Catecholamines (epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine)

Amine
I. Catecholamines, derived from the amino acid tyrosine, produced by the adrenal glands, which are found on top of the kidneys. are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine. The hormone are released into the blood during times of physical or emotional stress.

1. Catecholamine and dorsolateral prefrontal cortical networks
The symptoms of attention-deficit/hyperactivity disorder (ADHD) involve impairments in prefrontal cortical top-down regulation of attention and behavior. In the study of Catecholamine influences on dorsolateral prefrontal cortical networks, conducted by Yale University School of Medicine, indicated that the stimulant medications and atomoxetine appear to enhance PFC function by indirectly increasing these catecholamine actions through blockade of norepinephrine and/or dopamine transporters. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α(2A)-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD(1).

2. SRY regulation of catecholaminess and The male fight-flight response
According to the study by Brain and Gender, Prince Henry's Institute of Medical Research, The SRY gene, which is located on the Y chromosome and directs male development, may promote aggression and other traditionally male behavioural traits, resulting in the fight-or-flight reaction to stress(2).

3. Caffeine on the levels of brain serotonin and catecholamine
Caffeine, a stimulant, which can prompt lipolysis, has been applied on the therapy of obesity. In the study to measure  The brain neurotransmitters levels and body fat content  At 12-week of age, obese mice and their lean counterparts (+/?) were administered with caffeine (4 mg/d) in water for 4 weeks, showed that the obese mice without caffeine treatment had lower brain norepinephrine and epinephrine levels than the lean controls. And there had no difference between obese and lean mice in brain levels of serotonin, tryptophan, and 5-hydroxyindoleacetic acid. Caffeine treatment showed no effect on the food intake, but decreased the body fat content significantly in obese mice(3).

4. Dietary copper supplementation influences the catecholamine levels
In the study to investigate the effects of dietary Cu supplementation on the catecholamine levels in genetically obese mice, male obese (ob/ob) mice and their lean (+/?) counterparts, with either a control diet (4.0 mg/kg) or a Cu-supplemented diet (50 mg/kg) for 4 wk, researchers at the Taichung Veterans General Hospital, showed that catecholamine levels in ob/ob mice can be increased by dietary Cu supplementation. However, the interaction between Cu and sympathetic nervous activity in obesity was not elucidated in this study(4).

5. The effects of dietary protein source on serotonin and catecholamine synthesis rates
In the study of fed rats single meals, containing one of 5 proteins (zein, wheat gluten, soy protein isolate, casein, lactalbumin, 17% by weight) or no protein, and killed them 2.5 h later, 30 min after the injection of m-hydroxybenzylhydrazine, to allow serotonin and catecholamine synthesis rates to be measured in brain, showed that tryptophan concentrations and serotonin synthesis in brain neurons are remarkably sensitive to which protein is present in a meal. Conceivably, this relationship might inform the brain about the nutritional quality of the protein ingested(5).

6. The role of glucose, oxygen and epinephrine resuscitation
In the study of Cholinergic alterations and its further complications in learning and memory due to hypoxic insult in neonatal rats and the effect of glucose, oxygen and epinephrine resuscitation, showed that the reduction in acetylcholine metabolism is indicated by the down regulated choline acetyltransferase and up regulated acetylcholine esterase expression. These cholinergic disturbances were reversed to near control in glucose resuscitated hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration are also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia(6).

7. Endocrine regulation of neonatal hypoxia
In the study to assess and focus on changes in insulin and triiodothyronine concentration in serum, its receptors in the hearts of hypoxic neonatal rats and glucose, oxygen, and epinephrine resuscitated groups, found that the insulin concentration was significantly increased with a significant upregulation of receptors in hypoxic neonates. Triiodothyronine content and its receptors were significantly decreased in serum and the hearts of hypoxic neonates. The change in hormonal levels is an adaptive modification of the endocrine system to encounter the stress. The effectiveness of glucose resuscitation to hypoxic neonates was also reported(7).

8. Enhanced brain stem 5HT₂A receptor function under neonatal hypoxic insult
Molecular processes regulating brain stem serotonergic receptors play an important role in the control of respiration. In the study to evaluate the 5-HT(2A) receptor alterations in the brain stem of neonatal rats exposed to hypoxic insult and the effect of glucose, oxygen, and epinephrine resuscitation in ameliorating these alterations, found that Hypoxic stress increased the total 5-HT and 5-HT(2A) receptor number along with an up regulation of 5-HT Transporter and 5-HT(2A) receptor gene in the brain stem of neonates. These serotonergic alterations were reversed by glucose supplementation alone and along with oxygen to hypoxic neonates. The enhanced brain stem 5-HT(2A) receptors act as a modulator of ventilatory response to hypoxia, which can in turn result in pulmonary vasoconstriction and cognitive dysfunction. The adverse effects of 100% oxygenation and epinephrine administration to hypoxic neonates were also reported(8).

9. Catecholamine-releasing action in guinea-pig papillary muscles
In the study to  investigate wheather tetraethylammonium ion (TEA) prolongs the action potential (AP) was examined by standard microelectrode techniques in papillary muscles isolated from nonreserpinized and reserpinized guinea-pig hearts, showed that TEA modifies its intrinsic prolonging action of the AP by releasing norepinephrine from sympathetic nerve terminals; TEA prolongs the AP by reducing the time-independent outward current rather than the time-dependent outward current; and a TEA-sensitive current does not effectively contribute to the total ionic current at the time of Vmax(9).

10. The Effects of hypertension on cardiovascular responses to epinephrine
Cardiac beta-receptor responsiveness is diminished by both aging and hypertension. In the study to evaluate of14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women by echocardiography cardiac responses to intravenous infusion of epinephrine and to assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall respons, found that Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects(10).

11. Epinephrine, vasodilation and hemoconcentration in syncopal, healthy men and women
In the study to evaluate why healthy young people may become syncopal during standing, head up tilt (HUT) or lower body negative pressure (LBNP by measuring the hormonal indices of autonomic activity along with arterial pressure (AP), heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and measures of plasma volume, found that the presyncopal decline in blood pressure in otherwise healthy young people resulted from declining peripheral resistance associated with plateauing norepinephrine and plasma renin activity, rising epinephrine and rising blood viscosity. The increased hemoconcentration probably reflects increased rate of venous pooling rather than rate of plasma filtration and, together with cardiovascular effects of imbalances in norepinephrine, epinephrine and plasma renin activity may provide afferent information leading to syncope(11).

12. Adrenal glands and the activation of glucogenesis during undernutrition
In adults, the adrenal glands are essential for the metabolic response to stress, but little is known about their role in fetal metabolism. In the study to investigate the effects of adrenalectomizing fetal sheep on glucose and oxygen metabolism in utero in fed conditions and after maternal fasting for 48 h near term, showed that the circulating concentrations of cortisol and total catecholamines, and the hepatic glycogen content and activities of key gluconeogenic enzymes, were also less in AX than intact fetuses in fasted animals. Insulin concentrations were also lower in AX than intact fetuses in both nutritional states. Maternal glucose utilization and its distribution between the fetal, uteroplacental, and nonuterine maternal tissues were unaffected by fetal AX in both nutritional states. Ovine fetal adrenal glands, therefore, have little effect on basal rates of fetal glucose and oxygen metabolism but are essential for activating fetal glucogenesis in response to maternal fasting. They may also be involved in regulating insulin sensitivity in utero(12).

13. Catecholamine concentrations in hyperthyroidism and hypothyroidism
In the study to measure the plasma epinephrine (E) and norepinephrine (NE) concentrations in patients with thyroid dysfunction, showed that hyperthyroidism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possible in an attempt to compensate for the lack of thyroid hormones(13).



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(8) http://www.ncbi.nlm.nih.gov/pubmed/21484469
(9) http://www.ncbi.nlm.nih.gov/pubmed/3785438
(10) http://www.ncbi.nlm.nih.gov/pubmed/17307999
(11) http://www.ncbi.nlm.nih.gov/pubmed/11695710
(12) http://www.ncbi.nlm.nih.gov/pubmed/20959526
(13) http://www.ncbi.nlm.nih.gov/pubmed/958003

A. Epinephrine
1. Epinephrine and thyroidism
In the study of measurement of the secretion rate of epinephrine in 6 euthyroid, 6 hyperthyroid, and 6 hypothyroid subjects infused at a constant rate for a one hour period with tritiated epinephrine (.01 muc/kg/min) (New England Nuclear Inc.), found that plasma secretion rates averaged 48 +/- 27 mug/kg/day in normal subjects, compared to 54 +/- 18 mu/kg/day in hyperthyroidism and 43 +/- 20 mug/kg/day in hypothyroidism. Likewise, the mean urinary secretion rate was 55 +/- 27 mug/kg/day in normal subjects compared to 60 +/- 22 mug/kg/day in hyperthyroidism and 50 +/- 28 mug/kg/day in hypothyroidism. There is no statistical difference between the values found in the three groups of subjects (plasma and urine). Therefore, these results would indicate that the signs and symptoms encountered in hyperthyroidism are not secondary to a high secretion rate of epinephrine(1).

2. Epinephrine-containing local anesthesia and cardiovascular disease
In the study to examine the safety of epinephrine-containing local anesthesia for use on patients with cardiovascular diseasein twenty-seven patients with cardiovascular disease, showed that Systolic blood pressure and heart rate increased by 4.1% and 5.1%, respectively, immediately after the lidocaine-epinephrine injection. Consequently, rate pressure product increased by 10.0%. Cardiac index increased by 14.2%, and total peripheral resistance decreased by approximately 10%. No patient complained of cardiac symptoms. There were no significant differences in hemodynamic responses related to the extent of the cardiac functional capacity(2).

3. Propranolol administration epinephrine-stimulated SSRBC adhesion in Sickle red blood cells (SSRBCs)  patients
Sickle red blood cells (SSRBCs) adhere to both endothelial cells (ECs) and the extracellular matrix. In the study to investigate whether systemically administered propranolol inhibits SSRBC adhesion and to document the safety of propranolol in SCD, indicated that Propranolol administration significantly reduced epinephrine-stimulated SSRBC adhesion in a dose dependent manner (p = 0.03), with maximum inhibition achieved at 40 mg. Adverse events were not severe, did not show dose dependence, and were likely unrelated to drug. No significant heart rate changes occurred. These results imply that β-blockers may have a role as antiadhesive therapy for SCD(3).

4. Hormone Epinephrine and sickle cell disease (SCD).
The possible role of physiologic stress hormones in enhancing adhesion of sickle erythrocytes (SS RBCs) to endothelial cells (ECs) in sickle cell disease (SCD). In the study of Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions, found that up-regulation of intracellular cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) by epinephrine significantly increased sickle but not normal erythrocyte adhesion to both primary and immortalized ECs. Inhibition of serine/threonine phosphatases also enhanced sickle erythrocyte adhesion at least partially through a PKA-dependent mechanism. Adhesion was mediated through LW (intercellular adhesion molecule-4 [ICAM-4], CD242) blood group glycoprotein, and immunoprecipitation studies showed that LW on sickle but not on normal erythrocytes undergoes increased PKA-dependent serine phosphorylation as a result of activation(4).

5. Low dose of intravenous (IV) epinephrine and monomorphic ventricular tachycardia (VT) in the setting of coronary artery disease
There is a report of three cases of sustained monomorphic ventricular tachycardia (VT) in the setting of coronary artery disease, resistant to beta-blockers in two patients and to amiodarone in all, successfully terminated by low doses of intravenous (IV) epinephrine. VT was the first manifestation of coronary artery disease in one patient, whereas the other two patients had a previous history of myocardial infarction and were recipients of an implantable cardioverter-defibrillator (ICD). One of these two patients experienced an arrhythmic storm. All had hemodynamic instability at the time of epinephrine administration(5).

6. Vitamin C and epinephrine
Vitamin C has several well-established roles in physiology including synthesis of collagen, carnitine and epinephrine, absorption of dietary iron, and mobilization of storage iron for erythropoeisis. Loss of several of these functions explains the pathology of scurvy, where defective collagen synthesis and anemia are major symptoms. Vitamin C deficiency is very common in dialysis patients and may arise from dialytic vitamin C clearance, restricted intake of vitamin C-rich foods, and increased vitamin C catabolism in vivo from inflammation. In the dialysis population, greater vitamin C intake may be needed for optimal health(6).

7. Epinephrine and cardiac arrest
Epinephrine is widely used in cardiopulmonary resuscitation for out-of-hospital cardiac arrest (OHCA). In the study to evaluate the association between epinephrine use before hospital arrival and short- and long-term mortality in patients with cardiac arrest, researchers at the Department of Health Services Management and Policy, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, showed that among patients with OHCA in Japan, use of prehospital epinephrine was significantly associated with increased chance of return of spontaneous circulation before hospital arrival but decreased chance of survival and good functional outcomes 1 month after the event(7).

8. Epinephrine in the treatment of anaphylaxis
In the study to review recent literature that impacts the use of epinephrine in the therapy of anaphylaxis, found that the intramuscular route of administration for epinephrine is superior has now been recognized by the guidelines, and because the site of choice has been found to be the lateral aspect of the thigh, the needle used for injection must be long enough to penetrate the vastus lateralis muscle and  outdated EpiPens can usually be administered safely, and alternative routes of administration, which may be more acceptable to patients, may be on the horizon as a result of preliminary studies assessing the administration of sublingual epinephrine by wafer(8).

9. Local infiltration of epinephrine-containing lidocaine with bicarbonate reduces superficial bleeding and pain
In the study to determine whether skin infiltration with epinephrine-containing rather than plain lidocaine reduces superficial bleeding after catheter placement and whether adding epinephrine and/or sodium bicarbonate affected infiltration pain, showed that Local infiltration of epinephrine-containing lidocaine before epidural catheter insertion reduces superficial bleeding and the addition of bicarbonate decreases pain during skin infiltration(9).

10. Epinephrine and bronchospasm
there is a report of a 18-year-old female was admitted to hospital for an axillary abscess incision on a public holiday. The patient had a history of asthmatic episodes and an allergy to milk protein and 2 years previously an asthmatic attack had possibly been treated by mechanical ventilation. Retrospectively, this event turned out to be a cardiac arrest with mechanical ventilation for 24 h. During induction of anesthesia the patient suddenly developed massive bronchospasms and ventilation was impossible for minutes. Oxygen saturation fell below 80% over a period of 12 min with a lowest measurement of 13%. The patient was treated with epinephrine, prednisolone, antihistamine drugs, ß(2)-agonists, s-ketamine and methylxanthines and 15 min later the oxygen saturation returned to normal values, accoridng to the study by Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin(10).

11. Epinephrine and Hypoglycemia
In the study of thirty-four subjects with type 1 diabetes (14 women, 20 men; 37 ± 2.1 years old; glycosylated hemoglobin [HbA1c], 7.6  ±  0.21%) performed self-monitoring of blood glucose (SMBG) for a month, followed by an inpatient hyperinsulinemic euglycemic and hypoglycemic clamp, showed that higher insulin sensitivity and lower epinephrine response during hypoglycemia are related to increased glucose variability (as quantified by the ADRR), irrespective of HbA1c and other patient characteristics. Lower epinephrine relates to risk for hypoglycemia as well(11). other study in determination of  whether real-time continuous glucose monitoring (CGM) with preset alarms at specific glucose levels would prove a useful tool to achieve avoidance of hypoglycemia and improve the counterregulatory response to hypoglycemia in adolescents with type 1 diabetes with hypoglycemia unawareness, indicated that a greater epinephrine response during hypoglycemia suggests that real-time CGM is a useful clinical tool to improve hypoglycemia unawareness in adolescents with type 1 diabetes(12).

13. Epinephrine and Asthma
In a double-blind study to compare the safety and efficacy of 0.1-, 0.3- and 0.5-mg doses of epinephrine hydrochloride in the initial treatment of an acute asthma attack, as epinephrine hydrochloride 1:1000 was injected subcutaneously in 45 emergency room patients suffering from an acute asthma attack, found that Arterial blood gases, heart rate and blood pressure were not significantly different for the three groups (p > 0.05) and suggested that a 0.5-mg subcantaneous dose represents optimal epinephrine dosing for the initial therapy of acute asthma(13). Other study indicated that Intravenous epinephrine is a potentially safe vital therapy for patients with life-threatening asthma(14).

14. Epinephrine and laryngotracheitis (croup)
Aerosolized racemic epinephrine, but not L-epinephrine, is commonly used in treating croup. In the study to compare the efficacy and adverse effects of nebulized racemic and L-epinephrine in the treatment of laryngotracheitis, found that patients in both groups showed significant transient reduction of the croup score and respiratory rate following the aerosol (P less than .001), but there were no differences between treatment groups when croup score, heart rate, blood pressure, and respiratory rate over time and concluded that L-epinephrine is at least as effective as racemic epinephrine in the treatment of laryngotracheitis and does not carry the risk of additional adverse effects. L-Epinephrine is also more readily available worldwide, is less expensive, and can be recommended for this purpose(15).

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(12) http://www.ncbi.nlm.nih.gov/pubmed/20929999
(13) http://www.ncbi.nlm.nih.gov/pubmed/7424927
(14) http://www.ncbi.nlm.nih.gov/pubmed/12712039
(15) http://www.ncbi.nlm.nih.gov/pubmed/1734400


B. Norepinephrine
1. Catecholamine metabolism in thyroid disease
In the same measuredment of the secretion rate of norepinephrine (NE) in 6 euthyroid subjects, 6 hyperthyroid and 6 hypothyroid patients, infused at a constant rate (0.1 microC/kg/min) for 1 h with tritiated norepinephrine (New England Nuclear Inc.), showed that the plasma NE secretion rate is normal in hyperthyroidism, and is significantly elevated in hypothyroidism thereby explaining the higher plasma NE concentrations seen in hypothyroidism(1).

2. High-dose norepinephrine treatment in critically ill patients
Critically ill patients with circulatory shock sometimes need rescue treatment with high doses of norepinephrine, a treatment that may be associated with a poor outcome because of excessive vasoconstriction. In a retrospective study to evaluate the outcome of treatment and its determinants in patients with circulatory shock who received high doses of norepinephrine in the intensive care unit and to identify indicators of futility for the treatment of 113 consecutive patients with circulatory shock who received 0.9 μg/kg per minute or greater of norepinephrine during at least 1 hour at any time in the intensive care unit, found that dose, and duration of norepinephrine administration did not have prognostic significance. Scores greater than 40 on the Acute Physiology and Chronic Health Evaluation II, bicarbonate levels less than 9.0 mEq/L, or receipt of an epinephrine dose of 0.25 μg/kg per minute or greater were associated with 100% mortality and concluded that although the cause of shock and treatment with norepinephrine were not predictive of death when high doses of the drug were deemed necessary, rescue treatment with high-dose norepinephrine is futile in patients with severe disease and metabolic acidemia(2).

3. Norepinephrine in Regulation of the Fear Network by Mediators of Stress
In the study of neural modulators, especially those activated during stress, such as norepinephrine (NE), regulate synaptic transmission and plasticity in the network, found that Norepinephrine (NE) inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased toward the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance toward the faster but more primitive subcortical input(3).

4. Norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET
In a human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), found that The highest density of norepinephrine transporter (NET) was found in the MBR where the LC is located, followed by THL, whereas the lowest density was found in basal ganglia (lowest in CDT), consistent with the regional localization of NETs in the nonhuman primate brain. While all three doses of ATX were found to block most regions, no significant differences between doses were found for any region, although the average percent change across subjects of the MBR did correlate with ATX dose(4).

5. Atomoxetine and attention-deficit/hyperactivity disorder (ADHD)
Atomoxetine is a potent and selective norepinephrine transporter (NET) reuptake inhibitor acting as a nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). In the study to determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2 in nonhuman primate brain, found that after administration of atomoxetine, a dose-dependent occupancy from 38 to 82% was observed for various brain regions known to contain high densities of NET(5).

6. Norepinephrine and Cingulum
The midline and intralaminar thalamic nuclei (MITN), locus coeruleus (LC) and cingulate cortex contain nociceptive neurons. The MITN that project to cingulate cortex have a prominent innervation by norepinephrinergic axons primarily originating from the LC. Researchers at the Cingulum NeuroSciences Institute and SUNY Upstate Medical University,, found that  the LC may regulate nociceptive processing in the thalamus. The well established role of cingulate cortex in premotor functions and the projections of Pf and other MITN to the limbic striatum suggests a specific role in mediating motor outflow for the LC-innervated nuclei of the MITN(6).

7. Dopamine and the norepinephrine transporter
In the testing of the hypothesis that the norepinephrine transporter (NET) is involved in dopamine clearance in the hippocampus, found that  there is very little DAT in this area using ligand binding with radiolabelled RTI-55. Moreover, in contrast to raclopride (100 μM), a dopamine D2-autoreceptor antagonist, local administration of the α2-adrenoceptor antagonist idazoxan (100 μM) increased hippocampal dopamine. Taken together, our data demonstrate an interaction between dopamine and norepinephrine systems in the hippocampus. It is proposed that this interaction originates from a shared uptake mechanism at the NET level(7).

8. Norepinephrine stimulate the release of corticotropin-releasing factor-41 from the rat hypothalamus?
In the study the effects of the two putative neurotransmitters acetylcholine and norepinephrine on immunoreactive CRF-41 release from incubated rat hypothalami, found that there is an evidence for a stimulatory role of acetylcholine and norepinephrine on CRF-41 release, and consequently on hypothalamo-pituitary-adrenal axis in the rat, through actions at a hypothalamic level. The stimulatory effect of acetylcholine is mediated principally through muscarinic receptors and that of norepinephrine through beta-adrenoceptors(8).

9. Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex
In the study to examine the relationship between discharge rates of locus coeruleus noradrenergic neurons and rates of norepinephrine release, found that  In general, neither activation nor suppression of locus coeruleus neuronal discharge rates appeared to alter the relationship between discharge activity and norepinephrine efflux during subsequent epochs. The one exception to this was observed during recovery from relatively high-magnitude locus coeruleus activation. In two out of three cases in which locus coeruleus discharge rates were increased greater than 450%, a recovery of norepinephrine concentrations to basal levels occurred more quickly than the recovery of locus coeruleus neuronal discharge rates to basal levels. Although limited, these latter observations suggest that dysregulation of norepinephrine release may occur following sustained activation of locus coeruleus at the highest rates examined, which may mimic those associated with intense arousal or stress.(9).

10. Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord
. The activation of descending norepinephrine-containing fibers from the brain stem inhibits nociceptive transmission at the spinal level.In the study to evaluate  the descending noradrenergic pathways exert the analgesic effect, found that norepinephrine enhances inhibitory synaptic transmission in the substantia gelatinosa through activation of presynaptic alpha1 receptors, thus providing a mechanism underlying the clinical use of alpha1 agonists with local anesthetics in spinal anesthesia(10).

11. Olanzapine and dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum
The in vivo effects of olanzapine on the extracellular monoamine levels in rat prefrontal cortex (Pfc), nucleus accumbens (Acb) and striatum (Cpu) were investigated by means of microdialysis. In the study of the effect of Sequential doses of olanzapine at 0.5, 3 and 10 mg/kg (s.c.) dose-dependently in the extracellular dopamine (DA) and norepinephrine (NE) levels in all three brain areas, found that in the case of sequential dosing olanzapine more effectively enhances DA and NE release in the Pfc than in the subcortical areas, which may have an impact on its atypical antipsychotic actions(11).

12. Actions of norepinephrine in the cerebral cortex and thalamus
Norepinephrine (NE) has potent and long-lasting ionic effects on cortical and thalamic neurons. In the study by Yale University School of Medicine, indicated that  In cortical pyramidal cells, activation of beta-adrenergic receptors results in an enhanced excitability and responsiveness to depolarizing inputs. This enhanced excitability is expressed as a reduction in spike frequency adaptation and is mediated by a marked suppression of a slow Ca(++)-activated potassium current known as IAHP. In the thalamus, application of NE results in the suppression of ongoing rhythmic burst activity and a switch to the single spike firing mode of action potential generation. This effect is mediated through an alpha 1-adrenergic suppression of a resting leak potassium current, IKL, and through a beta-adrenoceptor-mediated enhancement of the hyperpolarization activated cation current Ih(12).

13. Peripheral hormone epinephrine (EPI) and brainstem nuclei
The peripheral hormone epinephrine (EPI) is known to modulate memory for arousing experiences. In the study to test the hypothesis of the actions of EPI on the LC suggest that its mnemonic properties may also be mediated by influencing NE output in the HIPP, dialysate levels of NE were collected from the HIPP of male rats given an i.p. injection of saline that was followed 100 min later by i.p. EPI (0.3 mg/kg). NE levels sampled 20 min after EPI injection were significantly larger than baseline and continued to show significant peaks for 60 min found that the mnemonic effects of EPI reported in a wide range of learning conditions may not be mediated solely by NE release in the amygdala, but may also involve coactivation of the HIPP NE system, according to the study by The University of Virginia(13).

14. Norepinephrine and Cerebellum
Presynaptic modulation of synaptic transmission is the primary function of central nicotinic acetylcholine receptors (nAChRs) in developing and adult brain. nAChR activation regulates release of various neurotransmitters, including norepinephrine (NA). In the study of to determine whether nAChRs modulate NA release in developing cerebellum. In vitro experiments using cerebellar slices examined the effects of nAChR stimulation on release of radiolabeled NA ([3H]NA), showed that these data support recent findings of a possible functional role of nAChRs in regulating cerebellar ontogeny, and provides further support for the role of NA as a neurotrophic factor during development(14).


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C. Dopamine
1. Acetylcholine-dopamine and CNS disorders
The substantia nigra pars compacta and ventral tegmental area of midbrain dopaminergic nuclei and their respective forebrain and cortical target areas are well established as serving a critical role in mediating voluntary motor control, as evidenced in Parkinson's disease, and incentive-motivated behaviors and cognitive functions, as exhibited in drug addiction and schizophrenia, respectively. According to the study by The University of Memphis, acetylcholine may be as important in regulating dopaminergic transmission. Midbrain dopaminergic cell tonic and phasic activity is closely dependent upon projections from hindbrain pedunculopontine and the laterodorsal tegmental nuclei, which comprises the only known cholinergic inputs to these neurons(1). Other study indicated that combinatorial signaling through dopamine and serotonin (DA and 5-HT) receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS(1a).

2. The effects of Dopamine and dobutamine on heart rate
In the study of twenty patients with symptomatic CHF (systolic dysfunction) were enrolled. After recording one-hour baseline electrocardiographs (ECGs), patients were randomly selected for either dopamine (4 micrograms/kg/minute, Group A) or dobutamine (4 micrograms/kg/minute, Group B) treatment for three days, conducted by Taichung Veterans General Hospital, found that Dopamine and dobutamine have comparable therapeutic effects in patients with CHF, but low-dose dopamine more favorably affects cardiac autonomic function(2).

3. Dopamine and blood pressure and cerebral hemodynamics
In a Standard meta-analytic techniques, including random and fixed effects models used to calculate combined effect size correlations and significance levels showed that Dopamine administration increases mean and systolic blood pressure in hypotensive preterm infants, and is more effective than dobutamine, colloid or hydrocortisone alone. Dopamine administration is associated with increased CBF, with greater increases in CBF in hypotensive than in normotensive preterm infants. Dopamine is not associated with a greater incidence of adverse effects than other therapies used to treat hypotension(3).

4. Dopamine in schizophrenia and Parkinson's disease
The neurotransmitter dopamine (DA) and the dopaminergic neurones play an important role in schizophrenia and Parkinson's disease (PD). According to the study byUniversity of Southampton, Royal South Hants Hospital, A decrease in DA in the substantia nigra of the brain has been implicated as the cause of PD. By contrast, it is argued that a functional excess of DA or oversensitivity of certain DA receptors is one of the causal factors in schizophrenia(4).

5. Dopamine and Attention deficit hyperactivity disorder
Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). According to the study by University of Cambridge, Cambridge, United Kingdom, Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified(5).

6.  Dopamine  and restless legs syndrome
Restless legs syndrome (RLS) is a common neurological disorder causing considerable impairment to daily living. In a study to assess the reporting quality of published RCTs according to the Consolidated Standards of Reporting Trials (CONSORT) statement and to synthesize the study results in terms of efficacy and tolerability to inform the clinical management of RLS, showed that
DAs were significantly more efficacious in the treatment of RLS compared with placebo(6).

7. Dopamine  receptors and cognitive and motor function
According to the study by, Columbia University College of Physicians & Surgeons, repeated administration of this methamphetamine (5 mg/kg administered three times at 2-h intervals) leads to a transition from horizontal hyperlocomotion to excessive orofacial stereotypy (taffy pulling) only in wild type and D3 mutants. In both genotypes, this transition is accompanied by a change in the relative ratios of striatal neuronal activation in two neurochemically distinct compartments, with striosomal neuronal activation exceeding that of the striatal matrix during stereotypy. Both the stereotypic response to METH and the associated predominant activation of neurons located in striosomes require D2-receptor expression. These studies indicate a differential requirement for D1- and D2-like receptor activation in mediating the effects of METH on cognitive and motor function(7). Other indicated that the 'D3 Dopamine Receptor Hypothesis' suggests D3 antagonists could prevent sensitization, and may interrupt the development of psychosis when administered during the prodromal phase of psychotic illness(7a).

8.  Dopaminergic neurotransmission and behavioral changes
Dehydration is a powerful stimulus causing disequilibrium in homeostasis of water and electrolytes resulting from depletion in total body water. In the study of desert animals allows improved understanding about water balance and resistance to dehydration and associated behavioral changes, including those related to voluntary movements, showed that dehydration is able to increase dopaminergic neurotransmission, which might be involved in generating hyperactivity in this desert animal(8).

9. Dopamine and motivation
Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. According to the mice study by Consejo Nacional de Investigaciones Científicas y Técnicas, midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine(9).

10. Dopimine in punishment and reward
In the study of Variations of extracellular dopamine (DA(ext)) levels in prefrontal cortex were assessed by in vivo microdialysis, found that a benzodiazepine-sensitive activation of mesoprefrontal DA neurones is induced by exposure to novel stressful surroundings and by food availability and consumption. The fact that cortical DA(ext) levels remained unchanged in rats that exerted complete control upon negative stimuli indicates that an activation of the mesoprefrontal DA system is not required for punishment-induced behavioural blockade(10).

11. Dopamine and the inhibition of prolactin production
Transcription of the prolactin gene is dynamically controlled by positive and negative hormone signals that target the regulatory promoter region. According to the study by University of Toronto, dopamine D2 receptor activation and inhibition of MAPK (ERK1/2) signaling lead to rapid deacetylation of histones at the genomic prolactin promoter. Recruitment of specific HDAC/ corepressor complexes may be an important mechanism for repression of target gene transcription by Gi/o-coupled receptors(11).

12. Dopamine and sleep behaviour disorder (IRBD)
 In a prospective study, 20 patients with IRBD (mean age 70·55 years [SD 6·02]) underwent serial DAT imaging with (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ((123)I-FP-CIT) SPECT at baseline and again after 1·5 years and 3 years; 20 age-matched and sex-matched control participants (69·50 years [6·77]) underwent imaging at baseline and 3 years, showed that in patients with  sleep behaviour disorder (IRBD), serial (123)I-FP-CIT SPECT shows decline in striatal tracer uptake that reflects progressive nigrostriatal dopaminergic dysfunction. Serial (123)I-FP-CIT SPECT can be used to monitor the progression of nigrostriatal deficits in patients with IRBD, and could be useful in studies of potential disease-modifying compounds in these patients(12).

13. Dopamine in depression
According to the study by New York State Psychiatric Institute, clinical evidence includes alterations in depressive symptoms with aging (concomitant with possible changes in dopamine metabolism), potential dopaminergic involvement in several subtypes of depression, similarities between some of the symptoms of Parkinson's disease and those of depression (including psychomotor retardation and diminished motivation), and potential dopaminergic abnormalities in seasonal mood disorder. The biochemical evidence in patients with depression derives from studies of homovanillic acid, a dopamine metabolite, indicating diminished dopamine turnover(13).

14. Dopamine and Mood disorder
Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). According to the study by University of Amsterdam,  monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed(14).

15. Dopamine in the regulation of cognition and attention
Dopamine (DA) acts as a key neurotransmitter in the brain.. In the early stages of Parkinson's disease (PD), alterations of executive functions also suggest a role for DA in regulating cognitive functions. Some other diseases, which can also involve DA dysfunction, such as schizophrenia or attention deficit hyperactivity disorder (ADHD) in children, as shown from the ameliorative action of dopaminergic antagonists and agonists, respectively, also show alteration of cognitive functions. According to the study by Université de La Méditerranée, a correlation exists between DA innervation and expression of cognitive capacities. Altering the dopaminergic transmission could, therefore, contribute to cognitive impairment(15).

16. Dopamine and working memory
There is accumulating evidence that training working memory (WM) leads to beneficial effects in tasks that were not trained. According to the study by Department of Neuroscience and Stockholm Brain Institute, Karolinska Institutet, variation in the dopamine transporter gene (DAT1) influences improvements in WM and fluid intelligence in preschool-age children following cognitive training. Our results emphasize the importance of the role of dopamine in determining cognitive plasticity(16).

17. Dopamine and learning
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. According to the University of Michigan in rat study, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control(17).

18. Dopamine on cellular and humoral immune responses
In vitro and in vivo studies have demonstrated that apart from its hemodynamic action dopamine can modulate immune responses. According to the study by Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum, dopamine reduces the synthesis of proinflammatory and induces the synthesis of anti-inflammatory mediators. Dopamine inhibits neurohormone synthesis, lymphocyte proliferation and platelet aggregation. It reduces the phagocytic activity of neutrophils and induces apoptosis. Particularly with regard to sepsis, where high serum dopamine levels are reached by enhanced endogenous production, exogenous application and impaired clearance, this immunomodulation may have a clinical impact(18).

19. Dopamine and Salience
What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? According to the study by University of Michigan,  instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for 'wanting' incentives, but not for 'liking' them or for learning new 'likes' and 'dislikes'(19).

20. Dopamine and human idea generation and creative drive
According to the study of FRONTOTEMPORAL AND DOPAMINERGIC CONTROL OF IDEA GENERATION AND CREATIVE DRIVE by Alice W. Flaherty , mesolimbic dopamine influences novelty seeking and creative drive. Dopamine agonists and antagonists have opposite effects on goal-directed behavior and hallucinations. Creative drive is not identical to skill—the latter depends more on neocortical association areas. However, drive correlates better with successful creative output than skill does(20).

21. Dopamine and  natriuresis (sodium loss) in the kidneys
Diuretic and natriuretic effects of renal dopamine (DA) are well established. In the study of male Wistar rats to determine the pattern of UDAV during volume expansion and to characterize the involvement of monoamine-oxidase (MAO) and aromatic amino-acid decarboxylase (AADC) , found that in C rats UDAV (ng/30 min/100g BWt) increased in the first 30 min expansion from 11.5 +/- 1.20 to 21.8 +/- 3.10 (p < 0.05) and decreased thereafter. IMAO showed a similar pattern but significantly higher than C at 30 min expansion (32.5 +/- 2.20, p < 0.05). IMAO greatly reduced MAO activity from 8.29 +/- 0.35 to 1.1 +/- 0.03 nmol/mg tissue/hour and significantly increased diuresis and natriuresis over controls. BNZ abolished the early UDAV peak to 3.2+/-0.72 (p < 0.01) and though, UDAV increased over C after 60 min expansion, natriuresis and diuresis were diminished by BNZ treatment. Results indicate that an increment in renal DA release into urine occurs early in expansion and in a peak-shaped way.(21).

22. Dopamine and obesity
According to the study by Institute for Translational Medicine and Therapeutics, University of Pennsylvania, chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior(22).

23. Dopamine and noradrenaline on cardiovascular function
In the study to assess the short-term haemodynamic effects of terminating dopamine and/or a combination of noradrenaline and nitroglycerin infusions in 21 patients in acute respiratory failure, found that off treatment, stroke index and cardiac index decreased significantly from 40.2 to 36.9 ml m-2 (P < 0.02) and from 3.80 to 3.42 litres m-2 (P < 0.02), respectively. Cardiac filling pressures decreased significantly and systemic vascular resistance increased, when infusions were stopped. As to heart rate, mean arterial pressure, mean pulmonary arterial pressure, right and left ventricular ejection fraction there were no significant changes between the data obtained during and off treatment. Although the haemodynamic status was significantly better during treatment with dopamine and/or noradrenaline-nitroglycerin in some respects, the overall beneficial effects of inotropic support were much less than anticipated(23).

24. Dopamine and Immunoregulatory
The neurotransmitter dopamine (DA) is an important molecule bridging the nervous and immune systems. According to the study by the Ohio State University, Columbus, DA through autocrine/paracrine manner modulates the functions of immune effector cells by acting through its receptors present in these cells. DA also has unique and opposite effects on T cell functions. Although DA activates naïve or resting T cells, but it inhibits activated T cells. In addition, changes in the expression of DA receptors and their signaling pathways especially in T cells are associated with altered immune functions in disorders like schizophrenia and Parkinson's disease. These results suggest an immunoregulatory role of DA(24).

25. Dopamine toxicity
Parkinson's disease (PD) is a common age-related neurodegenerative disorder. Dopamine neurotoxicity, mediated through oxidative stress, is implicated in disease pathogenesis. According to the study of using 6-hydroxydopamine hemiparkinsonian mouse model and transgenic DJ-1 knockout mice by the Felsenstein Medical Research Centre, Tel Aviv University, our experimental data point to a novel potential protective function of DJ-1, which could be used as a therapeutic tool(25).

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