Noradrenaline Ratio Research Articles

Norepinephrine modulation of heat dissipation in female rats lacking estrogen.

Postmenopausal hot flushes are caused by lack of estradiol (E2) but their neuroendocrine basis is still poorly understood. Here, we investigated the interrelationship between norepinephrine and hypothalamic neurons, with emphasis on kisspeptin neurons in the arcuate nucleus (ARC), as a regulatory pathway in the vasomotor effects of E2. Ovariectomized (OVX) rats displayed increased tail skin temperature (TST), and this increase was prevented in OVX rats treated with E2 (OVX + E2). Expression of Fos in the hypothalamus and the number of ARC kisspeptin neurons coexpressing Fos were increased in OVX rats. Likewise, brainstem norepinephrine neurons of OVX rats displayed higher Fos immunoreactivity associated with the increase in TST. In the ARC, the density of dopamine-ß-hydroxylase (DBH)-immunoreactive (ir) fibers was not altered by E2 but, importantly, DBH-ir terminals were found in close apposition to kisspeptin cells, revealing norepinephrine inputs to ARC kisspeptin neurons. Intracerebroventricular injection of the α2-adrenergic agonist clonidine (CLO) was used to reduce central norepinephrine release, confirmed by the decreased 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratio in the preoptic area and ARC. Accordingly, CLO treatment in OVX rats reduced ARC Kiss1 mRNA levels and TST to the values of OVX + E2 rats. Conversely, CLO stimulated Kiss1 expression in the anteroventral periventricular nucleus (AVPV) and increased luteinizing hormone secretion. These findings provide evidence that augmented heat dissipation in OVX rats involves the increase in central norepinephrine that modulates hypothalamic areas related to thermoregulation, including ARC kisspeptin neurons. This neuronal network is suppressed by E2 and its imbalance may be implicated in the vasomotor symptoms of postmenopausal hot flushes.

Psychosocial Stress and Age Influence Depression and Anxiety-Related Behavior, Drive Tumor Inflammatory Cytokines and Accelerate Prostate Cancer Growth in Mice.

Prostate cancer (PCa) prevalence is higher in older men and poorer coping with psychosocial stressors effect prognosis. Yet, interactions between age, stress and PCa progression are underexplored. Therefore, we characterized the effects of age and isolation combined with restraint (2 h/day) for 14 days post-tumor inoculation on behavior, tumor growth and host defense in the immunocompetent, orthotopic RM-9 murine PCa model. All mice were tumor inoculated. Isolation/restraint increased sympathetic and hypothalamic-pituitary-adrenal cortical activation, based on elevated serum 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratios and corticosterone levels, respectively. Elevated zero maze testing revealed age-related differences in naïve C57Bl/6 mice, and increased anxiety-like behavior in tumor-bearing mice. In open field testing, old stressed mice were less active throughout the 30-min test than young non-stressed and stressed, and old non-stressed mice, suggesting greater anxiety in old stressed mice. Old (18 month) mice demonstrated more depression-like behavior than young mice with tail suspension testing, without effects of isolation/restraint stress. Old mice developed larger tumors, despite similar tumor expression of tumor vascular endothelial growth factor or transforming growth factor-beta1 across age. Tumor chemokine/cytokine expression, commonly prognostic for poorer outcomes, were uniquely age- and stress-dependent, underscoring the need for PCa research in old animals. Macrophages predominated in RM-9 tumors. Macrophages, and CD4+ and CD4+FoxP3+ T-cell tumor infiltration were greater in young mice than in old mice. Stress increased macrophage infiltration in old mice. Conversely, stress reduced intratumoral CD4+ and CD4+FoxP3+ T-cell numbers in young mice. CD8+ T-cell infiltration was similar across treatment groups. Our findings support that age- and psychological stress interacts to affect PCa outcomes by interfering with neural-immune mechanisms and affecting behavioral responses.

An electrophysiological model of major depression: Relevance to clinical subtyping and pharmacological management

We present a neurochemical model of unipolar major depressive disorder that makes predictions for optimizing pharmacological treatment of this debilitating neuropsychiatric disorder. We suggest that there are two principal electrophysiological subtypes of depression, with the more common one involving a high excitatory/inhibitory (E/I) electrophysiological ratio, and a less common low E/I subtype. The high E/I subtype is paradoxically a variant of previous conceptions of atypical depression, whereas the low E/I subtype is a variant of melancholic depression. We focus on the ratio of norepinephrine (NE) to serotonin (5HT) as primary determinants of E/I ratio, which have opposing effects on mood regulation. We suggest that high NE/5HT (or E/I) ratio depressions should be treated with pharmacological agents that boost 5HT (such as SSRIs) and/or drugs that reduce noradrenergic transmission (such as clonidine, guanfacine, propranolol, prazosin). In contrast, low NE/5HT (or E/I) depressions should be treated with agents that boost NE (such as most tricyclics) and/or drugs that reduce serotonergic transmission. Our model predicts that the rapidly acting antidepressant ketamine (and possibly scopolamine), which has an acutely excitatory electrophysiological profile that may be followed by sustained increased inhibition, should improve the high NE/5HT subtype and worsen the low subtype.

Disorders of Sleep and Aggression Trait in Women Associated: What Underlies Staying “Woke”?

Narcolepsy is a sleep disorder where the patient falls asleep unwillingly. It is thought to be related to hyper functioning central sleep centers in the brain. Sleep apnea is a disorder of breathing disruption during sleep. Genes of the dopamine system have been implicated with high dopamine: norepinephrine ratio. Since dopamine has also been associated with personality traits, the hypothesis we studied herein was that patients with narcolepsy and sleep apnea would score low in catecholamine settings causing aggression trait. We found that narcolepsy and sleep apnea diagnoses showed significantly lower aggression trait using an online test. The conclusion is that narcolepsy and sleep apnea patients are not aggressive in personality, and since aggressiveness is related to sympathetic nervous system activity, this would be predictable given the role of sympathetic nervous system in wakefulness.

Comparison of the potency of phenylephrine and norepinephrine bolus doses used to treat post-spinal hypotension during elective caesarean section

BackgroundPhenylephrine, although considered the vasopressor of choice, can cause reflex bradycardia and a fall in cardiac output. Norepinephrine, due to its direct positive chronotropic and reflex negative chronotropic actions, is expected to overcome this problem. However, limited information about its effective dose for management of post-spinal hypotension, and its potency compared to phenylephrine, is available. MethodsOne hundred consecutive patients who developed post-spinal hypotension were treated with a predetermined dose of either phenylephrine or norepinephrine. Correction of hypotension after one minute was considered ‘success’. The starting dose for the first patient and testing interval (the incremental or decremental dosing) were 100 μg and 10 μg in the phenylephrine group, and 6 μg and 0.5 μg in the norepinephrine group. Doses for subsequent patients were determined by the responses of previous patients according to the Narayana rule for up-down sequential allocation. ED95 and ED50 of phenylephrine and norepinephrine boluses and their potency ratio were calculated. ResultsUsing Probit analysis, ED95 and ED50 values were 43.1 µg (95% CI 39.5 to 65.0 µg) and 33.2 µg (95% CI 5.1 to 37.0 µg) for phenylephrine, and 3.7 µg (95% CI 3.5 to 4.7 µg) and 3.2 µg (95% CI 1.8 to 3.4 µg) for norepinephrine. The relative potency ratio of norepinephrine and phenylephrine was 11.3 (95% CI 8.1 to 16.9). ConclusionBased on the results of this study, norepinephrine is about 11 times more potent than phenylephrine. When used as bolus doses for treatment of hypotension, 100 μg phenylephrine should be approximately equivalent to 9 μg norepinephrine.

Monitoring the Secretory Behavior of the Rat Adrenal Medulla by High-Performance Liquid Chromatography-Based Catecholamine Assay from Slice Supernatants.

Catecholamine (CA) secretion from the adrenal medullary tissue is a key step of the adaptive response triggered by an organism to cope with stress. Whereas molecular and cellular secretory processes have been extensively studied at the single chromaffin cell level, data available for the whole gland level are much scarcer. We tackled this issue in rat by developing an easy to implement experimental strategy combining the adrenal acute slice supernatant collection with a high-performance liquid chromatography-based epinephrine and norepinephrine (NE) assay. This technique affords a convenient method for measuring basal and stimulated CA release from single acute slices, allowing thus to individually address the secretory function of the left and right glands. Our data point that the two glands are equally competent to secrete epinephrine and NE, exhibiting an equivalent epinephrine:NE ratio, both at rest and in response to a cholinergic stimulation. Nicotine is, however, more efficient than acetylcholine to evoke NE release. A pharmacological challenge with hexamethonium, an α3-containing nicotinic acetylcholine receptor antagonist, disclosed that epinephrine- and NE-secreting chromaffin cells distinctly expressed α3 nicotinic receptors, with a dominant contribution in NE cells. As such, beyond the novelty of CA assays from acute slice supernatants, our study contributes at refining the secretory behavior of the rat adrenal medullary tissue, and opens new perspectives for monitoring the release of other hormones and transmitters, especially those involved in the stress response.

Influences of Experimental Air Pollution on Human Sympathetic Nerve Traffic and Norepinephrine Metabolism: A Double Blind, Randomized, Twofold Crossover Study

BackgroundMuch of the evidence linking air pollutant exposure with changes in human cardiovascular autonomic regulation relied on epidemiological studies, exposure estimates, and indirect autonomic nervous system measurements. We tested the hypothesis that in healthy older individuals, experimental exposure to fine particles increases sympathetic nervous system activity and more so with addition of ozone.Material and MethodsEighteen healthy participants (age >50 years) completed all study visits and were included in the final analysis. Participants were exposed to clean air (‘placebo’), ultrafine particles (UFP, 50μg/m3), and combination of UFP+ozone (250 ppb) for 3 hours combined with intermittent bicycle ergometer training in a randomized, three‐period, cross‐over, double‐blind fashion. Three hours following exposure, respiration, ECG, blood pressure, and muscle sympathetic nerve activity (MSNA) were continuously recorded at supine rest, during deep breathing, and during a Valsalva maneuver. Venous blood samples for plasma catecholamine measurements were taken at baseline. Induced sputum was obtained at the end of each study day.ResultsCombined exposure to ozone and UFP but not UFP alone caused a significant increase in sputum neutrophils and circulating leucocytes. We did not detect significant effects on blood pressure or heart rate. Resting MSNA was 47±12 with clean air, 47±14 with UFP, and 45±14 bursts/min with UFP+ozone. Maximum MSNA during Valsalva phase IIb was similar. Yet, with UFP+ozone plasma norepinephrine concentrations were significantly increased with concomitant reduction in the dihydroxyphenylglycol (DHPG)/norepinephrine ratio. Respiratory sinus arrhythmia and Valsalva ratio were unaffected by experimental air pollution.ConclusionExposure to ultrafine particles with or without ozone does not elicit clinically relevant changes in central sympathetic or parasympathetic activity in healthy older subjects. The paradoxical norepinephrine increase with UFP+ozone may be explained by reduced peripheral norepinephrine uptake and metabolism.Support or Funding InformationMM was funded by a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, awarded to JJ: JO 284/8‐1). The German Aerospace Center (DLR) supported JT, KH, and MM (50 WB1117, 50WB1517).

Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease.

Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer's disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered.

MicroRNA-19b associates with Ago2 in the amygdala following chronic stress and regulates the adrenergic receptor beta 1.

Activation of the stress response in the presence of diverse challenges requires numerous adaptive molecular and cellular changes. To identify specific microRNA molecules that are altered following chronic stress, mice were subjected to the chronic social defeat procedure. The amygdala from these mice was collected and a screen for microRNAs that were recruited to the RNA-induced silencing complex and differentially expressed between the stressed and unstressed mice was conducted. One of the microRNAs that were significantly altered was microRNA-19b (miR-19b). Bioinformatics analysis revealed the adrenergic receptor β-1 (Adrb1) as a potential target for this microRNA with multiple conserved seed sites. Consistent with its putative regulation by miR-19b, Adrb1 levels were reduced in the basolateral amygdala (BLA) following chronic stress. In vitro studies using luciferase assays showed a direct effect of miR-19b on Adrb1 levels, which were not evident when miR-19b seed sequences at the Adrb1 transcript were mutated. To assess the role of miR-19b in memory stabilization, previously attributed to BLA-Adrb1, we constructed lentiviruses designed to overexpress or knockdown miR-19b. Interestingly, adult mice injected bilaterally with miR-19b into the BLA showed lower freezing time relative to control in the cue fear conditioning test, and deregulation of noradrenergic circuits, consistent with downregulation of Adrb1 levels. Knockdown of endogenous BLA-miR-19b levels resulted in opposite behavioral and noradrenergic profile with higher freezing time and increase 3-methoxy-4-hydroxyphenylglycol/noradrenaline ratio. These findings suggest a key role for miR-19b in modulating behavioral responses to chronic stress and Adrb1 as an important target of miR-19b in stress-linked brain regions.

Striatal dopamine homeostasis is altered in mice following Roux-en-Y gastric bypass surgery.

Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity. Importantly, weight loss following RYGB is thought to result in part from changes in brain-mediated regulation of appetite and food intake. Dopamine (DA) within the dorsal striatum plays an important role in feeding behavior; we therefore hypothesized that RYGB alters DA homeostasis in this subcortical region. In the current study, obese RYGB-operated mice consumed significantly less of a high-fat diet, weighed less by the end of the study, and exhibited lower adiposity than obese sham-operated mice. Interestingly, both RYGB and caloric restriction (pair feeding) resulted in elevated DA and reduced norepinephrine (NE) tissue levels compared with ad libitum fed sham animals. Consequently, the ratio of NE to DA, a measure of DA turnover, was significantly reduced in both of these groups. The RYGB mice additionally exhibited a significant increase in phosphorylation of tyrosine hydroxylase at position Ser31, a key regulatory site of DA synthesis. This increase was associated with augmented expression of extracellular-signal-regulated kinases ERK1/2, the kinase targeting Ser31. Additionally, RYGB has been shown in animal models and humans to improve insulin sensitivity and glycemic control. Curiously, we noted a significant increase in the expression of insulin receptor-β in RYGB animals in striatum (a glucosensing brain region) compared to sham ad libitum fed mice. These data demonstrate that RYGB surgery is associated with altered monoamine homeostasis at the level of the dorsal striatum, thus providing a critical foundation for future studies exploring central mechanisms of weight loss in RYGB.

Abstract 429: Ambulatory Blood Pressure Dipping is Significantly Related to Night/Day Urinary Norepinephrine Ratio

Absence of the normal 10% reduction of ambulatory blood pressure (ABP) from day to night is associated with morbidity and mortality. The cause of this reduction (or its absence) is not completely understood. We studied excretion of norepinephrine (NE) and epinephrine (EPI) on the same day ABP monitoring was performed in 37 healthy volunteers aged 52±7years, with body mass index (BMI) 25±4 Kg/m 2 , and 24-hour ABP 130±11/82±9 mmHg. Overall SBP decreased from day to night 134±13 to 117±10 mmHg, diastolic blood pressure (DBP) from 86±9 to 72±8 mmHg, and heart rate (HR) from 80±10 to 70±9 beats per minute (bpm). Urinary NE and EPI excretion decreased (p<0.005) from 19±10 to 10±6 μmol/mol creatinine, and from 4±2 to 0.8±0.4 μmol/mol creatinine, respectively. Awake or asleep SBP was not correlated to the corresponding NE excretion (r=-0.2, and 0.19). We defined SBP dippers (n=22) as those with a night/day ratio (NDR) of <0.9. There were no differences in age, gender, BMI, 24-hour ABP, daytime DBP, sleep ABP, daytime or sleep HR, or daytime or overnight NE or EPI excretion. On the other hand awake SBP 129±11 mmHg was lower, p<0.05, and NDR DBP 0.89±0.05, NDR HR 0.90±0.05, and NDR NE 0.66±2.7, were significantly higher p<0.05, in the non-dippers (n=15) , than in dippers 138±17mmHg, 0.81±0.05, 0.86±0.8, 0.49±0.18, respectively. In a stepwise multiple regression analysis model with SBP NDR as the dependent variable, awake SBP, p=0.0008, and NDR NE p=0.03, were significant predictors, whereas age and BMI were excluded from the model. In conclusion although day and night blood pressure and urinary NE are not related, the nocturnal decrease of SBP is closely related to the degree of reduction in sympathetic activity as reflected by urinary NE excretion on the same day.

Spectrophotometric determination of norepinephrine with sodium iodate and determination of its acidity constants

A spectrophotometric method is proposed for the determination of norepinephrine (NE) and its bitartrate salts. The method was based on the development of a red color (λmax = 495 nm) with sodium iodate in aqueous alcoholic medium at pH 5. The color was stable for at least 4 hrs. The molar reacting ratio of NE to sodium iodate was 1:4. A linear relationship was obtained between the absorption intensity and NE concentration in the range of 3.384–37.224 μg/ml with detection limit of 0.067 μg/ml and correlation coefficient of 0.9972. The present work facilitated the determination of the three acidity constants, 7.564 ± 0.02, 9.036 ± 0.034, and 10.761 ± 0.023. The reaction mechanism was also described. The proposed method was successfully applied for the determination of NE in pharmaceutical formulations. Results for analysis of bulk drugs and injections agree with those of official methods.

393 NEUROADRENERGIC DYSFUNCTION ALONG THE DIABETIC CONTINUUM

Background: Neuroadrenergic function in type 2 diabetic (T2D) patients is poorly characterized, particularly in the early stages of disease, before the onset of peripheral neuropathy. We therefore compared sympathetic nervous system (SNS) activity at rest and during a standard oral glucose tolerance test (OGTT) in obese metabolic syndrome (MetS) subjects classified using WHO criteria as glucose intolerant (IGT) or treatment naïve T2D. Design and methods: Untreated subjects (17 IGT, 17 T2D) matched for age (mean 59 ± 1 yr), gender, body mass index (32.4 ± 0.6 kg/m2) and family history of diabetes were studied. We measured muscle sympathetic nerve activity (MSNA) by microneurography, whole-body noradrenaline kinetics by isotope dilution, neuronal noradrenaline re-uptake as the steady state tritiated 3,4-dihydroxyphenylglycol to tritiated noradrenaline ratio (3H-DHPG: 3H-NA), insulin sensitivity by euglycaemic hyperinsulinemic clamp (M/I) and MetS components. Results: T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats, P = 0.05) and arterial noradrenaline levels (264 ± 33 versus 167 ± 16 pg/ml, P = 0.02), lower plasma noadrenaline clearance (by 17%, P = 0.03) and reduced neuronal re-uptake compared with IGT subjects (by 46%, P = 0.04). Moreover, noradrenaline spillover responses to glucose ingestion were significantly blunted in T2D subjects. The M/I value independently predicted whole-body noadrenaline spillover (r = −0.47, P = 0.008), whilst fasting insulin level related to neuronal noradrenaline re-uptake (r = −0.35, P = 0.047). Conclusions: These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness and altered noradrenaline disposition.

Diagnosis of Small Adrenal Pheochromocytomas by Adrenal Venous Sampling with Glucagon Stimulation Test

: Background: Pheochromocytoma develops in 0.1–0.5% of the hypertensive population between the ages of 30–50 years and is classically characterized by either sustained or paroxysmal hypertension, flushing, sweating, palpitations, and severe anxiety.Objectives: To demonstrate the safety and usefulness of bilateral adrenal venous sampling (BAVS) in patients with pheochromocytoma, but with negative imaging resultsPatients and Methods: We used BAVS with glucagon stimulation (1 mg, IV bolus) and measured stimulated fractionated catecholamines (norepinephrine [NE] and epinephrine [EPI]).Results: We performed BAVS with glucagon stimulation on 41 patients who presented with signs and symptoms highly suggestive of the presence of pheochromocytoma, and also had equivocal imaging results. Twenty patients were diagnosed with unilateral pheochromocytoma. The minimum predictive cut-off value for the EPI ratio of affected vs. unaffected sides in diagnosing a unilateral pheochromocytoma was 6.8 (sensitivity; 88.9%, specificity, 87.5%, P = 0.001). The minimum predictive cut-off value for the norepinephrine (NE) ratio of affected vs. unaffected sides was 3.8 (sensitivity; 90%, specificity; 81.2%, P = 0.001). The 2-min post glucagon-stimulated levels of affected versus unaffected adrenals were: EPI; 29,162 ± 8,756 vs. 1,136 ± 546 pg/ml (ratio = 25.7) and NE; 7,156 ± 1,399 vs. 760 ± 228 pg/ml (ratio = 9.4). The EPI:NE ratio on the affected side was significantly higher (4.1 vs. 1.5, P < 0.001). During the follow-up period, patients who did not require post-operative medication were those who had a shorter duration of hypertension (4.8 ± 3 vs. 10 ± 10.8 years).Conclusions: BAVS with glucagon stimulation is a safe and useful approach for early diagnosis of pheochromocytoma.

Increased Adrenaline to Noradrenaline Ratio Is a Superior Indicator of Antemortem Hypothermia Compared with Separate Catecholamine Concentrations

The significance of urinary catecholamines and small gastric mucosal bleedings, Wischnewsky's spots, in postmortem diagnosis of hypothermia deaths was evaluated. Autopsy cases (n=358) were divided into hypothermia, suspected hypothermia, and control groups. The catecholamine levels did not correlate with the length of the postmortem period. The adrenaline to noradrenaline ratio was most effective in detecting hypothermia (68.9% sensitivity, 78.1% specificity). The median adrenaline concentrations were significantly higher in hypothermia than in control groups. The control group containing mostly sudden cardiac deaths with no cold exposure had a noradrenaline level comparable to the hypothermia groups. The sensitivity and specificity of determining Wischnewsky's spots in hypothermia deaths were 63.9% and 88.3%, respectively. The adrenaline to noradrenaline ratio is more suitable in proving antemortem cold stress than either of these independently, and its diagnostic value is comparable to that of Wischnewsky's spots.

Frontal lobes: twin orchestra conductors in cerebral symphony.

The brain has two processors. Left hemisphere functions like a serial processor and right hemisphere like a parallel processor. Though the brain to body ratio in apes and human beings is nearly the same but intellect-wise there is a great difference. It is probably differentiation of two hemispheres in human beings which increase their mental capacity. The control of opposite in both hemispheres may be due to inverted image of eye lenses, representing upside down images in opposite hemispheres and reciprocal control over the threats in the visual field. The cerebral hemispheres are different structurally, functionally and chemically.1 Right hemispheric cortex is thicker than that of left and it has forward protrusion (Yakovlevian torque).2 Cytoarchitecture shows increased number of spindle cells on the right side. Goldberg mentioned that the association fibers in the right hemisphere are longer and have greater speed of processing. In contrast, the left hemisphere consists of short fibers with lower speed of processing. The ratio of noradrenaline and dopamine in both hemispheres also differs.3 Frontal lobes, the expressive and the most humane part of brain is the most recently evolved region, important for cognition flexibility, motivation and control of social and behavioral impulses. Consciousness in animals may be limited to one sense. Dogs are smell conscious. In snakes touch, vision and taste are independent of each other. Human beings are unique having consciousness of SELF and all the senses are linked together and sampled in frontal lobes creating whole body image in relation to atmosphere. Frontal lobes are the twin orchestra conductors in cerebral symphony. These have inhibitory effect over other parts of brain to concentrate or meditate. Frontal lobes work in an economized state at low energy level. It has a braking system for thinking, motor activity and feelings; and regulates emotions. Hippocampalprefrontal cortical circuits are important to working memory. Pre-frontal cortex is used during consciously thinking and holds information to understand, decide, recall and memorize. It integrates different information gathered from different areas of brain into purposeful and planned behavior, anticipating future, making critical judgment and discerns various ideas to fit. It has multimodal association cortex. The heteromodal component is known as granular cortex, whereas the paralimbic component is known as dysgranular cortex.4 It processes information from various sensory modalities and integrated here for memory, perception, and diverse cognitive processes. Pre-frontal cortex is the last cortical area which myelinates in adolescence.5 According to Jacksonian Principle,6 evolution is passage from the simple, the most automatic, towards the complex, the most voluntary or least automatic. Dissolution is the reverse process of evolution which passes from the most complex, the least automatic towards the most simple, and the most automatic. In other words, in disease those parts suffer first and most, which have the highest, the most complex, or those functions that have developed latest. So the frontal lobes are latest and highly complex in the development and the first to be knocked out. Frontal lobes have 3 areas with different functions namely the motor and pre-motor unit, the frontal eye field area and the pre-frontal cortex (PFC). The later is divided into medial frontal cingulated cortex, dorsolateral cortex and the orbital frontal lobe.

Changes of Urine Dihydroxyphenylglycol to Norepinephrine Ratio in Children With Attention-Deficit Hyperactivity Disorder (ADHD) Treated With Atomoxetine

This study investigated changes in the urine dihydroxyphenylglycol to norepinephrine ratio in patients with attention-deficit hyperactivity disorder (ADHD) treated with atomoxetine. The possible relationship with clinical response was also explored. Newly ADHD diagnosed, treatment-naïve children or adolescents were double-blindly randomized (2:1) to atomoxetine (n = 28) or placebo (n = 13). The dihydroxyphenylglycol to norepinephrine ratio decreased in both groups, showing significantly greater changes with atomoxetine than with placebo at week 6 (-42% versus -14%; P = .001), when dosed at 1.2 mg/kg/day, than at week 2 (-20% versus -2%; P = .118) with a dose of 0.5 mg/kg/day. Although the significant dihydroxyphenylglycol to norepinephrine ratio decrease with atomoxetine indicated norepinephrine transporter blockade, no association with ADHD clinical response (ADHD Rating Scale-IV-Parent:Investigator) was found. Therefore, dihydroxyphenylglycol to norepinephrine ratio might be a useful pharmacodynamic/pharmacokinetic biomarker, although not sufficiently sensitive to predict clinical efficacy. It remains a possibility that this ratio might have value to facilitate personalized atomoxetine pharmacotherapy in ADHD patients.

Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas

Acute effects of estrogens on mnemonic processes were examined at the behavioral and neurochemical levels. 17β-estradiol and 17α-estradiol influences on memory consolidation were assessed using object placement (OP) and object recognition (OR) tasks. Subjects received treatment immediately after a sample trial (exploring two novel objects), and memory of objects (OR memory) or location of objects (OP memory) was tested 4 h later. Both isomers of estradiol enhanced memory. For spatial memory, 15 and 20 µg/kg of 17β-estradiol facilitated OP, while lower and higher doses were ineffective. 17α-estradiol had a similar pattern, but a lower dose was effective. When treatment was delayed until 45 min after a sample trial, memory was not enhanced. For non-spatial memory, OR was facilitated at 5 µg/kg of 17β-estradiol and at 1 and 2 µg/kg of 17α-estradiol and, similar to OP, lower and higher doses were ineffective. These data demonstrate that beneficial effects of estrogens are dose, time and task dependent, and the dose–response pattern is an inverted U. Because monoamines are known to have contributions to memory, brains were removed 30 min after treatment for measurements of dopamine (DA), norepinephrine (NE), serotonin (5-HT), and metabolites. Estrogen elevated 5HT, NE metabolite MHPG, turnover ratio of NE to MHPG, and DA metabolite DOPAC levels in the prefrontal cortex, while NE and MHPG were decreased in the hippocampus. Thus, acute estrogens exert rapid effects on memory consolidation and neural function, which suggests that its mnemonic effects may involve activation of membrane associated estrogen receptors and subsequent signaling cascades, and that monoamines may contribute to this process.

Temporal and periovulatory changes in ovarian catecholamines in the catfish Heteropneustes fossilis

A high performance liquid chromatography-fluorescence detection method was employed to demonstrate temporal and periovulatory changes in ovarian catecholamines in the catfish Heteropneustes fossilis. Tyrosine, l-DOPA, dopamine (DA), norepinephrine (NE) and epinephrine showed significant seasonal and diurnal changes during the reproductive cycle. A high concentration of tyrosine was detected, the values increased in day and decreased in night during recrudescence from preparatory to spawning phases. Similarly, l-DOPA increased during the breeding phase giving the day value concentration peak in the spawning phase and the night value peak in the postspawning phase. DA activity or turnover index (calculated as a ratio of DA to 3,4-dihydroxyphenylacetic acid, DOPAC) showed a bimodal pattern with the major activity peak in the postspawning phase and the minor one in the prespawning phase, the spawning phase registered the lowest activity. NE activity or turnover index (ratio of NE to normetanephrine, NME) increased during the recrudescent phase to give the peak in the spawning phase and decreased in the quiescent phase. Epinephrine elicited an inverse relationship in the day–night pattern, the day values increased to the peak in the spawning phase. All the study correlates showed significant periovulatory changes after hCG treatment. DA activity dropped to the nadir at 8 h but recovered at 16 and 24 h. NE activity showed only a marginal decrease up to 16 h but decreased drastically at 24 h. Epinephrine levels remained unchanged but only to increase at 24 h. The seasonal patterns and periovulatory changes strongly point to important functions for catecholamines in the ovary. The occurrence of tyramine (an invertebrate neurotransmitter) suggests the presence of alternate catecholamine pathway in fish ovary.

Relative Efficiencies of Plasma Catechol Levels and Ratios for Neonatal Diagnosis of Menkes Disease

Menkes disease is an X-linked recessive neurodevelopmental disorder resulting from mutation in a copper-transporting ATPase gene. Menkes disease can be detected by relatively high concentrations of dopamine (DA) and its metabolites compared to norepinephrine (NE) and its metabolites, presumably because dopamine-beta-hydroxylase (DBH) requires copper as a co-factor. The relative diagnostic efficiencies of levels of catechol analytes, alone or in combination, in neonates at genetic risk of Menkes disease have been unknown. Plasma from 44 at-risk neonates less than 30 days old were assayed for DA, NE, and other catechols. Of the 44, 19 were diagnosed subsequently with Menkes disease, and 25 were unaffected. Compared to unaffected at-risk infants, those with Menkes disease had high plasma DA (P < 10(-6)) and low NE (P < 10(-6)) levels. Considered alone, neither DA nor NE levels had perfect sensitivity, whereas the ratio of DA:NE was higher in all affected than in all unaffected subjects (P = 2 x 10(-8)). Analogously, levels of the DA metabolite, dihydroxyphenylacetic acid (DOPAC), and the NE metabolite, dihydroxyphenylglycol (DHPG), were imperfectly sensitive, whereas the DOPAC:DHPG ratio was higher in all affected than in all unaffected subjects (P = 2 x 10(-4)). Plasma dihydroxyphenylalanine (DOPA) and the ratio of epinephrine (EPI):NE levels were higher in affected than in unaffected neonates (P = 0.0015; P = 0.013). Plasma DA:NE and DOPAC:DHPG ratios are remarkably sensitive and specific for diagnosing Menkes disease in at-risk newborns. Affected newborns also have elevated DOPA and EPI:NE ratios, which decreased DBH activity alone cannot explain.