Reward dependence is positively related to urinary monoamines in normal men.

According to Cloninger, three major personality dimensions, novelty seeking, harm avoidance, and reward dependence, are dependent on central monoaminergic systems. This study examined the relationship between the urinary levels of different monoamines and the above personality dimensions. Fifty normal men answered the Tridimensional Personality Questionnaire (TPQ); their levels of dopamine, norepinephrine, epinephrine, normetanephrine, metanephrine, 3-methoxy-4-hydroxyphenylglycol, vanilmandelic acid, homovanilic acid, and serotonin metabolite 5-hydroxyindolacetic acid were measured in urine on two consecutive nights. Significant and positive correlations were found between reward dependence, 3-methoxy-4-hydroxyphenylglycol, and epinephrine (r = .50 and r = .51, respectively). Monoamine levels explained 44% of the variance of reward dependence. Cluster analysis identified three groups of subjects presenting specific patterns of monoamine excretion. The TPQ scores could discriminate among subjects belonging to these clusters. These results point out a narrow relationship between urinary monoamine excretion and the basic personality dimension of reward dependence.

Free and conjugated 3-methoxy-4-hydroxyphenylglycol in human urine: peripheral origin of glucuronide.

The aim of our study was to investigate the endogenous origin of the three forms of 3-methoxy-4-hydroxyphenylglycol (MHPG) present in human urine and to further examine the hypothesis of an independent (peripheral or central) origin of glucuronide and sulfate conjugates. The urinary levels of free, sulfate, and glucuronide MHPG were determined in control subjects under normal conditions in relation to age, sex, and diet and in two experimental situations known to alter sympathetic activity. The mean daily excretion of total MHPG in a group of 14 men and 14 women was 1780 +/- 122 micrograms, with the free, sulfate, and the glucuronide representing 8% +/- 0.5%, 40% +/- 1.5%, and 52% +/- 1.6%, respectively. No influence of sex, age, or diet was observed on any form. Strong physical activity and anticipatory stress increased norepinephrine excretion and selectively increased MHPG glucuronide levels without changing the free or the sulfate excretion. We conclude that the total amounts of free, sulfate, and glucuronide MHPG found in urine originate from endogenous body pools with no interference of dietary components. The sympathetic nervous system seems to be the main source of glucuronide and arguments are given supporting the central origin of sulfate.

Sex differences in the adrenergic response to hypoglycemic stress in human.

We have found different patterns of adrenergic response to insulin-induced hypoglycemia in men and women. The differences involve the readiness of adrenergic reactivity, the magnitude of the responses, and the nature of secreted amines. In men, a strong and transient discharge of epinephrine (E) is observed in plasma, corresponding to a great increase in the urinary level of this amine in the 2 h period following insulin. In women, the adrenergic response is delayed and consists of moderately increased amounts of E and norepinephrine (NE) which persist in plasma for a longer period. From the correlations observed between urinary amount and the increase of plasmatic catecholamines after 30, 45, and 60 min, it may be assumed that urinary data may reflect the cumulative plasma levels of catecholamines in the corresponding period, but not the precise pattern of plasmatic changes. Our findings show that the differences in adrenergic behavior previously observed in men and women under the effect of psychological stress, may also be induced by a metabolic stimulus such a insulin hypoglycemia; however, women, but not men, exhibit a mild release of NE under this metabolic stress.

Relationships between catecholamine or 3-methoxy 4-hydroxy phenylglycol changes and the mental performance under submaximal exercise in man.

Eleven young students were tested to determine the relationship between the improvement of mental performances observed under prolonged submaximal work and central or peripheral catecholamine changes. The subjects pedaled a bicycle ergometer for 1 h at a work load individually calculated to approximate 75% of maximal oxygen uptake. The mental test, consisting of 1-h sessions of time-limited word tests and arithmetical calculations, required a high degree of concentration (vigilance and short-term memory). Catecholamines [epinephrine (E), norepinephrine (NE), dopamine (DA)], metanephrine (MN), normetanephrine (NMN) and the glucuronide conjugate of 3-methoxy 4-hydroxyphenylglycol (MHPG) were assayed in urine to assess peripheral activity: E and MN as indexes of adrenomedullary secretion, NE, NMN and MHPG glucuronide as markers of NE metabolism in sympathetic nerves. Urinary MHPG sulfate was determined as a possible marker of central noradrenergic metabolism. When compared to the effect of single tests, the combination of prolonged submaximal work and mental task induced significant increases in MHPG sulfate and E + MN excretions. Both these increases were correlated each to one another and also correlated to the number of discriminated words. Altogether, the present data show that prolonged submaximal work under mental load activates catecholamine systems and suggest that a relationship exists between adrenomedullary activation and the improvement of mental performance. Based on literature data, the possible modulatory role of peripheral E on mental processes and central noradrenergic activity is discussed.

Chemosensitivity, plasticity, and functional heterogeneity of paraganglionic cells in the rat coeliac-superior mesenteric complex.

Chemosensitivity and plasticity of paraganglionic cells in the rat coeliac-superior mesenteric complex (CSMC) were investigated at a basal state of normoxia (21% O2) and after long-term moderate hypoxia (10% O2, 14 days). Chemical sympathectomy previous to hypoxia was performed to destroy principal ganglionic neurons and thus to allow measurement of the norepinephrine and dopamine content of paraganglionic cells. At the basal state, the CSMC contained dopaminergic (TH+/DBH-) and noradrenergic (TH+/DBH+) paraganglionic cells, the majority being of the noradrenergic type. After 14 days of hypoxia, this ratio was reversed and dopaminergic cells predominated, as indicated by a twofold increase of TH+ cells and a twofold decrease of DBH+ cells. Biochemically, hypoxia produced an increase in the content (1.6-fold) and utilization (1.4-fold) of dopamine as well as a smaller increase in the content of norepinephrine, with no change in its utilization rate. The dopaminergic activation induced by hypoxia persisted after sympathectomy with guanethidine. It is concluded that paraganglionic cells in the CSMC display a chemosensitive function. Furthermore, our findings indicate that paraganglionic cells are differentially affected by hypoxia, depending on their distribution and the nature of their neuromodulators. The alterations induced by hypoxia point out the phenotypic plasticity developed by paraganglionic cells in adaptation to hypoxia and further demonstrate the functional heterogeneity of this autonomic cell population in the rat CSMC.

Lower sex hormones in men during anticipatory stress.

Free cortisol, luteinizing hormone (LH), total testosterone and monoamines were measured in two successive nocturnal urine collections in 50 healthy men to assess the influence of anticipatory stress. The first collection (N-2) was two nights before and the second (N-1) was just on the night before a one-day experimental stressor consisting of participation in a one-day clinical research protocol. The mean cortisol level increased from 23.4 (N-2) to 66.6 micrograms (N-1), while mean LH level decreased from 2.68 (N-2) to 1.71 IU (N-1) and the mean testosterone level fell from 1.31 (N-2) to 0.70 microgram (N-1). There were no changes in monoamines. Inhibition of sex hormones is a relatively neglected area of stress research.

Norepinephrine release in the rat frontal cortex under treadmill exercise: a study with microdialysis.

Cortical norepinephrine (NE) release and metabolism were studied by using chronic microdialysis in rats performing a treadmill exercise at 25 m/min with a 3% slope. Cortical microdialysates and peripheral blood were collected at rest, during 1- or 2-h treadmill running, and for 1 h after exercise. Microdialysate NE and its main metabolites, 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol, and plasma epinephrine (Epi) and NE were determined by high-performance liquid chromatography with electrochemical detection. The results show that treadmill running is able to stimulate concomitantly peripheral catecholamine secretion and central noradrenergic activity, i.e., NE turnover and release. The duration of the central activation and its prolongation over recovery period increases as the duration of the running increases. A positive correlation was found between the central noradrenergic activation and peripheral Epi secretion but not peripheral NE. These findings confirm and extend our previous observations in exercising men and give support to the hypothesis that the elevation of circulating Epi can be a relevant factor mediating, directly or indirectly, the exercise-induced central neurochemical, psychological, and cognitive changes.

Adrenal response to long-term hypoxia is still increased after carotid body denervation in rat.

This study investigated the effects of long-term normobaric hypoxia (10% O2 in N2 for 2, 7, 14, and 28 days) on the metabolism of catecholamines in rat adrenals and the role of the carotid body chemoreceptors in the adrenal response. The content and utilization of dopamine were significantly increased from the 7th day of hypoxia and remained enhanced thereafter. The content of norepinephrine and epinephrine decreased after 2 days of hypoxia and increased thereafter; after 28 days of hypoxia the norepinephrine amounts remained enhanced but the epinephrine levels were no longer significantly increased. In vivo tyrosine hydroxylation increased after 7 days of hypoxia. Bilateral transection of the carotid sinus nerve 1 wk before hypoxia failed to abolish the increase in the content and utilization of dopamine after 7, 14, or 21 days of hypoxic exposure. These results indicate that long-term normobaric hypoxia elicits a long-lasting increase in the metabolism of catecholamines in adrenals, especially as assessed by dopamine measurement, and that this response does not involve a carotid body chemoreflex pathway.

Free, glucuronide, and sulfate catecholamines in the rat: effect of hypoxia.

The formation and excretion of conjugated catecholamines (CA) was studied in conscious rats after sympathetic stimulation by hypoxia (5.5-6% O2, 4 h). Hypoxia induced a rapid and intense increase of free epinephrine (E, X 12) and norepinephrine (NE, X 6) but only a limited enhancement of free dopamine (DA, X 2). Sulfate conjugates of E and NE had kinetics similar to the free forms, while glucuronides were only moderately and lately altered. In contrast to free and sulfated DA, DA glucuronide, the major plasma conjugate, was decreased (-25%). This result suggests that DA glucuronide, unlike other CA conjugates, is not related to detoxication but might supply a CA precursor. Urinary conjugates badly reflected plasma conjugates. In normoxic controls, CA conjugates prevailed in the plasma, whereas the free amines prevailed in the urine. Hypoxia increased mainly the excretion of E and NE glucuronide but not of the free amines. Urinary DA, free or conjugated, was decreased (-25%), a result in keeping with plasma DA glucuronide only. The poor relations between plasma and urine catecholamines pinpoint the importance of the kidney in CA handling.

Free dopamine in dog plasma: lack of relationship with sympathoadrenal activity.

To investigate the relationship between dopamine (DA) released into the bloodstream and sympathoadrenal activity, levels of free DA, norepinephrine (NE), and epinephrine (E) in plasma were recorded in four dogs subjected to three tests: treadmill exercise at two work levels [55 and 75% maximal O2 uptake; 15 min], normobaric hypoxia (12% O2; 1 h), combined exercise and hypoxia. Normoxic exercise induced slight nonsignificant decreases in the arterial partial pressure of O2 (PaO2), increases in NE [median values and ranges during submaximal work vs. rest: 1086 (457-1,637) vs. 360 (221-646) pg/ml; P less than 0.01] and E [277 (151-461) vs. 166 (95-257) pg/ml; P less than 0.05], but it failed to alter the DA level. Hypoxia elicited large decreases in PaO2 [hypoxia vs. normoxia: 42.8 (40.3-50.0) vs. 97.6 (83.2-117.6) Torr; P less than 0.01], increases in DA [230 (105-352) vs. 150 (85-229) pg/ml; P less than 0.01] and NE [383 (219-1,165) vs. 358 (210-784) pg/ml; P less than 0.05], but it failed to alter the E level. Combined exercise and hypoxia further increased NE levels but did not alter the DA response to hypoxia alone. The data indicate that free DA in plasma may vary independently of the sympathoadrenal activity.

Differential effects of long-term hypoxia on norepinephrine turnover in brain stem cell groups.

The influence of long-term hypoxia on noradrenergic cell groups in the brain stem was assessed by estimating the changes in norepinephrine (NE) turnover in A1, A2 (subdivided into anterior and posterior parts), A5, and A6 groups in rats exposed to hypoxia (10% O2-90% N2) for 14 days. The NE turnover was decreased in A5 and A6 groups but failed to change significantly in A1. The NE turnover was increased in the posterior part of A2 and remained unaltered in the anterior part. In normoxic rats, the hypotensive drug dihydralazine induced a reverse effect, namely increased NE turnover in anterior A2 and no change in posterior A2. The neurochemical responses to hypoxia were abolished by transection of carotid sinus nerves. The results show that long-term hypoxia exerts differential effects on the noradrenergic cell groups located in the brain stem. Peripheral chemosensory inputs control the hypoxia-induced noradrenergic alterations. The A2 cell group displays a functional subdivision: the posterior part is influenced by peripheral chemosensory inputs, whereas the anterior part may be concerned with barosensitivity.

Inhibitory effect of almitrine on dopaminergic activity of rat carotid body.

Almitrine increases ventilation by stimulating the peripheral arterial chemoreceptors. This study assessed the effects of acute and chronic almitrine treatments on the dopamine (DA) and norepinephrine (NE) contents and utilization rates in the rat carotid body. Almitrine (5 mg/kg ip) caused a 34% reduction in DA content after 30 min. Extending the almitrine treatment for 15 days (one daily ip injection) produced a further progressive diminution in DA stores (-55%; P less than 0.01). The utilization rate of DA measured after inhibiting catecholamine biosynthesis by alpha-methyl-p-tyrosine was strongly reduced by almitrine (-98% after 15 days; P less than 0.01). The effects of almitrine were dose dependent. The noradrenergic activity was much less altered by the drug. The data showed that almitrine can modify the dynamics of DA in rat carotid body producing a decrease in both content and utilization rate.

Epinephrine, norepinephrine, and dopamine during a 4-day head-down bed rest.

Head-down bed rest at an angle of 6 degrees was used as an experimental model to simulate the hemodynamic effects of microgravity, i.e., the shift of fluids from the lower to the upper part of the body. The sympathoadrenal activity during acute (from 0.5 to 10 h) and prolonged (4 days) head-down bed rest was assessed in eight healthy men (24 +/- 1 yr) by measuring epinephrine (E), norepinephrine (NE), dopamine (DA), and methoxylated metabolite levels in their plasma and urine. Catecholamine (CA) and methoxyamine levels were essentially unaltered at any time of bed rest. Maximal changes in plasma were on the second day (D2): NE, 547 +/- 84 vs. 384 +/- 55 pg/ml; DA, 192 +/- 32 vs. 141 +/- 16 pg/ml; NS. After 24 h of bed rest, heart rate decreased from 71 +/- 1 to 63 +/- 3/min (P less than 0.01). Daily dynamic leg exercise [50% maximum O2 uptake (VO2 max)] used as a countermeasure did not alter the pattern of plasma CA during bed rest but resulted in a higher urinary NE excretion during postexercise recovery (+45% on D2; P less than 0.05). The data indicate no evident relationship between sympathoadrenal function and stimulation of cardiopulmonary receptors or neuroendocrine changes induced by central hypervolemia during head-down bed rest.

6-Hydroxydopamine lesions of dopaminergic A10 neurons. Long-term effects on the urinary excretion of free and conjugated catecholamines and their metabolites in the rat.

Free and conjugated catecholamines (dopamine, noradrenaline, adrenaline) and their methoxylated and/or deaminated metabolites were studied in rat urine after the bilateral destruction of the A10 dopaminergic cell group. Two months after the lesion, dopamine (DA) loss reached 91% in the nucleus accumbens, and was greater than 80% in olfactory tubercles, lateral septum and frontal cortex. At the same time urinary conjugated dihydroxyphenylacetic acid (DOPAC) was decreased by 45% whilst homovanillic acid (HVA) was increased only in its sulfated form (+62%). In contrast, no changes were observed in the free and conjugated forms of urinary DA, 3-methoxytyramine noradrenaline, normetanephrine, adrenaline, vanylmandelic acid, 3-methoxy-4-hydroxyphenylglycol and in the free forms of DOPAC and HVA. The present report confirms and extends our previous findings on the relationships between central dopaminergic activity and urinary deaminated metabolites of DA in the rat. It emphasizes the interest of urinary assays which could provide in vivo information on CNS functions.

Biochemical evidence for norepinephrine stores outside the sympathetic nerves in rat carotid body.

Adult rats were submitted to pharmacological or surgical sympathectomy. The chronic administration of guanethidine caused tremendous reductions in the norepinephrine stores in heart and superior cervical ganglion due to the destruction of the sympathetic nerve fibers and cell bodies. Guanethidine-sympathectomy resulted in a 70% loss of norepinephrine in the carotid body, whereas the dopamine and DOPAC contents were unaltered. The surgical sympathectomy induced by removing the superior cervical ganglion led to similar results. The present data indicate that a considerable part of norepinephrine in the rat carotid body is stored in the sympathetic nerves. In addition, a significant part of norepinephrine resides outside the sympathetic nerves, probably within the glomus cells.

The dynamics of dopamine metabolism in the rat superior cervical, coeliac and mesenteric ganglia.

Dopamine (DA) metabolism was compared in rat superior cervical ganglion, coeliac ganglion, mesenteric ganglion and adrenal medulla. Substantial amounts of DA, 3-4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were found in all the above structures. The proportion of DA metabolites over total adrenergic compounds increased from the superior cervical (22 +/- 2.2%) to the mesenteric ganglia (37 +/- 1.4%) and was much higher in ganglia (30 +/- 1.6%) than in adrenal medulla (1.1 +/- 0.3%). The turnover rates of DOPAC and HVA were calculated in sympathetic ganglia after pargyline (75 mg/kg i.p.) or probenecid (200-500 mg/kg i.p.). After pargyline, the DOPAC levels decreased faster than HVA levels in all ganglia. The corresponding half-lives and calculated turnover rates were: about 4 and 10 min and 100 and 40 pmol/mg protein per h for DOPAC and HVA respectively. No differences were observed between the three ganglia. After probenecid, DOPAC accumulated in all the ganglia in a dose-dependent way; HVA accumulated in the superior cervical and coeliac ganglia but not in the mesenteric ganglion. As in central areas, the turnover rates of DOPAC and HVA calculated on the basis of the greatest accumulation of acidic levels after probenecid were much smaller than those obtained after pargyline. Probenecid increased DOPAC levels in adrenal medulla, but the concomitant changes in DA and epinephrine (E) amounts suggest that probenecid was able to enhance adrenomedullary activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the central or peripheral origin of free and sulfated 3,4-dihydroxyphenylacetic acid in rat plasma.

The concentrations of free and sulfated 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in rat plasma to investigate their potential central or peripheral origin. Stimulation of central dopamine (DA) metabolism by a long-acting neuroleptic, pipotiazine (PPZ) selectively increased plasma levels of DOPAC sulfate whereas peripheral inhibition of monoamine oxidase by debrisoquin sulfate decreased free DOPAC levels only. These data suggest that the two forms of plasma DOPAC (free and sulfate) may have independent topographic origins. Peripheral DA pools seem to be the most likely sources for plasma free DOPAC whereas central dopaminergic neurons mainly contribute to plasma sulfated DOPAC. Our findings thus demonstrate that plasma DOPAC sulfate may be a useful indicator for central DA function in rat. Although further experiments are necessary to extrapolate our findings from rat to man, arguments are given indicating that measurements of plasma DOPAC sulfate might be of interest in human pathological and pharmacological investigations.

Striatal and mesolimbic dopaminergic contribution to 3,4-dihydroxyphenylacetic acid sulfate in rat plasma.

Free and sulfated 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in rat plasma after bilateral 6-hydroxydopamine lesions of striatum or mesolimbic tissue (nucleus accumbens + olfactory tubercle). Both lesions selectively reduced plasma DOPAC sulfate levels without altering free DOPAC or catecholamine levels in plasma, sympathetic ganglia or adrenal medulla. The present work confirms our previous findings and suggests that DOPAC sulfate functional state of striatal and mesolimbic dopaminergic neurons.

Urinary free and conjugated catecholamines and metabolites in autistic children.

Urinary catecholamines (DA, NE, E) and their main metabolites (HVA, DOPAC, MHPG) were analyzed both as free and conjugates in eight children diagnosed as autistic according to DSM-III criteria and eight normal children. Significant differences appeared for the urinary excretion of both DA and NE and their respective metabolites: Autistic children showed low DA, high HVA, high NE, low MHPG urinary levels. These results are consistent with previous findings on altered catecholamine metabolism in autistic children. They suggest that autistic behaviors might be related to an abnormal functional imbalance among monoamines either at a molecular level or at a system level. Furthermore, they emphasize the special interest of urinary assays in pediatric research.

Specific sound-induced noradrenergic and serotonergic activation in central auditory structures.

We have studied the noradrenergic and serotonergic changes induced by white noise stimulation at 70, 90 or 110 dB SPL for 45 min, in cochlear nuclei, inferior colliculus (IC), primary auditory cortex (PAC) and as a comparison in locus coeruleus (LC) and raphe dorsalis using HPLC. Both noradrenergic and serotonergic pathways were activated in the dorsal+posteroventral cochlear nuclei (DCN+PVCN) without changes in the anteroventral cochlear nucleus (AVCN) and IC. In the DCN+PVCN the noradrenergic activation was restricted to animals exposed to 70 dB SPL whereas the increase of serotonin content was intensity-dependent. In PAC serotonergic activation was observed only after 70 dB SPL exposure. These data suggest that in physiological conditions (70 dB SPL) noradrenergic and serotonergic regulation of the processing of auditory information occurs specifically in the dorsal cochlear nucleus where the control of incoming information to higher auditory structures takes place (i.e. IC and PAC). We suggest that the serotonergic activation in the primary auditory cortex for 70 dB SPL sound stimulation could be related to the fact that low-intensity white noise stimulation could be the most plastic-demanding processing in the auditory cortex.