Peripheral Noradrenergic Activity Research Articles

Plasma cortisol and norepinephrine in Alzheimer's disease: opposite relations with recall performance and stage of progression.

Alzheimer's disease (AD) is characterized by effortful retrieval memory impairments, loss of hippocampal neurons and elevated plasma cortisol (CORT) concentrations. The latter could induce further memory decline. AD is also characterized by increased central and peripheral noradrenergic activity. Since noradrenergic function is involved in memory formation, this upregulated function could counteract memory decline. The aim of the present study was to test these hypotheses using plasma norepinephrine (NE) as a noradrenergic parameter, and recall of the prerecency part of neutral valence word lists as a measure of effortful retrieval. Area under the curve (AUC) of morning, midday and afternoon plasma CORT and plasma NE concentrations was related to two measures of recall performance, ie summated recall scores of the prerecency and recency parts of three word lists, and to the stage of the Clinical Dementia Rating (CDR). Partial correlation between each hormone AUC value and prerecency recall performance, controlling for the effect of the other hormone, showed opposite relations between recall and either plasma CORT or NE. Similar stronger correlations were found with the CDR score. Plasma CORT and NE are oppositely related with effortful retrieval and the stage of progression in AD.

Chronic lithium administration enhances noradrenergic responses to intravenous administration of the alpha2 antagonist idazoxan in healthy volunteers.

The acute and chronic effects of lithium carbonate administration at therapeutic blood levels on peripheral noradrenergic activity and sympathetic responses to alpha2 adrenoceptor blockade were examined in 10 medically and psychiatrically healthy volunteers. Supine resting levels of plasma norepinephrine and the increases in norepinephrine following intravenous infusion of 200 microg/kg of idazoxan, a selective alpha2 adrenoceptor antagonist, were determined before lithium (Li+) administration and after 5 days and after 4 weeks of daily Li+ treatment. Chronic Li+ treatment significantly increased mean resting plasma norepinephrine levels by 53.6%. The noradrenergic responses to infusions of idazoxan were slightly enhanced after 5 days of Li+ administration and significantly increased following 4 weeks of Li+ treatment. The possibility that Li+ produces functional alpha2 subsensitivity causing enhanced peripheral noradrenergic activity in humans is supported by the findings of increased mean resting plasma norepinephrine and increased response to idazoxan following chronic Li+ administration. Alteration of regulatory mechanisms in the noradrenergic system may be relevant to understanding the clinical effects of Li+ in manic-depressive illness.

Involvement of the catecholaminergic system in glucagon-induced thermogenesis in Muscovy ducklings (Cairina moschata).

Physiological studies have shown that glucagon is a potential mediator of nonshivering thermogenesis (NST) in birds. The present work was undertaken in order to investigate whether the observed thermogenesis results from a direct action of glucagon on avian thermoregulatory mechanisms or in fact requires the participation of other agents such as catecholamines. Our experiments were performed using cold-acclimated (CA) ducklings which developed muscle NST. A comparison was made with thermoneutral (TN) ducklings of the same age. Our principal results showed that: (1) at ambient temperature (25 degrees C), circulating norepinephrine (NE) was markedly decreased in CA ducklings (-42%), while circulating epinephrine (E) did not undergo any consistent change; (2) in CA and TN ducklings, an intraperitoneal injection of glucagon (360 microg x kg(-1)) was followed after 10 min by prominent lipolysis and a large increase in circulating NE (4- to 6-fold) and E (14- to 17-fold), which was sustained for at least 1 h. The elevation of circulating NE was less pronounced in CA ducklings. The thermogenic action of glucagon in birds is probably indirect and involves at least the mobilization of lipids and sympatho-adrenal stimulation. The changes in peripheral noradrenergic activity during cold acclimation could be associated with adaptive changes leading to NST.

Norepinephrine uptake modifications in circumventricular organs, pons and myelencephalic areas and nuclei in prehepatic portal hypertensive rats

Peripheral noradrenergic activity is enhanced in portal hypertension and correlates with the progression of the disease. However, little is known about the status of central norepinephrine (NE) in portal hypertension. The aim of the present work was to study the uptake of NE in several areas rich in NE in experimental prehepatic portal hypertension. The experiments were performed in vitro in several encephalic areas and nuclei, obtained according to the ‘punch-out technique’. Results showed that in portal hypertensive rats NE uptake enhanced in all areas and nuclei studies (subfornical organ, organum vasculosum lamina terminalis, area postrema, locus coeruleus and nucleus tractus solitarius). The present results suggest that these encephalic areas and brainstem nuclei may be related to the development and/or maintenance of portal hypertension in this animal model.

Factors affecting the development of spontaneous recurrence of methamphetamine psychosis.

The process triggering spontaneous recurrences of methamphetamine (MAP) psychosis (i.e. flashbacks) was studied in 41 flashbackers, along with 84 non-flashbackers with a history of MAP psychosis. Plasma monoamine metabolite levels were assayed in 25 of the 41 flashbackers, 16 of the 84 non-flashbackers, 9 subjects with persistent MAP psychosis and 28 control subjects. All flashbackers had experienced threatening events or frightening paranoid-hallucinatory states during previous MAP use. The dominant factor triggering flashbacks was a mild fear of other people. Plasma norepinephrine levels were elevated during flashbacks. The results suggest that a mild fear of other people may have elicited memories of MAP psychosis associated with threatening experiences through increased sensitivity to psychosocial stressors. As a result the flashbacks occurred, including an increase in peripheral noradrenergic activity.

Monoamine Metabolites Analysis in Blood and the Relation to Flashback Occurrence in Methamphetamine Psychosis

We analyzed monoamine metabolites concentrations in blood plasma of flashbackers who had a history of methamphetamine(MAP) abuse. Subjects were composed of 12 flashbackers, 8 non-flashbackers, 13 MAP users who were not experienced MAP psychosis, and 15 MAP non-users. Flashbackers and non-flashbackers had previously all experienced MAP psychosis. Flashbacks were mostly triggered by mild fear of other people. Plasma norepinephrine(NE) levels were higher in 12 flashbackers during flashbacks than during periods of normalcy. Also plasma NE levels during flashbacks were higher than those in the 13 users and 15 non-users. Plasma NE levels in flasbackers during periods of normalcy were higher than those in the 13 user controls. Other monoamine metabolites concentrations in blood plasma were not significantly different among the subject subgroups. These results suggest that repeated MAP use with threatening experiences may produce sensitivity of neurotransmitter systems including noradrenergicsystems to psychosocial stressors at pharmacologic levels. An increase in peripheral noradrenergic activity may be related to occurrence of flashbacks.

Methamphetamine psychosis: spontaneous recurrence of paranoid-hallucinatory states and monoamine neurotransmitter function.

We studied the process that triggers spontaneous recurrences of methamphetamine (MAP) psychosis, a phenomenon known as flashbacks, in 28 female patients who experienced flashbacks, by comparing them with 92 female nonflashbackers with a history of previous MAP psychosis. The study evaluated plasma monoamine neurotransmitter function in 12 of the 28 flashbackers and in 8 of the 92 nonflashbackers. Control data were obtained from 28 normal, healthy females composed of 13 MAP users and 15 nonusers, none of whom became psychotic. The 28 flashbackers had experienced significantly greater frequencies of threatening events and frightening paranoid-hallucinatory states during previous MAP abuse than the 92 nonflashbackers. The dominant triggering factor was a mild fear of other persons. Plasma norepinephrine (NE) levels were significantly higher in the 12 flashbackers during flashbacks than during periods of normalcy and were significantly higher than those in the 13 user and 15 nonuser control subjects. Plasma NE levels in the 12 flashbackers during periods of normalcy were significantly higher than those in the 13 user control subjects. The eight nonflashbackers had significantly higher NE levels than the 13 user control subjects. This suggests that an increase in peripheral noradrenergic activity may be related to the occurrence of flashbacks. The present study suggests that repeated MAP use with frightening experiences may induce sensitivity to psychosocial stressors. A mild fear of other persons may have actualized the encoded frightening memories associated with the frightening experiences via increased sensitivity to psychosocial stressors. Thus, flashbacks may have been caused through an increase in peripheral noradrenergic activity.

Monoamine Neurotransmitter Metabolites and Spontaneous Recurrence of Methamphetamine Psychosis

The present study was conducted to evaluate plasma levels of monoamine neurotransmitter metabolites in spontaneous recurrences of methamphetamine psychosis (i.e., flashbacks). The subjects were 50 physically healthy females comprised of 25 who experienced flashbacks (flashbackers), 16 who did not experience flashbacks (nonflashbackers), even though they had previously experienced methamphetamine psychosis, and 9 who were currently suffering from persistent methamphetamine psychosis. The control data were available from 28 normal healthy females, of whom 20 had previously abused methamphetamine (users) and 8 who had not (nonusers), none of whom had ever become psychotic. Plasma levels of norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT), and their respective metabolites were assayed. Plasma NE levels were significantly higher in the 25 flashbackers during their flashbacks than during their periods of normalcy, and were significantly higher than those in the 20 user and 8 nonuser controls. Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels during flashbacks were significantly higher than those in the 20 user controls. The nine subjects with persistent methamphetamine psychosis had significantly higher NE levels than the user and nonuser controls. The 16 nonflashbackers had significantly higher MHPG levels than the user controls. The present study suggests that an increase in peripheral noradrenergic activity is related to the occurrence of flashbacks.

Oral physostigmine in alzheimer's disease: Effects on norepinephrine and vasopressin in cerebrospinal fluid and plasma

Physostigmine is a cholinesterase inhibitor which enhances central and peripheral cholinergic activity. In this study, we explored in persons with Alzheimer's disease (AD) the effects of an acute dose of physostigmine in patients receiving chronic physostigmine treatment on the activity of the cholinergically regulated noradrenergic and arginine vasopressin (AVP) systems. Specifically, we estimated the effects of sustained release oral physostigmine on central and peripheral noradrenergic and AVP systems by measuring norepinephrine (NE) and AVP in cerebrospinal fluid (CSF) and plasma. Lumbar punctures were performed in both physostigmine and no drug treatment conditions. In some subjects the effects of physostigmine on the plasma AVP response to the osmolar stimulus of a hypertonic saline infusion also were measured. NE concentrations in both CSF and plasma were significantly lower in the physostigmine than in the no drug condition. AVP concentrations did not differ between conditions in either compartment, nor did physostigmine affect the AVP response to hypertonic saline. Physostigmine appears to decrease both central and peripheral noradrenergic activity in AD.

Decreases in catecholamine concentrations of cisternal cerebrospinal fluid and plasma in rats caused by pentobarbital anesthesia.

Pentobarbital anesthesia led to a decrease of noradrenaline concentrations of both cisternal cerebrospinal fluid and plasma and adrenaline concentration of plasma with a concomitant decrease in blood pressure in rats. These data suggest that pentobarbital suppresses both central and peripheral noradrenergic nervous activity.

Peripheral dopamine in pathophysiology of hypertension. Interaction with aging and lifestyle.

Dopamine, an ancestral catecholamine, is physiologically natriuretic and vasodilating, thus essentially protecting against hypertension. Its actions are overshadowed by the opposite effects of its main biological partner, norepinephrine, and this is accentuated with aging. Clinical observations combined with molecular biology approaches to catecholamine-synthesizing and catecholamine-metabolizing enzymes and receptors permit the identification of some inborn defects. Subtle changes in the dopamine-norepinephrine balance may account for the enhanced peripheral noradrenergic activity seen in the setting of decreased dopaminergic activity in advanced age. These changes may contribute to the diminished ability of the aged kidney to excrete a salt load, as well as to the finding that systolic blood pressure increases with age in populations with a high, but not in those with a low, intake of salt. The attainment of advanced age in Western societies with adverse lifestyle changes (mental rather than physical stress, excess salt intake, overeating, sedentarism) appears to facilitate the development of hypertension. The adaptation to all the preceding lifestyle changes necessitates an increased dopamine generation, which may initially compensate to maintain appropriate natriuresis and vasodilation since many patients with initial borderline essential hypertension express their sympathetic hyperfunction, in addition to increased norepinephrine release, by excessive dopamine release. However, the progression of hypertension is accompanied by a peripheral dopaminergic deficiency and diminished ability to excrete salt. This may represent an eventual inadequacy of a phylogenetically redundant system resulting in decreased natriuresis and vasodilation and may account for the responsiveness of established chronic hypertension to salt restriction, diuretics, and dopaminomimetic medication.

Prenatal nicotine exposure impairs β-adrenergic function: Persistent chronotropic subsensitivity despite recovery from deficits in receptor binding

Gestational exposure to nicotine has been shown to interfere with biochemical markers of development of central and peripheral noradrenergic activity. The current study examines the development and function of cardiac β-adrenergic receptors in the offspring of pregnant rats given nicotine infusions of 6 mg/kg/day from gestational days 4 through 20, administered by subcutaneously implanted osmotic minipumps. Prenatal nicotine exposure delayed the development of β-adrenergic receptor binding capabilities, as assessed with [ 125I]pindolol in membrane preparations from heart and kidney. The deficits in receptor binding were associated with marked subsensitivity of chronotropic responses to administration of a β-adrenergic agonist, isoproterenol. Although the effects on receptor binding resolved after weaning, functional deficiencies in responsiveness to isoproterenol or to preganglionic electrical stimulation of sympathetic nerves to the heart persisted into adulthood. These results indicate that prenatal exposure to nicotine produces long-term alterations in adrenergic responsiveness of sympathetic target tissues.

Central Mechanisms of Hypertension

Central monoaminergic neurons, particularly noradrenergic neurons, are involved in the pathogenesis of hypertension. Dietary NaCl supplementation in NaCl-sensitive spontaneously hypertensive rats (SHR-S) elevates blood pressure, increases peripheral sympathetic nervous system activity, and depresses endogenous noradrenaline stores and noradrenaline release in the anterior hypothalamus (AHA). NaCl-resistant spontaneously hypertensive rats (SHR-R) and normotensive Wistar-Kyoto (WKY) rats are resistant to the NaCl-induced alterations in blood pressure and central and peripheral noradrenergic activity, whereas uninephrectomized Sprague-Dawley rats treated with DOCA + NaCl and Dahl-S rats receiving dietary NaCl supplementation develop NaCl-induced increments in blood pressure, but not depressed AHA noradrenaline release. The AHA is a major cardiovascular regulatory region, and depressor responses elicited by pharmacological (alpha 2-adrenoceptor) stimulation of this area are exaggerated in SHR-S fed a high NaCl diet compared to SHR-S fed a basal diet and SHR-R and WKY fed a high or basal NaCl diet. alpha 2-Adrenoceptors in the AHA are increased in number in SHR-S fed a high NaCl diet, presumably reflecting upregulation in response to reduced local noradrenaline release. These findings are consistent with the hypothesis that decreased noradrenergic activity of sympathoinhibitory neurons in the AHA may mediate the exacerbation in hypertension that occurs in SHR-S during dietary NaCl supplementation.

Altered peripheral noradrenergic activity in intact and sinoaortic denervated Dahl rats

Development of salt-induced hypertension in Dahl salt-sensitive (S) rats is dependent on sympathetic overactivity which may be partially related to arterial baroreflex dysfunction and, therefore, is regionally selective. Our first experiment was designed to determine which regions have elevated sympathetic activity in Dahl S compared with Dahl salt-resistant (R) rats. Weanling (4-week-old) female Dahl R and S rats were fed low or high salt diets (0.13% and 8% NaCl) until 10 weeks of age. Norepinephrine (NE) synthesis was blocked with alpha-methyl-p-tyrosine, and the fractional decline of NE concentration was measured in various tissues. Dahl S rats with increases in both arterial pressure and left ventricular weight demonstrated increased NE turnover in the sinoatrial node, the atrial appendages, the cardiac ventricles, and the renal cortex. In all of these tissues except the cardiac ventricle, increases were associated with high salt intake. Our second experiment was designed to test if arterial baroreflex dysfunction could account for regional increases in sympathetic activity. Separate groups of Dahl R and S rats fed high salt were subjected to either sham surgery or sinoaortic baroreceptor denervation 1 week prior to turnover determinations. Sinoaortic baroreceptor denervation abolished differences in NE turnover between salt-fed Dahl R and S rats in the cardiac sinoatrial node and the atrial appendages, but not in the cardiac ventricles and the renal cortex. Sinoaortic baroreceptor denervation also abolished differences between salt-fed Dahl S and R rats in the spleen but not the duodenum.(ABSTRACT TRUNCATED AT 250 WORDS)

The Neural Basis of Salt Sensitivity in the Rat: Altered Hypothalamic Function

Dietary NaCl supplementation in NaCl-sensitive spontaneously hypertensive rats (SHR-S) elevates blood pressure, increases peripheral sympathetic nervous system activity and depresses endogenous noradrenaline stores and noradrenaline release in the anterior hypothalamus. NaCl-resistant spontaneously hypertensive rats (SHR-R) and normotensive Wistar Kyoto (WKY) rats are resistant to the NaCl-induced alterations in blood pressure and central and peripheral noradrenergic activity, suggesting that the alterations observed in the SHR-S during NaCl loading are genetically mediated. The anterior hypothalamus is a major cardiovascular regulatory region, and depressor responses elicited by pharmacologic (alpha 2 adrenoceptor) stimulation of this area are exaggerated in SHR-S fed a high NaCl diet compared with SHR-S fed a basal diet and compared with SHR-R and WKY fed a high or basal NaCl diet. Membrane-binding techniques confirm that alpha 2 adrenoceptors in the anterior hypothalamic area are increased in number in SHR-S fed a high NaCl diet, presumably reflecting upregulation in response to reduced local noradrenaline release. These findings are consistent with the hypothesis that decreased noradrenergic activity of sympathoinhibitory neurons in the anterior hypothalamic area may mediate the exacerbation in hypertension that occurs in SHR-S during dietary NaCl supplementation.

Brain and peripheral noradrenergic neuron activity in developing genetically hypertensive rats of the Lyon strain.

In order to estimate the alterations in the activity of noradrenergic brain areas and peripheral nerves in relation to genetic hypertension, the concentration and the in-vivo turnover (TO) of norepinephrine (NE) were measured in various brain and peripheral structures of 5 and 22 week-old genetically hypertensive (LH), normotensive (LN) and low blood pressure (LL) male rats of the Lyon strains. LH rats significantly differed from both LN and LL age-matched controls by: i) at 5 weeks, a lowered TO of NE in the anterior hypothalamic region and the median eminence; an elevated TO of NE in the A6 and A7 areas, and in the kidney cortex, and an elevated TO of dopamine in the adrenal medulla, ii) at 22 weeks, a decreased TO of NE in A1 and A6 regions and an increased TO of NE in the thoracic spinal cord. These data suggest that an increased activity of the renal nerves and of the adrenal medulla, possibly originating in central alterations of noradrenergic neurons, could be involved in the development of hypertension in the Lyon strain.

The Ability of the α2-Adrenergic Agonist Clonidine to Suppress Central Noradrenergic Hyperactivity Secondary to Hemodynamic or Environmental Stimuli

Summary: Metabolism of catecholamines was monitored by in vivo voltammetry in the ventrolateral medulla (encompassing the A1 group of noradrenergic cell bodies) of anesthetized rats and in the locus coeruleus of behaving rats. Activation of metabolism of catecholamines was produced by using: (1) controlled hypotension (sodium nitroprusside, mean arterial pressure reduced to approximately 60 mm Hg for 60 min, n = 5) in anesthetized animals; and (2) immobilization (10 min) of conscious rats (n = 5). Clonidine, 200 μg/kg (i.p., n = 3), suppressed almost entirely the activation of the metabolism of catecholamines secondary to controlled hypotension in the ventrolateral medulla. Clonidine, 50 (n = 3) to 200 (n = 5) μg/kg (i.p.), produced a dose-dependent suppression of the activation of the metabolism of catecholamines induced by immobilization in the locus coeruleus of conscious rats. The results obtained from this study provide a biochemical rationale for the use of α2-agonists in conditions where central or peripheral noradrenergic activity is heightened.

Effects of propranolol, clonidine and hydrochlorothiazide treatment and abrupt discontinuation on central and peripheral noradrenergic activity in essential hypertension

This study was undertaken to investigate further the CNS actions of commonly employed antihypertensive drugs. Measurements of cerebrospinal fluid (CSF) and plasma catecholamines (CA) were made in an attempt to estimate the activity of central and peripheral noradrenergic neurons during treatment with or after abrupt discontinuation of treatment with clonidine (CLO), propranolol (PRO), hydrochlorothiazide (HCTZ) or placebo, in patients with essential hypertensio. A randomized, parallel, placebo-controlled, single-blind design was employed. BP reductions equal to or greater than 10 mmHg were observed with CLO (0.36 ± 0.07 mg daily), PRO (160 mg ± 0 mg daily) or HCTZ (70 ± 12 mg daily). CLO reduced plasma norepinephrine (NE) by 64% and PRO increased it by 25%. Neither HCTZ nor placebo modified plasma NE. Plasma renin activity (PRA) was reduced by PRO (51%, P < 0.01) and CLO (35%, P < 0.05). CSF-NE levels (pg/ml) were significantly lower in the CLO group (CLO: 175 ± 23 PRO: 278 ± 35; HCTZ: 255 ± 34; placebo: 203 ± 7).

The Ability of the α2-Adrenergic Agonist Clonidine to Suppress Central Noradrenergic Hyperactivity Secondary to Hemodynamic or Environmental Stimuli

Metabolism of catecholamines was monitored by in vivo voltammetry in the ventrolateral medulla (encompassing the A1 group of noradrenergic cell bodies) of anesthetized rats and in the locus coeruleus of behaving rats. Activation of metabolism of catecholamines was produced by using: (1) controlled hypotension (sodium nitroprusside, mean arterial pressure reduced to approximately 60 mm Hg for 60 min, n = 5) in anesthetized animals; and (2) immobilization (10 min) of conscious rats (n = 5). Clonidine, 200 micrograms/kg (i.p., n = 3), suppressed almost entirely the activation of the metabolism of catecholamines secondary to controlled hypotension in the ventrolateral medulla. Clonidine, 50 (n = 3) to 200 (n = 5) micrograms/kg (i.p.), produced a dose-dependent suppression of the activation of the metabolism of catecholamines induced by immobilization in the locus coeruleus of conscious rats. The results obtained from this study provide a biochemical rationale for the use of alpha 2-agonists in conditions where central or peripheral noradrenergic activity is heightened.

Influence of renal nerves on noradrenergic responses to changes in arterial pressure.

Renal denervation has been shown previously to lower the increased arterial pressure as well as the increased hypothalamic and peripheral noradrenergic activity found in neurogenic and Goldblatt models of experimental hypertension. In the present study conscious Wistar rats with or without renal nerves were subjected to 60 min of saline infusion (controls), hypotension (intravenous sodium nitroprusside), or hypertension (intravenous phenylephrine HCl). Changes in the turnover of norepinephrine (NE) in the anterior hypothalamus, posterior hypothalamus, kidney, intestine, and skeletal muscle were assessed by measuring the decline of NE concentration 90 min after administration of alpha-methyl tyrosine. There was a significant increase in NE turnover in the posterior hypothalamus and all peripheral organs examined in the nitroprusside-infused group with intact renal nerves. In renal-denervated animals, acute hypotension produced similar changes in NE turnover in peripheral organs, but no significant change was observed in the posterior hypothalamus. In the acutely hypertensive group with intact renal nerves, there was no significant change in NE turnover in the hypothalamic sections or the peripheral organs; however, the turnover of NE was significantly decreased in both the anterior and posterior hypothalamus of the renal-denervated hypertensive group. Overall these studies suggest the presence of an interaction between inhibitory influences from baroreceptor afferents and excitatory influences from renal afferents on noradrenergic activity in the hypothalamus and changes in noradrenergic activity in hypothalamic structures may not be directly related to changes in sympathetic outflow.