Effect of metabolic control on urinary excretion and plasma levels of catecholamines in diabetics.

Urinary excretion and plasma levels of catecholamines were determined in 20 normal and 39 diabetic subjects to evaluate the sympathetic activity. Diabetic patients were divided into 4 groups according to the metabolic control. Sympathetic activity showed no differences between normal and subjects with chemical diabetes (group I, n = 5). In insulin-treated diabetics in good metabolic control (group II, n = 11) only urinary excretion of free norepinephrine was significantly higher than normals (p less than .05). In insulin-treated diabetics in poor metabolic control (group III, n = 16) urinary excretion and plasma levels of norepinephrine showed a marked increase over groups I and II (p less than .001). In insulin-treated diabetics with ketosis (group IV, n = 7) urinary excretion and plasma levels of both norepinephrine and epinephrine showed the highest values (p less than .001 and less than .1). Finally, in groups III and IV, after achieving improved metabolic control, a significant decrease of urinary excretion and plasma levels of catecholamines was observed. The results confirm that there is an increased rate of catecholamine release in poorly controlled diabeties and suggest a close correlation between sympathetic activity and metabolic derangement in diabetes.     

Simultaneous analysis of human plasma catecholamines by high-performance liquid chromatography with a reversed-phase triacontylsilyl silica column

The clinical importance of simultaneous analysis of 3,4-dihydroxyphenylglycol with other human plasma catecholamines has been investigated to better understand the sympathetic nervous system. However, previous reports have had analytical difficulties with both resolution and extraction. The current study uses a reversed-phase triacontylsilyl silica (C30) column under the mobile phase condition without ion-pair reagents to separate catecholamines and their metabolites, with above 91% recoveries for intra-assay, above 85% for inter-assay, and less than 10% (n=5) coefficient of variation. Lower detection limits (S/N=4) and quantification limits (S/N=6) were 40 and 100 pg/mL for norepinephrine, 3,4-dihydroxyphenylglycol, and 3,4-dihydroxyphenylalanine, 10 and 20 pg/mL for epinephrine, 10 and 40 pg/mL for dopamine. Linear ranges were from 40 to 5000 pg/mL for norepinephrine and 3,4-dihydroxyphenylalanine, from 100 to 5000 pg/mL for 3,4-dihydroxyphenylglycol, and from 10 to 2000 pg/mL for epinephrine and dopamine. The C30 column may prove clinically useful, as it provides a convenient and simultaneous method of evaluation of human plasma catecholamines.     

Adrenomedullary Secretion of DOPA, Catecholamines, Catechol Metabolites, and Neuropeptides

Abstract: Catecholamines and their metabolites have been proposed as markers of sympathetic nervous system stimulation. However, the adrenal medulla is a rich source of catecholamines and catecholamine metabolites and may play a significant role in plasma levels of these compounds. In addition to adrenal catecholamine metabolite efflux, the role of the catecholamine precursor 3,4-dihydroxyphenylalanine (DOPA) has not been fully evaluated. The simultaneous effluxes of catecholamines, metabolites, DOPA, and neuropeptides were measured in perfusates from isolated dog adrenals. The relative abundance of compounds detected consistently during unstimulated conditions was epinephrine ≫ norepinephrine > 3,4-dihydroxyphenylglycol > metanephrine > normetanephrine > dopamine > 3,4-dihydroxyphenylacetic acid > 3-methoxy-4-hydroxyphenylglycol ≥ DOPA ≫ [Met]enkephalin ≫ neuropeptide Y. Effluxes of analytes were not affected by cocaine and the ratios of catecholamines to metabolites increased dramatically with carbachol stimulation, consistent with negligible reuptake into adrenal cells. Thus, most of the 3,4-dihydroxyphenylglycol is expected to be derived from epinephrine and norepinephrine subsequent to translocation from chromaffin vesicles into the cytosol. The efflux of DOPA increased dramatically during stimulation with 30 µ M carbachol in a calcium-dependent manner. Efflux of DOPA during the initial stabilization period of the perfusion preparation declined exponentially, in parallel with the effluxes of the catecholamines and neuropeptides but not with metabolites. Evoked release of DOPA was Ca²⁺-dependent. These data suggest that DOPA can be stored and released exocytotically from chromaffin granules.     

Chromogranin A correlates with norepinephrine release rate.

Chromogranin A (CgA) is an acidic protein co-released with catecholamines during exocytosis from sympathetic nerve terminals and chromaffin cells. Previous work has demonstrated that large scale perturbations in sympathetic nervous system (SNS) functioning result in corresponding changes in CgA levels in plasma. Little is known about the physiologic significance of CgA. We hypothesized that, since CgA and catecholamines are co-released from the same storage vesicles, and since CgA is not subject to reuptake or enzymatic metabolism, plasma CgA should reflect norepinephrine release from sympathetic terminals. We therefore measured venous CgA, norepinephrine levels, and norepinephrine release rate in 30 unmedicated subjects. Although the correlation of CgA with plasma norepinephrine was only modest (r = 0.37, p less than 0.05), its correlation with norepinephrine release rate was highly significant (r = 0.58, p less than 0.001). Thus, CgA may offer a novel perspective on peripheral sympathetic activity.     

Corelease of neuropeptide Y like immunoreactivity with catecholamines from the adrenal gland during splanchnic nerve stimulation in anesthetized dogs

The release of neuropeptide Y like immunoreactivity (NPY-li) from the adrenal gland was studied in relation to the secretion of catecholamines (CA: NE, norepinephrine; E, epinephrine) during the left splanchnic nerve stimulation in thiopental-chloralose anesthetized dogs (n = 16). Plasma concentrations of NE, E, and NPY-li were determined in the left adrenal venous and aortic blood. Adrenal outputs of NPY-li, NE, and E were 2.4 +/- 0.4, 1.4 +/- 0.2, and 7.3 +/- 1.7 ng/min, under basal conditions, respectively. These values increased significantly (p less than 0.05; n = 8) in response to a continuous stepwise stimulation at frequencies of 1, 3, and 10 Hz given at 3-min intervals during 9 min, reaching a maximum output of 4.6 +/- 0.9 (NPY-li), 240.2 +/- 50.2 (NE), and 1412.5 +/- 309.7 ng/min (E) at a frequency of 10 Hz. Burst electrical stimulation at 40 Hz for 1 s at 10-s intervals for a period of 10 min produced similar increases (p less than 0.05) in the release of NPY-li (4.8 +/- 1.0 ng/min, n = 8), NE (283.5 +/- 144.3 ng/min, n = 8), and E (1133.5 +/- 430.6 ng/min, n = 8). Adrenal NPY-li output was significantly correlated with adrenal NE output (r = 0.606; n = 24; p less than 0.05) and adrenal E output (r = 0.640; n = 24; p less than 0.05) in dogs receiving the burst stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in human plasma catecholamines and dopamine-beta-hydroxylase produced by prostaglandin F2 alpha

Clinical research was conducted into the possible interrelationships between prostaglandin (PG) F2alpha and the human sympathetic nervous system. The study also permitted comparison of the relative sensitivity of 2 indicators of sympatho-adrenal activity: 1) the determination of circulating catecholamines, epinephrine and norepinephrine; and 2) analysis of plasma dopamine-8-hydroxylase activity. Intravenous PGF2alpha infusion was administered to college students 12-18 weeks pregnant to produce abortion; the results were compared to results from nonpregnant controls. Circulating norepinephrine but not plasma epinephrine or dopamine-8-hydroxylase levels were increased in response to the PG. There was no correlation between plasma epinephrine and plasma norepinephrine levels. Plasma dopamine-8-hydroxylase activity was found not to be significantly changed by pregnancy, administration of the analgesic and antiemetic, or the PG infusion. In fact, central venous dopamine-8-hydroxylase activity did not differ significantly from that of arterial blood. The PG did not affect cardiac output or maximal expiratory flow rate. It is suggested that the nausea and diarrhea accompanying PGF2alpha infusion may put stress on the sympathetic nervous activity causing the observed increase in plasma norepinephrine concentration. Since no changes in blood pressure, heart rate, central venous pressure, or cardiac output were observed, it is unlikely that PGF2alpha causes even slight impairment of sympathetic nervous system activity.     

Plasma dopamine responses to standing and exercise in man

Increases in plasma concentration of dopamine in response to standing are comparable to those observed for norepinephrine and epinephrine. Also, bicycle exercise to maximum heart rate produced 1.5 to 2.5-fold increases above basal plasma concentrations in each of the three catecholamines. Thus, maneouvres which are associated with increases in sympathetic activity are associated with parallel increases in each of the three catecholamines. However, the origin and significance of plasma dopamine remain unknown.     

Plasma free and sulfoconjugated catecholamine responses to varying exercise intensity

Plasma free catecholamines rise during exercise, but sulfoconjugated catecholamines reportedly fall. This study examined the relationship between exercise intensity and circulating levels of sulfoconjugated norepinephrine, epinephrine, and dopamine. Seven exercise-trained men biked at approximately 30, 60, and 90% of their individual maximal oxygen consumption (VO2max) for 8 min. The 90% VO2max period resulted in significantly increased plasma free norepinephrine (rest, 219 +/- 85; exercise, 2,738 +/- 1,149 pg/ml; P less than or equal to 0.01) and epinephrine (rest, 49 +/- 49; exercise, 555 +/- 516 pg/ml; P less than or equal to 0.05). These changes were accompanied by consistent increases in sulfoconjugated norepinephrine at both the 60% (rest, 852 +/- 292; exercise, 1,431 +/- 639; P less than or equal to 0.05) and 90% (rest, 859 +/- 311; exercise, 2,223 +/- 1,015; P less than or equal to 0.05) VO2max periods. Plasma sulfoconjugated epinephrine and dopamine displayed erratic changes at the three exercise intensities. These findings suggest that sulfoconjugated norepinephrine rises during high-intensity exercise.     

Influence of caffeine on metabolic responses of men at rest in 28 and 5 degrees C

Cold stress and caffeine ingestion are each reported to increase plasma catecholamines, free fatty acid (FFA) concentrations, and energy metabolism. This study examined the possible interaction of these two metabolic challenges in four double-blind counterbalanced trials. Young adult men (n = 6) ingested caffeine (5 mg/kg) or placebo (dextrose, 5 mg/kg) and rested for 2 h in 28 or 5 degrees C air. Cold stress alone elevated (P less than 0.05) plasma norepinephrine, metabolism (O2 consumption, VO2), and respiratory exchange ratio (RER). Caffeine alone increased (P less than 0.05) plasma epinephrine and FFA but not RER. When the two challenges were combined (caffeine plus 5 degrees C for 2 h) norepinephrine and epinephrine were increased (P less than 0.05) as was FFA. However, VO2, RER, and skin and rectal temperatures were not different from the responses observed at 5 degrees C after placebo ingestion. The data suggest that caffeine selectively increases plasma epinephrine, whereas cold air increases norepinephrine. During the cold exposure, increasing epinephrine and FFA above normal levels did not appear to influence the metabolic or thermal responses to the cold stress. In fact the increase in RER suggested a greater carbohydrate oxidation.     

Glucocorticoid suppression of the sympathetic nervous system and adrenal medulla

Studies were performed to evaluate the effects of glucocorticoids on the activity of the sympathetic nervous system and adrenal medulla. Plasma concentrations of norepinephrine and epinephrine were measured in rats in which endogenous glucocorticoids were removed by bilateral adrenalectomy and in rats to which exogenous glucocorticoids were administered. In intact rats, dexamethasone (2.5, 25 or 250 micrograms) pretreatment suppressed ether vapor-induced elevations of norepinephrine and epinephrine concentrations in plasma. Corticosterone (3 mg/kg), similar to dexamethasone, attenuated the elevation of plasma concentrations of norepinephrine and epinephrine in rats exposed to ether vapor. Glucocorticoids did not alter the elevation of plasma catecholamines stimulated by intracerebroventricular injections of corticotropin-releasing factor or calcitonin gene-related peptide, thus demonstrating functional integrity of the sympathetic nervous system and adrenal medulla. Adrenalectomy resulted in elevation of basal plasma norepinephrine levels and accentuation of ether vapor-induced elevations of plasma norepinephrine concentrations in rats. Dexamethasone (25 ug) administration blunted the effects of adrenalectomy on both basal and ether vapor-stimulated levels of plasma norepinephrine. It is concluded that glucocorticoids acting at as yet undefined sites may be involved in the regulation of sympathetic nervous system and adrenal medullary function.     

The protective effect of vagus nerve stimulation on catecholamine-halothane-induced ventricular fibrillation in dogs

Parasympathetic neural activity modulates some ventricular arrhythmias in man. Therefore, a canine model of arrhythmias produced by the interaction of halothane and catecholamines was used to study the effects of vagal stimulation on the induction of ventricular fibrillation. The dose of catecholamine required to induce ventricular fibrillation was determined during a constant heart rate. Vagal stimulation reversibly raised the norepinephrine dose that produced ventricular fibrillation from 16.4 +/- 2.4 to 30.0 +/- 3.8 micrograms (p less than 0.001, n = 10), and the epinephrine dose from 15.5 +/- 2.0 to 22.5 +/- 2.6 micrograms (p less than 0.001, n = 5). Following atropine, vagal stimulation failed to raise the threshold dose of norepinephrine (16.8 +/- 2.4 vs. 18.3 +/- 3.3 micrograms, nonsignificant, n = 6) or epinephrine (15.5 +/- 2.0 vs. 16.0 +/- 2.3 micrograms, nonsignificant, n = 5). Ligation of the cervical vagus nerves did not affect the epinephrine threshold dose (16.3 +/- 3.3 vs. 17.5 +/- 2.7 micrograms, nonsignificant, n = 5). Following elevation of basal vagal tone by morphine premedication, the norepinephrine threshold of 53.0 +/- 9.2 micrograms declined by a nonsignificant amount to 46.5 +/- 11.5 micrograms after vagotomy (nonsignificant, n = 5). Thus resting vagal tone does not prevent catecholamine-halothane-induced ventricular fibrillation, whereas increasing vagal tone by electrical stimulation substantially protects against this arrhythmia. The protection is mediated through a muscarinic cholinergic receptor.     

NPY Y1 receptor is not involved in the hemodynamic response to an acute cold pressor test in mice

The vasoconstrictor neuropeptide Y (NPY) has been shown to down-regulate tyrosine hydroxylase expression in cultured adrenal chromaffin cells, which probably accounts for the higher plasma resting norepinephrine (NE) and epinephrine (E) concentrations observed in Y(1) knock-out mice (Y(1)-/-) than in wild-type mice (Y(1)+/+). The aim of this work was to study the hemodynamic response of Y(1)-/- mice to an acute stimulation of the sympathetic nervous system (cold pressor test, CPT). Plasma catecholamine concentrations were higher in Y(1)-/- mice than in wild-type animals at the end of the CPT. The CPT-induced increase in mean arterial blood pressure (MAP) and heart rate (HR) was similar in both genotypes. Independently of the genotype, females had significantly slower HR than males throughout the 15min duration of the CPT. There was no difference in the sensitivity of the baroreceptor reflex, as reflected by the change in HR divided by the concurrent change in MBP between Y(1)-/- and Y(1)+/+ mice. In conclusion, mice lacking the Y(1) receptor can maintain normal hemodynamic response to an acute activation of the sympathetic system, albeit at the expense of increased catecholamine discharge.     

Influence of sodium intake on circulating levels of neuropeptide Y

Neuropeptide Y (NPY) is present in the adrenal medulla, in sympathetic neurons as well as in the circulation. This peptide not only exerts a direct vasoconstrictor effect, but also potentiates the vasoconstriction evoked by norepinephrine and sympathetic nerve stimulation. The vasconstrictor effect of norepinephrine is also enhanced by salt loading and reduced by salt depletion. The purpose of this study was therefore to assess whether there exists a relationship between dietary sodium intake and the levels of circulating NPY. Uninephrectomized normotensive rats were maintained for 3 weeks either on a low, a regular or a high sodium intake. On the day of the experiment, plasma levels of NPY and catecholamines were measured in the unanesthetized animals. There was no significant difference in plasma norepinephrine and epinephrine levels between the 3 groups of rats. Plasma NPY levels were the lowest (65.4 ± 8.8 fmol/ml, n=10, Mean ± SEM) in salt-restricted and the highest (151.2 ± 25 fmol/ml, n=14, p < 0.02) in salt-loaded animals. Intermediate values were obtained in rats kept on a regular sodium intake (117.6 ± 20.1 fmol/ml). These findings are therefore compatible with the hypothesis that sodium balance might to some extent influence blood pressure regulation via changes in circulating NPY levels which in turn modify blood pressure responsiveness.     

Circadian variations of catecholamines and blood pressure in patients with pseudohypoparathyroidism and hypertension

The relationship between 24-h recumbent blood pressure levels and secretory patterns of catecholamines was investigated in 4 patients with pseudohypoparathyroidism (PsHP) and hypertension and in 9 patients with essential hypertension. A clear circadian rhythm of blood pressure and catecholamines was documented in both groups with lowest levels of blood pressures and catecholamines occurring during sleep. During the 24-h period of recumbency mean arterial blood pressure (MAP) was correlated (r = 0.63, p less than or equal to 0.01) with plasma norepinephrine (N) in the patients with essential hypertension, but this correlation was weaker in patients with PsHP (r = 0.38, p less than or equal to 0.05). MAP was more closely related to plasma epinephrine (E) (r = 0.62, p less than or equal to 0.01) than to plasma NE in patients with PsHP. Plasma NE and E levels were considerably lower in patients with PsHP than in patients with essential hypertension throughout the 24-h recumbent period. The sleep-related decline in blood pressure and NE was less than in patients with essential hypertension. These results suggest that while the sympathetic nervous system may have a role in hour-to-hour maintenance of blood pressure in patients with PsHP and hypertension, it does not appear to be responsible for the elevated arterial pressure in these patients. Factors other than those investigated, such as obesity, alterations in sodium homeostasis of refractoriness of the vascular smooth muscle to the vasodilatory effect of PTH may be involved in the pathogenesis of hypertension in PsHP.     

Inhibition of sympathetic responses at birth in sheep by lesion of the paraventricular nucleus

Birth is characterized by a surge in sympathetic outflow, heart rate (HR), mean arterial blood pressure (MABP) and circulating catecholamines. The paraventricular nucleus (PVN) of the hypothalamus is an important central regulatory site of sympathetic activity, but its role in the regulation of sympathoexcitation at birth is unknown. To test the hypothesis that the PVN regulates sympathetic activity at birth, experiments were performed in chronically instrumented near-term (137- to 142-day gestation, term 145 days) sheep before and after delivery by cesarean section. Stereotaxic guided electrolytic lesioning of the PVN (n = 6) or sham lesioning (n = 6) was performed 48 h before study. At 30 min after birth, renal sympathetic nerve activity (RSNA) increased 128 +/- 26% above fetal values in the sham-lesioned animals (P < 0.05). In contrast, at a similar time point, RSNA decreased to 52 +/- 12% of the fetal value in the PVN-lesioned animals. Lesioning of the PVN did not affect the usual postnatal increases in MABP and epinephrine levels although HR failed to rise above fetal values. ANG II but not arginine vasopressin or norepinephrine levels increased in PVN-lesioned animals after birth, whereas all three hormones increased (P < 0.05) in sham-lesioned animals. Fetal and newborn HR baroreflex responses were similar in both groups. However, the usual postnatal attenuation of baroreflex-mediated inhibition of RSNA was blunted in the PVN-lesioned group. The results of this study demonstrate that ablation of the PVN abolishes sympathoexcitation with birth at near-term gestation. The PVN may play a critical role in physiological adaptation at birth.     

Chemical sympathectomy alters food intake and thermogenic responses to catecholamines in rats

It has been suggested that the sympathetic nervous system contributes to the short-term control of feeding. The adrenergic innervation of some splanchnic organs seems to be especially involved in such processes, since catecholamines reduce feeding only when injected intraperitoneally or intraportally. In this work, the effects of neonatal sympathetic denervation with guanethidine (Gnt) upon food intake were assessed in adult rats. Gnt-treated male rats had lower body weight gain. The hypophagic response to intraperitoneal (ip) norepinephrine was 70% higher in Gnt-treated animals as compared to controls (P < 0.05); that of epinephrine (E) by 33% (P < 0.05) and that of isoproterenol was not significantly modified. As in normal rats, the hypophagic effect was much stronger after ip than after intramuscular (im) administration (P < 0.05). On the other hand, resting oxygen consumption (VO2) was consistently lower in denervated animals. Ip E administration did not modify VO2, while im E caused increased motor activity and VO2 (P < 0.05). In contrast to control rats, the respiratory exchange ratio in ad libitum fed Gnt rats did not decrease after Ip E administration, suggesting a lack of effect upon lipid mobilization. The lower rate of body weight gain induced by neonatal Gnt sympathectomy might be due to lower daily food intake possibly related, in part, to the sensitization of the alpha-adrenergic porto-hepatic response to endogenous catecholamines. Compared with controls, Gnt-treated rats also showed a limited thermogenic capacity not related to feeding, and a greater degree of carbohydrate oxidation, possibly due to a defect in E-induced lipolysis, which is beta-adrenergic.     

Adrenal vein catecholamines and neuropeptides during splanchnic nerve stimulation in cats

Splanchnic nerve stimulation in bursts at low (5 Hz) and high (50 Hz) frequency (30 V, 1 msec; train duration 1 sec; train rate 0.5/second) was employed in 10 cats under halothane anesthesia, during 10-minute periods, while blood samples were concurrently collected from the adrenal vein and femoral artery for the measurement of norepinephrine (NE), epinephrine (EPI), dopamine (DA), Met-enkephalin (ME), neuropeptide Y (NPY), peptide YY (PYY) and neurotensin (NT). In Group I (n = 5), splanchnic nerve stimulation was initially applied at 5 Hz followed after 20 min by a 50 Hz stimulus, while in Group II (n = 5) the stimulation sequence was reversed. Adrenal vein and femoral artery plasma levels of catecholamines and neuropeptides were not significantly affected by the stimulation sequence, while a significant decrease in blood pressure response was observed in Group II during the 5 Hz stimulation as compared to Group I, indicating desensitization. Splanchnic nerve stimulation at 5 Hz caused a preferential increase in adrenal vein NE (9-fold) versus EPI (7-fold) levels as compared to baseline, while 50 Hz stimulation led to further comparable increases in NE (5-fold) and EPI (6-fold) levels. Significant increases in adrenal vein DA and neuropeptide levels were only observed during 50 Hz stimulation, with DA showing a 5-fold, ME a 2.6-fold and NPY a 3-fold increase as compared to 5 Hz stimulation, and NT a 3.6-fold increase as compared to baseline. Present findings indicate different dynamics in the movement of catecholamines and neuropeptides from the adrenal.     

Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR

Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system.W...     

Inhibition of dihydropteridine reductase by catecholamines and related compounds

Catecholamines and related compounds, such as dopamine, 5- or 6-hydroxydopamine, N-methyldopamine, tyramine, octopamine, norepinephrine and epinephrine, inhibit human liver dihydropteridine reductase (NADH:6,7-dihydropteridine oxidoreductase, EC 1.6.99.10) noncompetitively with Ki values ranging from 7.0 X 10(-6) - 1.9 X 10(-4)M (I50 values = 2.0 X 10(-5) - 2.0 X 10(-4)M). The tyrosine analogs alpha-methyltyrosine and 3-iodotyrosine are weak inhibitors of this enzyme (I50 greater than 10(-3)M). The inhibitory effect of catecholamines is slightly decreased by O-methylation of one hydroxyl group, but is essentially abolished by total methylation. The inhibitory strength of the catecholamines and related compounds tested against this enzyme can be arranged in the following order: dopamine, 6-hydroxydopamine, 5-hydroxydopamine, N-methyldopamine greater than tyramine, 3-O-methyldopamine, 4-O-methyldopamine much greater than epinephrine, 3-O-methylepinephrine, norepinephrine, octopamine less than tyrosine much less than alpha-methyltyrosine, 3-iodotyrosine much less than homoveratrylamine. These results suggest that dopamine, norepinephrine and epinephrine may serve as physiological regulators of mammalian dihydropteridine reductase.     

Plasma concentrations of 5-HT, 5-HIAA,norepinephrine, epinephrine and dopamine in ecstasy users

Recreational use of the synthetic methamphetamine derivative MDMA (3,4-methylenedioxymethamphetamine), the main constituent of the illegal drug "ecstasy", has increased dramatically in recent years. The reasons for ecstasy-associated cardiovascular complications like tachycardia, arrhythmias and hypertensive crises and psychiatric symptoms like psychotic episodes are not well understood. We have measured the plasma concentrations of 5-HIAA, 5-HT, norepinephrine, epinephrine and dopamine in 159 ecstasy users and controls. Ecstasy users showed elevated resting sympathetic activity, reflected in increased norepinephrine, epinephrine and dopamine levels. The levels of these catecholamines correlated positively with the cumulative dose and also with consumption during the last 30 days and 12 months. Although it is known that significant changes in 5-HT and 5-HIAA appear in the cerebrospinal fluid in ecstasy users, we could not detect alterations in serotonergic neurotransmitters in plasma in this large sample of subjects. Thus, in the drug-free interval, ecstasy users show lowered central serotonergic activity (lowered 5-HT and 5-HIAA concentrations in CSF) along with unchanged central noradrenergic and dopaminergic activity (HVA and MHPG unchanged in CSF) and elevated peripheral noradrenergic, dopaminergic and adrenergic activity along with unchanged peripheral serotonergic activity (plasma levels). We conclude, that the data presented here could argue for a noradrenergic hyperreactivity in the drug-free interval in ecstasy users resulting from previous ecstasy consumption. Also for an association with psychotic episodes and cardiovascular complications like tachycardia, arrhythmias.