypothesized that morning urine catecholamine levels would be correlated with the severity of obstructive sleep apnea and degree of obesity in children. Methods:Children referred to the pediatric sleep center for habitual snoring underwent overnight polysomnography, and the first morning voided urine sample was collected. Urinary concentrations of norepinephrine, epinephrine and dopamine were measured and corrected for creatinine levels.  In a subset of children, blood sampleswere drawn and gene expression of catecholamine-relevant genes analyzed by quantitative real-time PCR. Results: One hundred fifty-nine children were recruited and completed the protocol. Children with OSA had significantly higher urinary norepinephrine and epinephrine levels, but not dopamine, compared to habitual snorers (norepinephrine: 40.1_24.7 ng/mg creatinine vs. 31.6_16.2 ng/mg creatinine, P<0.01; epinephrine: 6.4_10.5 ng/mg vs. 4.5_0.5 ng/mg, P<0.01). There was a positive correlation between norepinephrine and epinephrine values and polysomnographic indices, but no effect of obesity on catecholamine levels. In addition, expression of several of the major genes involved in synthesis and transport of catecholamines, as well as in selected receptors were compatible with increased bioavailability of catecholamines.  Conclusions: In children with OSA, morning urinary norepinephrine and epinephrine levels are significantly higher than those without OSA, and correlate with the severity of the disease. Gene expression patterns are in agreement with such findings. Urine catecholamine levels do not appear to be influenced by the presence of obesity. Thus, altered sympathetic activity in OSA patients appears to occur independently of the presence of obesity.

14. G. De Pergola1, F. Giorgino, Ritanna Benigno1, Pietro Guida1 and Riccardo Giorgino.  Independent Influence of Insulin, Catecholamines, and Thyroid Hormones on Metabolic Syndrome.  Obesity (16), 2405–2411, 2008.

The objective of this study was to examine whether metabolic syndrome, defined according to adult treatment panel III criteria, is associated with insulin, catecholamines, and thyroid hormones, independently of age and gender. A cohort of 651 euthyroid overweight and obese patients, 440 women and 211 men, aged 18–68 years, were examined. Central fat accumulation (indirectly measured by waist circumference), fasting thyroid-stimulating hormone (TSH), FT3, FT4, insulin, glucose, and lipid (cholesterol, HDL-cholesterol, and triglyceride) serum concentrations, 24-h urinary catecholamines, and the level of insulin resistance (estimated by homeostasis model assessment for insulin resistance (HOMAIR)) were measured. Patients with metabolic syndrome showed higher insulin (P < 0.001) and FT3 (P < 0.001) serum levels and higher 24-h urinary noradrenaline (P < 0.001) than subjects without this syndrome. The number of metabolic syndrome parameters was directly associated with insulin (P < 0.001) and FT3 (P < 0.05) serum levels, and with 24-h urinary noradrenaline (P < 0.001) in the whole population. When a multiple regression analysis was performed with the metabolic syndrome as the dependent variable, and age, gender, and insulin, and TSH, FT3, FT4 serum levels, and 24-h urinary noradrenaline and adrenaline as independent variables, the metabolic syndrome maintained an independent positive association with age (P < 0.001), male sex (P < 0.001), insulin (P < 0.001), and 24-h urinary noradrenaline (P < 0.001). In conclusion, this study suggests that insulin and noradrenaline cooperate independently to the development of the metabolic syndrome.

15.  A. Elmasry, E. Lindberg, J. Hedner, C. Janson, G. Boman.  Obstructive sleep apnoea and urine catecholamines in hypertensive males: a population-based study.  Eur Respir J, (19): 511–517, 2002.

>ABSTRACT: Studies addressing the relationship between obstructive sleep apnoea (OSA) and sympathoadrenal activity have been criticized for poor control of factors known to confound sympathetic function, including hypertension. The aim of this study was to investigate the relationship between OSA and urinary catecholamines in a population-based sample of hypertensive males.  In 1994, 2,668 males aged 40–79 yrs answered a questionnaire regarding sleep disorders and somatic diseases. Of those who reported hypertension, an age-stratified sample of 116 was selected for monitoring of breathing during sleep and overnight urine analysis.Subjects with OSA, defined as apnoea-hypopnoea index ¢10?h-1, had higher concentrations of urinary normetanephrine (182¡57 versus 141¡45 mmol?mol-1 creatinine, pv0.001) and metanephrine (70¡28 versus 61¡28 mmol?mol-1 creatinine, pv0.05) in comparison to subjects without OSA. In a multiple regression analysis, there was an association between variables of sleep-disordered breathing and normetanephrine and metanephrine concentrations, independent of major confounding factors. The authors concluded that, in a population-based sample of hypertensive males, obstructive sleep apnoea is associated with increased urinary concentrations of extraneuronal metabolites of catecholamines independent of major confounding factors, suggesting increased sympathoadrenal activity. Elevated sympathoadrenal activity may explain the increased cardiovascular morbidity associated with obstructive sleep apnoea.

16.  Whiting, M J.  Simultaneous measurement of urinary metanephrines and catecholamines by liquid chromatography with tandem mass spectrometric detection.  Ann Clin Biochem. Volume: 46, (2): 129-36, 2009.

The measurement of catecholamines and metanephrines in urine is an important diagnostic test in biochemical screening for phaeochromocytoma. Tandem mass spectrometry (MSMS) has the potential to be used in a profiling method for simultaneous assay of these analytes. METHODS: Optimal conditions were established for the MSMS detection of catecholamines (noradrenalin, adrenalin and dopamine) and metanephrines (normetanephrine and metanephrine), including commercially available isotopically labelled compounds for use as internal standards. Chromatographic separation of all five polar biogenic amines was achieved under solvent conditions that were compatible with MSMS and multiple reaction monitoring. Several types of solid-phase extraction cartridge were used to investigate clean-up conditions for urine, and acid-hydrolysates of urine, prior to LC-MSMS. RESULTS: Total catecholamines and metanephrines from acid-hydrolysed urines, or free catecholamines and free metanephrines from native urines, were complexed with diphenyl-boronate and recovered in high yield from polymer cartridges after elution with formic acid. Direct injection of eluates into the LC-MSMS system allowed quantitation of catecholamines and metanephrines with a run time of 6 min per sample.  Biogenic amine concentrations for patient urines and quality assurance programme samples, and assay imprecision, were similar to values obtained with high-performance liquid chromatography methods, which used electrochemical detection. In normal urines, the ratio of free to total catecholamines was around three-fold higher than the ratio of free to total metanephrines. CONCLUSION: The assay of urinary catecholamines and metanephrines can be achieved simultaneously using one LC-MSMS method, which is rapid and reduces labour and consumable costs for routine application.

17. Duhon, A.  The role of excitatory and inhibitory neurotransmitters in fibromyalgia.  Dissertation Abstracts Inter. Vol. 68, no. 01, suppl. B, p. 101, 2007.

While the etiological roots of fibromyalgia syndrome remain a mystery, numerous studies have pointed to an imbalance in the neurotransmitter system. An imbalance between excitatory and inhibitory neurotransmission can manifest itself in both physiological and psychological symptomology. This study examined the role of neurotransmitter imbalances and suggests a possible neurochemical relationship between anxiety, fibromyalgia and to a lesser extent depression. Urinalysis was used to measure neurotransmitter levels from 10 women between the ages of 25-75, all with a clinical diagnosis of fibromyalgia. Anxiety, depression, and fibromyalgia status were assessed using the Beck Anxiety Inventory, Beck Depression Inventory-II, and the Fibromyalgia Impact Questionnaire respectively. Descriptive statistics and Pearson r were computed to examine the data. Findings indicated a pattern of neurotransmitter imbalances among subjects. One hundred percent of subjects displayed deficiencies in both serotonin and epinephrine. There was also a positive relationship between FIQ scores and BAI scores, and between BAI scores and neurotransmitter levels. No relationship was found between FIQ scores and BDI scores, or between FIQ scores and neurotransmitter levels. Clinical implications and suggestions for future research are discussed.

18.  Sharma, A M.; Schorr, U; Thiede, H M; Distler, A.  Effect of dietary salt restriction on urinary serotonin and 5-hydroxyindoleacetic acid excretion in man.  Journal of Hypertension. 11(12):1381-1386, 1993.

Objective: To determine the effect of dietary salt restriction on urinary excretion of serotonin and its principal metabolite 5-hydroxyindoleacetic acid (5-HIAA) in man.  Design: We studied 16 healthy male volunteers (age range 20-28 years) who ate a standard diet containing 20mmol/day NaCl, to which either 220mmol/day NaCl or placebo was added as a supplement for 1 week each, according to a randomized, single-blind crossover design.  Methods: Urinary excretion of serotonin, 5-HIAA, noradrenaline and vanillylmandelic acid (VMA) were measured during the low- and high-salt periods using reverse-phase high-performance liquid chromatography.  Results: During the low-salt diet, 24-h urinary excretion of serotonin increased by 42%, accompanied by a 52% rise in the excretion of 5-HIAA. Salt restriction also increased noradrenaline excretion by 77% and VMA excretion by 40%. Regression analysis revealed a strong positive relationship between the excretion of serotonin and of noradrenaline (r=0.84, P< 0.001) and between that of 5-HIAA and of VMA (r=0.74, P< 0.001).  Conclusions: Salt restriction stimulates the serotonergic system in man. Stimulation of this system, in conjunction with the sympathetic nervous system, may contribute to renal sodium conservation during dietary salt restriction in man.

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The following is a review of medications that are often prescribed for conditions such as depression, anxiety, insomnia, ADD/ADHD, as well as Parkinson's Disease. Their biological action, specifically, their theorized mechanism of action on particular neurotransmitter networks is listed below.

Neurotransmitters play a major role in influencing our emotions, thoughts, memory, ability to handle stress, sleep cycle, and every function that affects our daily lives.  Neurotransmitters play a vital role in our mental, emotional, and physical health.  The following is a review of the basic role neurotransmitters play as chemical messengers.

Neurotransmitters are the chemical messengers whose function is to transmit nerve signals, or impulses, from one nerve cell to another. A neurotransmitter can either "excite" a neighboring nerve cell thereby increasing its activity, or it can "inhibit" an nearby nerve cellthus decreasing its activity.  Consequently, neurotransmitters are generally classified as being excitatory or inhibitory.  They are released from the presynaptic neuron, pass across the synapse, and activate receptors on the postsynaptic membrane of the next neuron in order to propagate the signal throughout the body.  The activity of each nerve cell, or neuron, greatly depends on the balance between the number of excitatory and inhibitory signals received, as they occur simultaneously. It is thus imperative that a "balance" between inhibitory and excitatory neurotransmission is maintained.

A shift in the balance between excitatory and inhibitory neurotransmission can significantly impact the way we feel.  For example, a deficiency in the inhibitory (calming) neurotransmitters, such as serotonin and GABA, can affect our ability to cope with daily stress, to fall or stay asleep, or to stay in a good mood.  A lack of excitatory neurotransmitters such as Dopamine, Norepinephrine, Epinephrine, or Glutamate can result in mental or physical fatigue, or can manifest as a decrease in memory, concentration, focus, and motivation.  Excessive excitatory neurotransmission can result in irritability, restlessness, agitation, and insomnia.

Several factors affect the biochemical structure of the brian at the neuronal level.  Our genetic code, which we inherited from our parents, governs the neurotransmitter regulation mechanisms. Other factors, such as stress and anxiety levels, will have a dynamic effect on the brain, constantly shifting the balance of our neurotransmitters. Everytime we have a new experience, memory, or experience stress or disease, our brain changes due to a phenomenon known as neuronal plasticity.  Throughout our lives, our neurotransmitter composition will vary depending on the intake and metabolism of amino acids in our diet.  From a nutritional standpoint, there are some amino acids that serve as precursors to the various neurotransmitters, and increasing the consumption of these protein building blocks can increase the synthesis of the respective neurotransmitter.  For example, 5-HTP (5-hydroxytryptophan) is the direct precursor molecule of serotonin, and can be used as a supplement to help control excessive excitatory activity by boosting serotonin production in the brain to help control excessive excitatory activity.  Magnesium is an essential mineral known as "nature's tranquilizer", and provides a calming effect by blocking the binding of Glutamate (the brain's main excitatory neurotransmitter) to its receptor, thereby inhibiting the stimulatory effect.

GABA (Gamma-amino butyric acid)

GABA is one of the brain's main inhibitory neurotransmitters, and provides an opposing effect to the brain's primary excitatory neurotransmitter, glutamate.  GABA and glutamate coordinate with each other to balance the overall level of excitation in the brain.  Many of the drugs that have been used to control anxiety exert their effect by mediating GABA receptor function.  Within the body, a number of steroid metabolites (progesterone and allopregnanolone) that have a high affinity for GABA receptors are produced, inducing a sedative-like reaction.  Plasma and brain concentrations of allopregnanolone increase dramatically during the third trimester of pregnancy, followed by a rapid reduction in the post-partum period.  For example, benzodiazepines  (Xanax/alprazolam) provide their anxiolytic, anti-convulsant, muscle-relaxant, and sedative properties by affecting GABA (A) receptor function.  Alcohol has also been shown to modulate GABA receptor function, also.

GLUTAMATE

Glutamate, or glutamic acid, is the primary excitatory neurotransmitter within the central nervous system, and plays a major role in learning and memory. The glutamate system is involved in activating synaptic transmission, which is imperative for maintaining proper neuronal plasticity, as well as cognitive function. A number of glutamic acid receptors are involved in glutaminergic transmission. This includes N-methyl-D-aspartate (NMDA), kainic acid (KA), and amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA).  Maintaining balance within the Glutaminergic system is crucial in maintaining health and avoiding disease.  A slight imbalance or over-activity of this excitatory system can lead to symptoms such as an increase in anxiety, agitation, compulsive thoughts, depression,and insomnia.  Severe imbalances in this system can lead to  excitotoxic-mediated neuronal injury resulting in neurodegenerative diseases including memory loss, Alzheimer's disease, Huntington's disease, epilepsy and seizure disorders.  Children suffering from excessive glutamate levels are in danger of forming early-adulthood mental illnesses.  Several nutritional therapies can help prevent excessive glutaminergic activity.  One measure includes consuming foods that are high in anti-oxidants, such as colorful fruits and vegetables.  Amino acid therapy that boosts the inhibitory system, such as taurine and 5-HTP (5-hyroxy-tryptophan), can help reduce excessive activity.  Another example is magnesium, which antagonizes the binding of glutamate to NMDA receptors resulting in less excitatory response.

SEROTONIN

Serotonin is the master neurotransmitter. When serotonin is out of range depression, anxiety, orry, obsessive thoughts and behaviors carbohydrate cravings, PMS, difficulty with pain control, and sleep cycle disturbances can result. Additionally, patient may experience pain when serotonin levels are abnormal.  Occasionally, none of these symptoms will occur when serotonin is low; the patient may simply present as lethargic.  Adequate amounts of serotonin are needed for a stable mood, and to balance any excessive excitatory (stimulatory) signaling in the brain.  Stimulant medications or caffeine in the daily regimen can cause a depletion of serotonin over time.

DOPAMINE

Dopamine is our focus neurotransmitter. When dopamine is not in the proper ratio relative to serotonin, there are typically issues with the person’s ability to focus and memory, such as forgetting where we put our keys or daydreaming. Dopamine is involved in the reward center of our brain, and depleted levels can lead to emotional "doldrums", lack of motivation, extreme behavior, and addictive disorders. Stimulants such as medications for ADD or drugs such as marijuana and cocaine can cause an elevation in the excretion of dopamine. Unfortunately, stimulating dopamine consistently can cause a depletion of dopamine over time.

NOREPINEPHRINE

Norepinephrine is an excitatory neurotransmitter that is responsible for stimulatory processes in the body. Concentration and focus are affected when the body’s sympathetic nervous system is activated by norepinephrine and epinephrine.  Elevated norepinephrine excretion levels may result in "mood dampening" effects or result in impulsive thoughts and actions, extreme fatigue, and anxiety/nervousness. The patient may appear as being withdrawn or introverted, with signs including increased heart rate, hypertension, and increased production of epinephrine.  Low levels of norepinephrine can result in low energy, depression, and decreased ability to focus.

EPINEPHRINE

Epinephrine is converted from norepinephrine, and is an excitatory neurotransmitter involved in the body’s “fight or flight” response.  This neurotransmitter regulates brain function, metabolism, heart rate, and blood pressure.  Elevated levels of epinephrine are associated with hyperactivity, anxiety, and low adrenal function.  With lower than normal levels of epinephrine, the patient may experience decreased energy, fatigue, depression, insufficient cortisol production, chronic stress, burnout, poor recovery from illness, dizziness upon standing, and persistent adrenal stimulation.  Long-term over-stimulation of the adrenal glands can cause epinephrine stores to be depleted, resulting in low energy and weight gain.

HISTAMINE

Histamine is an excitatory neurotransmitter that helps to control our sleep-wake cycle. Elevated excretion values of histamine are typically associated with allergic reactions and inflammation, and may be an indicator of reduced energy production and adrenal dysfunction.  Low levels are associated with circadian rhythm disruption, adrenal deficiency, and lethargy.

 

Tobacco Nicotine facilitates the release of several neurotransmitters including Dopamine (addiction), Norepinephrine (socially outgoing), GABA (calming), Glutamate (effects on Cognition), and Serotonin (relaxing properties. Caffeine Decreases GABA activity while increasing Glutamate activity.  Caffeine can bind to adenosine receptors, a bi-product of ATP production. Adenosine accumulation throughout the day caused drowsiness by slowing down nerve cell activity, thus promoting sleep.  Although caffeine is able to bind to adenosine-receptors, it produces wakefulness (rather than drowsiness) by causing cells to increase their activity. Alcohol Alcohol's effects on the CNS are similar to benzodiazepenes and barbituates in that it modulates the activity of GABA (A) receptors. Alcohol decreases excitatory glutamate activity by interacting with Glutamate receptor function (NMDA receptors). Opiates Opiates bind to different receptors, including the mu opioid receptors subtype.  This binding inhibits the release of GABA from the nerve terminal, reducing the inhibitory effect of GABA on dopaminergic neurons.  The increased activation of dopaminergic (reward pathway) neurons and the release of dopamine into the synaptic results in sustained activation of the post-synaptic membrane.  Continued activation leads to the feelings of euphoria and the ‘high’ associated with opiate use. Cocaine, Amphetamine, and Methamphetamine Cocaine, Amphetamine, and Methamaphetamine affect mesolimbic dopamine activity, which accounts for their highly addictive properties.  These drugs bind to the dopamine transporter and prevent dopamine reuptake into the nerve cell, thereby increasing synaptic dopamine neurotransmission and producing a strong euphoria. Marijuana THC, the main active ingredient in marijuana, binds to and activates cannabinoid receptors.  By mediating the effects of GABA receptors in various parts of the brain, it can affect memory, thought, concentration, time and depth perception, and coordinated movement.