Increased Norepinephrine Turnover Research Articles

Noradrenergic response to acute ethanol administration in heathly subjects: comparison with intravenous yohimbine

The effects of oral administration of ethanol [1.1 ml/kg 95% ethanol administered as a 20% (by volume) solution] and intravenous administration of the alpha 2 adrenergic receptor antagonist yohimbine hydrochloride (0.4 mg/kg), alone and in combination, were compared using a double-blind, placebo-controlled design. Twelve healthy subjects completed 4 test days during which drug effects on subjective measures of intoxication and anxiety, plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and cortisol, and cardiovascular indices were assessed. Acutely administered oral ethanol significantly increased the subjective measures of intoxication and anxiety, plasma MHPG, and sitting systolic blood pressure compared with placebo. Intravenous yohimbine significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and blood pressure relative to placebo. The ethanol-induced increase in plasma MHPG was significantly greater than that following yohimbine, whereas yohimbine resulted in significantly greater increases in anxiety, plasma cortisol, and blood pressure measurements than ethanol. The combined administration of ethanol and yohimbine had a clear additive effect of increasing the severity of acute intoxication compared with ethanol or yohimbine alone, and resulted in a significantly greater plasma MHPG response compared with either drug given alone. Although the pharmacokinetic effects of ethanol administration on NE metabolism must be considered, these findings suggest that the intoxicating and anxiogenic effects of acute ethanol administration may be associated with increased NE turnover, as measured by plasma MHPG, in healthy human subjects. In addition, these results indicate that ethanol and yohimbine may act additively to increase ethanol intoxication and that they may increase NE turnover through different physiological mechanisms.

Focal traumatic brain injury causes widespread reductions in rat brain norepinephrine turnover from 6 to 24 h

The effect of right sensorimotor traumatic brain injury (TBI) in male Sprague-Dawley rats on brain norepinephrine (NE) turnover was assessed by measuring the decline of endogenous NE levels following tyrosine hydroxylase inhibition produced with α-methyl-p-tyrosine. Right sensorimotor cortex contusions were produced by a pneumatically driven piston which depressed the dural surface by 2 mm at 3.2 m/s. TBI rats were compared to uninjured, anesthetized controls at 6 h and 24 h after surgery. While NE turnover was not affected at the lesion site at 6 h after TBI, it was either abolished or decreased by 33–75% bilaterally in the hypothalamus and in the cerebral cortex surrounding and rostral to the lesion site. In the cortex caudal to the lesion site, NE turnover was completely abolished. NE turnover in cerebral cortex opposite the lesion site and in the contralateral cerebellum was decreased by 51 and 43%, respectively, at 6 h. At 24 h, NE turnover was either abolished or decreased bilaterally by 45–92% in all cortical areas, in the hypothalamus, cerebellum, locus coeruleus and medulla. Thus, right sensorimotor cortex contusion causes a marked, early and widespread depression of brain NE turnover. Since amphetamine increases NE turnover, this may explain the dramatic improvement in behavioral deficits which occurs following amphatamine administration at 24 h after such lesions.

Altered norepinephrine turnover in the brown fat of rats with chronic renal failure.

Disturbances of the sympathetic nervous system (SNS) have been described in chronic renal failure, but their role in the metabolic derangements of uremia has not been well established. In these studies, SNS activity has been measured in the ventromedial hypothalamic (VMH) nuclei and in the intercostal brown adipose tissue (IBAT) of Sprague Dawley 5/6 nephrectomized or sham-operated rats. SNS activity was determined by calculating the norepinephrine (NE) turnover rate (in picograms per milligram per hour) 3, 6, and 12 h after the inhibition of NE synthesis with L-methyltyrosine. The endogenous NE concentration was significantly (P < 0.01) higher in the VMH (14,567 +/- 1,130 pg/mg wet wt) and IBAT (17,902 +/- 2,308 pg/mg wet wt) of uremic than control rats (9,600 +/- 1,110 and 5,752 +/- 320 pg/mg wet wt, respectively). The turnover rates of NE in the VMH (582 +/- 146 pg/mg per hour) and in the IBAT (1,432 +/- 179 pg/mg/hr) of uremic rats were significantly faster (P < 0.01) than in control rats (192 +/- 96 and 173 +/- 58 pg/mg per hour, respectively). These studies demonstrate a significant increase in NE turnover in the VMH nuclei and IBAT of uremic rats. It is suggested that increased efferent sympathetic nerve discharge from the VMH to the IBAT may play a role in the pathogenesis of malnutrition in uremia.

Clinical Response to Clozapine in Patients With Schizophrenia

One of the take-home messages from our recent report regarding the clinical and biological effects of the atypical neuroleptic, clozapine, was that the admixture of clozapine's effects on dopaminergic, serotonergic, and noradrenergic systems may underlie its unique efficacy in otherwise poorly responsive patients with schizophrenia. 1 We agree with a suggestion by R. W. Pies, MD, (unpublished communication to theArchives, May 1992) that clozapine's diverse pharmacologic properties indicate strategies for augmentation of neuroleptic drugs in treatment-resistant patients and that thioridazine or mesoridazine besylate may be particularly useful, given their relatively low incidence of extrapyramidal side effects. Whereas much attention has been given to the 5-hydroxytryptamine 2 (5-HT 2 ) antagonism of clozapine, including the ratio of 5-HT 2 to D 2 affinities as a predictor of neuroleptic atypicality, 2 we have noted that clozapine's relatively potent α 2 -antagonism (putatively contributing to observed increases in norepinephrine turnover) is distinct among

A CRF antagonist attenuates stress-induced increases in NA turnover in extended brain regions in rats

We investigated the effects of intracerebroventricular (i.c.v.) administration of a corticotropin-releasing factor (CRF) antagonist, α-helical CRF 9–41 (ahCRF), on increases in noradrenaline (NA) turnover caused by immobilization stress in rat brain regions. Pretreatment with ahCRF (50 or 100 μg) significantly attenuated increases in levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO 4), the major metabolite of NA in rat brain, in the locus coeruleus (LC) region, and attenuated the MHPG-SO 4/NA ratio after immobilization stress for 50 min in the cerebral cortex, hippocampus, amygdala, midbrain and hypothalamus. However, stress-induced increases in plasma corticosterone levels were not decreased significantly by pretreatment with ahCRF. These results suggest that CRF, released during stress, causes increases in NA release in extended brain regions of stressed rats.

Functional reorganization of the noradrenergic system after partial fornix section: a behavioral and autoradiographic study.

Previous experiments revealed that the cholinergic deficit in rats with a partial fornix section was accompanied by an increase in turnover of noradrenaline (NE) in the hippocampus. This noradrenergic hyperactivity contributed to the cognitive deficit in lesioned rats, probably by interaction with the cholinergic system. The present experiment examines the reorganization of the noradrenergic system after the damage induced by partial fornix section and attempts to determine if the increase in NE turnover is of locus coeruleus (LC) origin, or if it is a result of local regulation at the noradrenergic terminals. Rats were submitted to knife-cut section of the fornix, resulting in a decrease in choline acetyltransferase activity in the hippocampus, correlated with a significant behavioral deficit in a spatial memory task. Lesioned rats learned a nonspatial memory task normally. Sections of brains of these rats were submitted to quantitative autoradiography. [125I]Iodopindolol binding was assessed in the dorsal and ventral hippocampus to determine availability of beta receptors. This was found to be significantly lower in lesioned rats. [125I]Iodoclonidine was used to determine alpha 2 receptors binding in dorsal and ventral hippocampus and in LC. There was no difference in alpha 2 receptors in LC, a significant decrease in dorsal regions of the hippocampus, and a significant increase in ventral regions. Muscarinic M1 receptors in the hippocampus showed no changes after the lesion.

Norepinephrine turnover in the goldfish brain is modulated by sex steroids and GABA

It is known that norepinephrine (NE) is important in the neuroendocrine control of pituitary gonadotropin II (GTH-II) and growth hormone (GH) release but very little is known about the factors regulating NE neurons in the goldfish brain. Female gonad-intact goldfish were implanted intraperitoneally (100 μg/g) with testosterone (T) or estradiol (E 2) to elevate serum steroid levels. High-performance liquid chromatography measurements showed that steroid implantation had no effect on NE content in the telencephalon, including preoptic area (TEL-POA), or the hypothalamus (HYP). The turnover rate of NE was estimated from the rate of depletion of NE content from tissues following inhibition of tyrosine hydroxylase byα-methyl- p-tyrosine (240 μg/g). The present study demonstrates that E 2 can decrease NE turnover rates in TEL-POA and HYP of sexually regressed goldfish (August). The results in recrudescent fish (November), however, indicate a more complex interaction of E 2 with NE neurons since E 2 increased NE turnover in TEL-POA and HYP in these animals. Testosterone (T) has less prominent effects on NE turnover rates in TEL-POA and HYP; the only significant effect of T-implantation was a small reduction of NE turnover in the TEL-POA of sexually recrudescent fish. Elevation of endogenous brain GABA concentrations by injection of the GABA transaminase inhibitor, γ-vinyl-GABA (300 μg/g), significantly reduced NE turnover in TEL-POA. These data demonstrate that goldfish NE neurons in the TEL-POA are sensitive to regulation by changes in circulating sex steroids and by increases in brain GABA.

Cytokine-induced change in hypothalamic norepinephrine turnover: involvement of corticotropin-releasing hormone and prostaglandins

Changes in norepinephrine (NE) turnover in restricted brain regions were examined in rats after administration of the major mediators of the acute phase response, interleukin-1β (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF). An increase in NE turnover was observed after intraperitoneal injection of IL-1 (1 μg/rat) in the whole hypothalamus and several specific hypothalamic nuclei, but not in the medulla oblongata and cerebral cortex. The stimulatory effect of IL-1 was mimicked by an intracerebroventricular injection of much lower doses of IL-1 (10–100 ng/rat). This IL-1-induced increase in hypothalamic NE turnover was blocked by the pretreatment with either indomethacin (cyclooxygenase inhibitor) or anti-corticotropin releasing hormone (CRH) antibody but not by naloxone. Intracerebroventricular injection of CRH increased NE turnover not only in the hypothalamus but also in the medulla oblongata and cerebral cortex. However, prostaglandin (PG) E 2 and PGF 2α did not show such effect. It was therefore suggested that IL-1 activates noradrenergic neurons projecting to the hypothalamus by its direct action to the brain, and that CRH and eicosanoid-cyclooxygenase product(s) within the brain are involved in this process. In contrast, neither IL-6 nor TNF influenced brain NE turnover regardless of whether they were given intraperitoneally or intracerebroventricularly. Thus, although IL-6 and TNF, as well as IL-1, show common central effects such as fever and pituitary-adrenal activation, these effects may be independent of the activation of NE metabolism in the hypothalamus.

Neuroendocrine and neurochemical responses to novelty stress in young and old male F344 rats: Effects of d-fenfluramine treatment

To understand some of the mechanisms underlying the neuroendocrine and neurochemical changes associated with aging, we administered the serotonin [5-hydroxytryptamine (5-HT)] releaser and reuptake inhibitor d-fenfluramine ( d-FEN; 0.0, 0.2, or 0.6 mg/kg/day, p.o) for 30–38 days to young (4 months) and old (22 months) F344 male rats. Rats were stressed by placement into a novel open field (OF) for 20 min before sacrifice. Control animals were sacrificed immediately upon removal from their home cage (HC). Old rats exhibited less ( p < 0.05) exploratory behavior than young rats, which was not altered by treatment with d-FEN. Old HC rats also had higher ( p < 0.05) basal plasma levels of adrenocorticotropic hormone (ACTH) and prolactin (PRL) than young HC rats. Old OF rats showed higher ( p < 0.05) levels of ACTH and corticosterone (CORT) than young OF animals. A stress-induced increased in PRL secretion was not observed in old rats. Subchronic low-dose d-FEN normalized the enhanced ACTH and CORT responses of old animals to novelty. In addition to these endocrine changes, stress-induced increases in medial frontal cortex (MFC) dopamine (DA) and norepinephrine (NE) turnover also were observed. The increase in NE turnover was greater ( p < 0.01) in old than in young rats. d-FEN treatment blocked the stress-induced increase in MFC NE but not MFC DA turnover in both young and old rats. These data support a role for 5-HT and/or NE in some age-related neuroendocrine perturbations and suggest that increased 5-HT neurotransmission can normalize the hyperactivation of the hypothalamo-pituitary-adrenal axis of old male rats.

Tissue-specific noradrenergic activity during acute heat stress in rats

The purpose of this study was to determine whether nonexertional heat stress alters the behavior of internal organ and skeletal muscle sympathetic nervous system (SNS) activity in unrestrained conscious rats. Norepinephrine (NE) synthesis was blocked with alpha-methyl-p-tyrosine, and the rate of decline in tissue NE concentration after synthesis blockade was used to estimate SNS activity in the left ventricle, kidney, liver, adrenal gland, and soleus and extensor digitorum longus muscles of the hindlimb. Male Sprague-Dawley rats (250-320 g) were maintained in thermoneutral control conditions (ambient temperature = 24 degrees C, n = 10) or exposed to an ambient temperature of 42 degrees C until a colonic temperature (Tc) of 39.5 or 41.0 degrees C (n = 10 each) was attained. During heating, as Tc rose from control levels (approximately 38 degrees C) to 41.0 degrees C, mean arterial pressure and heart rate increased from 120 +/- 3 to 141 +/- 3 mmHg and from 381 +/- 4 to 420 +/- 5 beats/min, respectively (P < 0.05). There was a strong trend for increased NE turnover rates in the left ventricle, liver, and adrenal gland in NE synthesis-blocked rats attaining a Tc of 39.5 degrees C compared with the normothermic values, whereas the turnover rate in the kidney was significantly elevated at this level of hyperthermia (126%) vs. the control condition. In animals heated to a Tc of 41.0 degrees C, the NE turnover rate was markedly increased in the left ventricle (590%), kidney (531%), liver (262%), and adrenal gland (602%) compared with normothermic control values.(ABSTRACT TRUNCATED AT 250 WORDS)

1009 Tissue-specific increase in norepinephrine turnover by IL-1 and TNF, but not by IL-6, in rats: Involvement of prostaglandins

1009 Tissue-specific increase in norepinephrine turnover by IL-1 and TNF, but not by IL-6, in rats: Involvement of prostaglandins

Central administration of interleukin-1β increases norepinephrine turnover in the spleen

We have previously shown that intracerebroventricular(ICV) injection of interleukin-1β (IL-1β) suppressed splenic macrophage function. Sympathetic noradrenergic innervation of the spleen was implicated as a mediator of this IL-1β signal as surgical sympathectomy ablated the macrophage suppression. In this study, we have determined whether ICV administration of IL-1β has an effect on sympathetic outflow and norepinephrine (NE) turnover in the spleen. Adult male rats were injected with 5 ng of IL-1 or saline, and NE turnover in the spleen was determined using the rate of decline of NE content in the spleen after synthesis inhibition. The splenic NE turnover rate was increased significantly from 69.52 ng/g/h in saline-treated animals to 111.05 ng/g/h in IL-1-treated animals. In addition, serum corticosterone and ACTH were significantly elevated in IL-1β-treated animals 4 h postinjection. These data indicate that central administration of IL-1β increases both sympathetic outflow to the spleen and activates the hypothalamic-pituitary-adrenal axis during the period when IL-1β induces immunosuppression.

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.

Effects of glucose and fat antimetabolites on norepinephrine turnover in rat hypothalamus and brainstem

Rats were injected acutely with antimetabolites of either glucose (2 deoxy- d-glucose, 2DG), fat (methylpalmoxirate, MP or mercaptoacetate, MAC), or the combination of these agents, in dosages known to stimulate food intake. Norepinephrine (NE) turnover in hypothalamus and brainstem was determined after these treatments by the method of synthesis inhibition. Glucoprivation (2DG) increased NE turnover in hypothalamus, confirming previous studies. Fat antimetabolites alone had no effect on NE turnover, nor did a peripherally-acting fructose antimetabolite. Combination of MP and 2DG, but not MAC and 2DG, produced a greater NE turnover than 2DG alone. These data suggest that peripheral signals of metabolic emergency do not activate brain NE systems, except when these systems are already activated by an ongoing cerebral metabolic emergency. The role of hypothalamic NE in metabolic integration of feeding is discussed, and possible hemispheric differences.

Brain cortical tissue levels of noradrenaline and its glycol metabolites: effects of ischemia and postischemic administration of idazoxan.

The brain noradrenaline (NA) system is known to modulate ischemic neuronal damage, and the turnover of NA has been suggested to increase in the early recovery period following cerebral ischemia. Using HPLC and gas chromatography-mass spectrometry we analyzed the tissue levels of NA and its metabolites, 3,4-dihydroxyphenylethyleneglycol (DHPG) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), in rat brain cortex after 10 min of forebrain ischemia followed by 1 h of recirculation. The effect of idazoxan, given in cerebro-protective doses, as a bolus of 0.1 mg.kg-1 immediately after ischemia followed by 10 micrograms.kg-1.min-1 for 1 h, was also investigated. Ischemia decreased basal NA cortical levels from 384 ng/g tissue in control animals to 214 ng/g, while DHPG increased from 74 to 103 ng/g (+39%) and MHPG from 82 to 154 ng/g (+88%). Conjugated but not free DHPG increased, while both free and conjugated MHPG increased equally. The findings indicate an enhanced postischemic NA turnover with a major proportion of uptake and metabolism occurring extraneuronally, possibly secondary to a saturation of neuronal NA uptake in the postischemic phase. Idazoxan further increased NA turnover, as evidenced by higher postischemic levels of free MHPG and a higher MHPG/NA ratio. A correlation may exist between the protective action of idazoxan and its effect on NA turnover.

Noradrenergic hyperactivity after partial fornix section: role in cholinergic dependent memory performance

Rats with unilateral or bilateral partial section of the fornix were impaired on an eight arm radial maze task. Neurochemical analysis of hippocampal tissue four weeks after the lesions revealed a 50% reduction of choline acetyltransferase (ChAT) activity. The cholinergic marker was correlated negatively with the number of errors in the maze; the lower the ChAT activity, the higher the error score. The fornix lesion also induced a 50% reduction in norepinephrine (NE), but no change in the noradrenergic metabolite methylhydroxyphenylglycol (MHPG), suggesting a net increase in turnover of NE in these animals. Additional lesion of the noradrenergic system with the neurotoxin DSP4 reduced both MHPG and NE levels by more than 90%, compared to nonlesioned controls, and reversed the behavioral deficit. This treatment had no further effect on cholinergic markers. There was a significant negative correlation between ChAT activity and the index of NE turnover, suggesting that hyperactivity in the noradrenergic system after fornix section inhibits the spared cholinergic function and thus exacerbates the cognitive deficit. The pattern of neurochemical results bear a striking resemblance to those seen in some Alzheimer's patients and suggest that an equilibrium among neurotransmitters is important to cognitive function.

Central noradrenergic activity is responsible for nitroglycerin-induced cardiovascular effects in the nucleus tractus solitarii

The studies show that unilateral microinjection of nitroglycerin (NTG) into nucleus tractus solitarii (NTS) produce dose-dependent decreases in mean arterial pressure (MAP) and heart rate, but injection of sodium nitroprusside (SNP) into the area induced slight effects. Hypotensive responses to NTG injected into the NTS showed that the compound was 20 times more potent than after i.v. administration. Responses to NTG injected into the NTS were abolished in an additive fashion by either rauwolscine, anα 2-adrenoceptor antagonist, or guanethidine which inhibits release of norepinephrine (NE). Injection of prazosin, anα 1-adrenoceptor antagonist, into the NTS reduced the hypotensive responses of NTG, but did not alter the bradycardia induced by the drug. Tachycardic responses following i.v. administration of either NTG or SNP were attenuated by bilateral injection of rauwolscine into the NTS, whereas only hypotensive responses to i.v. NTG were reduced by the pretreatment. NTG produced a dose-dependent increase in concentrations of 3,4-dihydroxyphenylalanine in media bathing medulla-pons, which were quantified using high-performance liquid chromatography with electrochemical detection. NE and 3,4-dihydroxyphenylglycol concentrations in media of incubated medulla-pons slices were simultaneously increased following higher concentrations of NTG. The results suggest that NTG in the NTS induces hypotensive and bradycardiac responses, and an increase in turnover of NE may stimulateα 2-adrenoceptors and be responsible for the effects of the drug. The NTS may contribute a component of action to the cardiovascular effects of intravenous NTG. The cardiovascular responses of intravenous SNP appear to involve peripheral action.

NMDA receptor antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal

Pretreatment with the non-competitive NMDA (N-methyl-D-aspartate) antagonist MK801 (0.5, 1.0 mg/kg, s.c.) suppressed the behavioral signs of withdrawal in morphine-dependent rats. However, the same doses of MK801 that suppressed morphine withdrawal also simultaneously produced phencyclidine (PCP)-like behaviors. Pretreatment with the competitive NMDA antagonist LY274614 (25, 50, 100 mg/kg i.p.) also suppressed the behavioral signs of withdrawal in morphine-dependent rats but did not produce PCP-like behavioral effects. Single unit recordings were made from noradrenergic neurons in the locus coeruleus (LC) and, at doses that suppressed morphine withdrawal behaviors, neither MK801 nor LY274614 blocked the withdrawal-induced activation of LC neurons. Biochemical analysis indicated that, at the same behaviorally relevant doses, neither MK801 nor LY274614 blocked the withdrawal-induced increase in norepinephrine turnover in the hippocampus, cerebral cortex, or hypothalamus. These results indicate that NMDA antagonists attenuate the behavioral signs of morphine withdrawal without blocking the withdrawal-induced increase in norepinephrine turnover or the withdrawal-induced increase in LC unit activity. In addition, non-competitive NMDA antagonists, like MK801, may not be useful to alleviate opiate withdrawal symptoms in man because of their PCP-like side effects. However, competitive NMDA antagonists, like LY274614, could be of great benefit for alleviating opiate withdrawal symptoms in man.

O-259 - Diazepam-morphine synergistic effect on stress-induced increases in noradrenaline turnover in brain regions of rats.

O-259 - Diazepam-morphine synergistic effect on stress-induced increases in noradrenaline turnover in brain regions of rats.

Interleukin-1 increases norepinephrine turnover in the spleen and lung in rats

To clarify effects of interleukin-1 on sympathetic nerve activity, norepinephrine turnover in various organs was assessed in rats after intraperitoneal injection of recombinant human interleukin-1 beta. Interleukin-1 administration increased norepinephrine turnover in the spleen, lung and hypothalamus without appreciable effect in the heart, liver, submandibular gland, thymus, pancreas, brown adipose tissue and medulla oblongata. Similar changes in norepinephrine turnover were also found after the administration of bacterial endotoxin. It was concluded that interleukin-1 activates the sympathetic nerves specifically in the spleen and lung.