Brain Norepinephrine Levels Research Articles

Long Term Effects of α-Methyl-p-Tyrosine and p-Chlorophenylalanine on the Rate of Synthesis of Brain Monoamines in Rats

Pretreatment with inhibitors of monoamine synthesis, α-methyl-p-tyrosine (AMPT) and p-chlorophenylalanine (PCPA), did not induce significant changes in the resting levels of brain serotonin, 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, dopamine and homovanillic acid (HVA), when measured 10 weeks later. However, when treated with an inhibitor of monoamine oxidase (MAO), tranylcypromine, the PCPA-treated animals showed a significantly lower accumulation of the biogenic amines than the animals treated with tranylcypromine alone. Furthermore, pretreatment with AMPT had no effect on the accumulation rate of these biogenic amines induced by tranylcypromine.

EFFECT FO DIETARY COPPER DEFICIENCY ON BRAIN CATECHOLAMINES OF NEWBORN RATS

To investigate the effect of dietary copper deficiency on brain catecholamines of newborn rats an experimental model was developed. Three groups of 10 female Sprague - Dawley rats were used. Group 1, copper deficient group, was fed with a copper-free diet 5 weeks prt-gestation and during gestation until delivery. Group II, the control, received a copper addecuate diet (6ppm). Group III, the pairfed, received a copper addecuate diet, but restringed according to the caloric input of the copper deficient group. Inmediatly after birth, the newborn rats from a total of 7; 4 and 7 litters of the groups I, II and III, respectively were decapited. Eleven assays of each group were performed. For each assay we used 1, 2, 3, or 4 whole brains minus cerebella. Whole brain dopamine and noradrenaline levels were quantified by high performance liquid chromatography with electrochemical detector. Copper deficient group showed a highly significant decrease in brain noradrenaline levels (50% lesser than others two groups: p = 0.0341), whereas dopamine concentrations remained largely unaltered. The levels of brain copper in the newborn rats in group 1 were significantively reduced (p = 0,0001) as well as brain weight (p = 0,0012). The CA1 sector neuronal counting was unaltered, however the girus dentatus counting showed a significant decrease in neuronal cellularity in Group I. We conclude that the materno-fetal copper deficiency altered the synthesis of noradrenaline. This could be a consequence of a functional impairment (possibly Dopamine - - hidroxilase enzyme dismiinished activity), however the possible role of the hypocellularity as the one observed in the girus dentatus sector can not be excluded.

Effect of chemical sympathectomy on cerebral blood flow in rats

Thirty male Wistar rats, weighing 350 to 400 gm each, received stereotactic injections of 6-hydroxydopamine (300 micrograms/kg) into the left lateral ventricle. The same amount of saline was injected into a control group of 15 rats. Seven days after this procedure, cerebral blood flow (CBF) was measured by the hydrogen clearance method. A hypertensive condition at a mean arterial pressure of about 160 mm Hg was maintained for 1 hour by intravenous infusion of phenylephrine. In the 6-hydroxydopamine-treated group, CBF increased significantly after the elevation of systemic blood pressure compared with that in the control group, and cerebral autoregulation was impaired. After a 1-hour study, the specific gravity of the cerebral tissue in the treated group significantly decreased; electron microscopic studies at that time revealed brain edema. It is suggested that depletion of brain noradrenaline levels causes a disturbance in cerebral microvascular tone and renders the cerebral blood vessels more vulnerable to hypertension.

Determination of the role of noradrenergic and 5-hydroxytryptaminergic neurones in postsynaptic alpha 2-adrenoceptor desensitization by desipramine and ECS.

1. Experiments were conducted to determine the respective roles which noradrenergic and 5-hydroxytryptaminergic neurones play in the down-regulation of postsynaptic alpha 2-adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine-induced mydriasis in conscious mice. 2. Mydriasis to clonidine (0.1 mg kg-1, i.p.) was markedly attenuated by administration of either desipramine (10 mg kg-1, i.p.) for 14 days or ECS (200 V, 2s) given five times over ten days confirming our previous observations. 3. The neurotoxin, DSP-4 (100 mg kg-1, i.p. X 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS. 4. Lesioning of central 5-hydroxytryptaminergic neurones with 5,7-dihydroxytryptamine (75 micrograms, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS. 5. Since noradrenergic neurones are essential for the desensitization of postsynaptic alpha 2-adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5-HT-containing neurones do not play a permissive role in the down-regulation of postsynaptic alpha 2-adrenoceptors by either antidepressant treatment.

Changes in brain dopamine levels, oocyte growth and spermatogenesis in rainbow trout, Oncorhynchus mykiss, following sublethal cyanide exposure.

Whole brain dopamine (DA) and norepinephrine (NE) levels were measured in sexually maturing (2 years +) male and female rainbow trout, Oncorhynchus mykiss, following exposure to 0.01 mg/L hydrogen cyanide (HCN). Following a 12 day exposure period in July and August 1988, whole brain DA levels of HCN exposed fish were significantly higher (p less than 0.05), relative to control fish, as measured by high performance liquid chromatography (HPLC). Brain NE levels were unaffected by HCN exposure. Whole brain DA and NE levels showed a strong correlation in control fish (r = +0.81), but not in HCN exposed fish (r = +0.28), likely due to altered DA levels in the latter group. No significant differences were found in brain DA and NE levels between males and females. Mean diameters of oocyte from ovaries of the vitellogenic females were significantly (p less than 0.01) reduced from 226 to 183 microns in control and HCN exposed fish respectively. Testes from males revealed significantly (p less than 0.001) higher numbers of spermatogonial cysts in HCN exposed fish. Evidence is given that chronic exposure to sublethal levels of HCN significantly alters brain DA levels in both sexes of rainbow trout, reduces growth in vitellogenic oocytes of the ovary in females and interferes with the passage of spermatogonia to the spermatocyte stage in sexually maturing males. Collectively, these results suggest that sublethal HCN affects the reproductive mechanisms via the hypophyseal-gonad axis in sexually maturing rainbow trout.

Significant correlation between cerebrospinal fluid and brain levels of norepinephrine, serotonin and acetylcholine in anesthetized rats

The present study was undertaken to determine cerebrospinal fluid (CSF) and brain levels of norepinephrine (NE), serotonin (5-HT) and their metabolites--3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA)--in rats pretreated with 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT). In the 6-OHDA pretreated rats, both CSF and brain concentrations of NE, DOPAC and HVA sustained significant decreases as compared with those in non-treated rats. Positive and significant correlations between CSF and brain levels were observed in respect to NE, DOPAC and HVA. In 5,7-DHT pretreated rats, both CSF and brain concentrations of 5-HT and 5-HIAA were significantly decreased. A positive and significant correlation between CSF and brain levels in respect to 5-HT and 5-HIAA was observed. Further studies were carried out to determine ACh levels of both the CSF and the brain in microspheres (MS)-treated rats, which are used as a model of microembolization. The CSF ACh concentrations in MS-treated groups were significantly decreased as compared with those in non-treated rats. The brain ACh contents also tended to decrease in this group. A positive and significant correlation was observed between CSF and brain levels of ACh. These findings suggest that NE, 5-HT and ACh concentrations in the CSF are direct indications of central noradrenergic, serotonergic and cholinergic nerve activity, respectively.

Changes in Convulsion Susceptibility of Lidocaine by Alteration of Brain Catecholaminergic Functions.

Influences of the manipulation of brain catecholaminergic neuronal activity on the incidence of lidocaine-induced convulsions in mice were studied and compared with those of pentylenetetrazol (PTZ)-induced convulsions. alpha-Methyl-p-tyrosine (alpha-MPT) decreased both brain noradrenaline (NA) and dopamine (DA) levels, and disulfiram decreased the NA level and increased the DA level. The incidence of lidocaine-induced convulsions was decreased by treatments with alpha-MPT and disulfiram, while that of PTZ was increased by either treatment. The incidence of lidocaine-induced convulsions was slightly, but not significantly increased by L-dihydroxyphenylalanine (L-DOPA), although the brain DA level was increased by L-DOPA. Methamphetamine and desipramine increased the incidences of lidocaine-induced convulsions. These results may suggest that brain catecholaminergic neurons, differing from their role in inhibiting control of PTZ-seizure, act to facilitate lidocaine-induced convulsions.

Hyperammonaemia causes many of the changes found after portacaval shunting

1. Portacaval shunting in rats results in several metabolic alterations similar to those seen in patients with hepatic encephalopathy. The characteristic changes include: (a) diminution of cerebral function; (b) raised plasma ammonia and brain glutamine levels; (c) increased neutral amino acid transport across the blood-brain barrier; (d) altered brain and plasma amino acid levels; and (e) changes in brain neurotransmitter content. The aetiology of these abnormalities remains unknown. 2. To study the degree to which ammonia could be responsible, rats were made hyperammonaemic by administering 40 units of urease/kg body weight every 12 h and killing the rats 48 h after the first injection. 3. The changes observed in the urease-treated rats were: (a) whole-brain glucose use was significantly depressed, whereas the levels of high-energy phosphates remained unchanged; (b) the permeability of the blood-brain to barrier to two large neutral amino acids, tryptophan and leucine, was increased; (c) blood-brain barrier integrity was maintained, as indicated by the unchanged permeability-to-surface-area product for acetate; (d) plasma and brain amino acid concentrations were altered; and (e) dopamine, 5-hydroxytryptamine (serotonin) and noradrenaline levels in brain were unchanged, but 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-hydroxytryptamine, was elevated. 4. The depressed brain glucose use, increased tryptophan permeability-to-surface-area product, elevated brain tryptophan content and rise in the level of cerebral 5-HIAA were closely correlated with the observed rise in brain glutamine content. 5. These results suggest that many of the metabolic alterations seen in rats with portacaval shunts could be due to elevated ammonia levels. Furthermore, the synthesis or accumulation of glutamine may be closely linked to cerebral dysfunction in hyperammonaemia.

Age- and diabetes-associated alterations in regional brain norepinephrine concentrations and adrenergic receptor populations in C57BL/KsJ mice

The diabetes-associated changes in regional brain norepinephrine (NE) concentrations and related adrenergic receptor types were correlated with changes in blood glucose levels and body weight (obesity) in 4–16-week-old C57BL/KsJ ( db/ db) mice relative to corresponding age-matched control (+/?) parameters. Regional brain (i.e. frontal cortex, septal area, amygdala, hypothalamus and medulla) NE levels were determined by high performance liquid chromatography and compared to the associated changes in tissue alpha-1,2 and beta-adrenergic membrane receptor populations. All db/db mice exhibited overt hyperglycemia and obesity relative to controls between 4 and 16 weeks of age. Regional brain NE levels in diabetics were chronically elevated as compared to those of age-matched controls. All of the α 1 and α 2 adrenergic receptor populations were elevated in the regional brain samples of diabetics relative to controls. In contrast, β-adrenergic receptor populations were depressed in diabetics as compared with age-matched controls. These data demonstrate that a marked modification in regional brain adrenergic parameters occurs in association with the overt expression of the diabetes mutation in this species. The observed changes in adrenergic influences in specific CNS loci may be causally related to the recognized diabetes-associated alterations in regional brain structure, function and metabolism in C57BL/KsJ ( db/db) mice.

Corticosterone-dependent alterations in utilization of catecholamines in discrete areas of rat brain

This study investigated the impact of chronic adrenalectomy (ADX), and subsequent corticosterone (CORT) replacement to ADX rats, on brain levels of norepinephrine (NE) and dopamine (DA) and their extent of depletion after α-methyl- p-tyrosine (α-MpT) administration. Seven discrete hypothalamic areas, namely, the paraventricular nucleus (PVN), medial preoptic nucleus (POM), dorsomedial nucleus (DMN), ventromedial hypothalamus (VMH), perifornical lateral hypothalamus (PLH), supraoptic nucleus (SON), and arcuate nucleus/median eminence (ARC-ME), were examined. The steady-state content of NE and DA in all areas remained essentially unaltered 7 days after ablation of the adrenal glands, as well as after subsequent CORT replacement therapy in ADX rats. However, ADX, which reduced circulating CORT levels to 0.3 μg% as compared to > 3.0 μg% in sham rats, caused a significant increase in the depletion of NE following α-MpT treatment, in 4 out of the 7 brain sites examined (PVN, PLH, DMN and ARC-ME). In these brain sites, the NE turnover rate (K,pg/μg protein/h) and rate constant (K,h −1) increased following ADX. The chronic subcutaneous CORT implant (200 mg), which raised circulating CORT levels of ADX rats to 11 μg%, prevented this enhancement of NE turnover in the PVN, PLH and ARC-ME, but not the DMN. Unlike NE, DA utilization in the 7 discrete hypothalamic areas of α-MpT-treated rats remained unaltered after ablation of the adrenal glands, as well as after the CORT replacement therapy in ADX rats. These results indicate that circulating CORT may have a modulatory role in the regulation of NE in specific discrete hypothalamic areas, and thereby have an impact on the control of various physiological responses.

Methylphenidate and pemoline do not cause depletion of rat brain monoamine markers similar to that observed with methamphetamine

Methyl-phenidate (Ritalin) and pemoline (Cylert) are central nervous system stimulants which are widely prescribed for attention deficit and other psychiatric disorders. Several other related stimulants, including amphetamine and methamphetamine, have been shown to cause long lasting decreases in monoamine markers in rat brain, characteristic of axonal degeneration. To assess the neurotoxic potential of methylphenidate and pemoline, we compared the effects of multiple injections (sc, bid for up to 4 days) of methylphenidate (21 and 50 mg/kg) and pemoline (20 and 70 mg/kg) with methamphetamine (5 and 15 mg/kg) on rat brain norepinephrine, dopamine, and serotonin levels and transport sites. While decreases were observed in all brain monoamine markers measured in rats treated with methamphetamine, no changes were observed in animals treated with methylphenidate as compared to saline-treated controls. Pemoline failed to induce significant changes in the level of monoamine transport sites; however, a wide array of changes were observed in the levels of 5-hydroxyindoleacetic acid, dopamine, and norepinephrine in various brain areas after a 3-day treatment regimen with a high dose (70 mg/kg) of pemoline. The lack of changes in monoamine transport sites following the repeated administration of high doses of methylphenidate and pemoline suggests that these drugs do not affect axonal integrity. However, the pattern of changes observed in the levels of monoamines after pemoline treatment may have relevance to the self-injurious behavior seen in these animals.

Further Characterization of the Neurofunctional Effects of the Calcium Ionophore A23187

Calimycin (A23187), a divalent cationic ionophore which increases intraneuronal concentrations of calcium, has been shown to produce neurofunctional changes associated with depression of brain excitability. The present report describes further characterization of the neurofunctional effects of acute parenteral exposure to A23187. Adult male rats were tested for the effects of A23187 on operant performance and general motor activity. In order to gain some insight into the neuronal systems which may be affected by A23187, brain levels of norepinephrine (NE), dopamine, serotonin, and their metabolites were determined. In addition, provocative pharmacologic challenges were employed to assess the interaction between A23187 and the centrally active drugs amphetamine (AMPH), scopolamine (SCOP), or chlorpromazine (CPZ). A23187 was found to effectively suppress fixed ratio-15 operant performance (p less than 0.001) at a dose of 0.5 mg/kg. This effect was temporary in nature inasmuch as performance was normalized by the day after dosing. This same dose of A23187, which produces a selective hypomotility, was found to have no apparent latent effects on the processes controlling circadian motor activity. Neurochemically, A23187 at 1 mg/kg induced a 64% increase (p less than 0.01) in the NE metabolite 3-methoxy-4-hydroxyphenylglycol, although levels of NE were unaffected. In the pharmacological challenge studies, AMPH and SCOP both attenuated and CPZ enhanced the acute hypomotility induced by 0.5 mg A23187/kg. The data show that low doses of A23187 induce a specific pattern of neurobehavioral dysfunction which may involve some interaction between the central catecholaminergic and cholinergic systems.

Tyrosine availability and brain noradrenaline synthesis in the fetus: control by maternal tyrosine ingestion

In spite of substantial evidence that tyrosine availability modulates catecholamine synthesis, under a variety of conditions, in adult brains, its possible influence during brain development has received little attention. In the present paper, the effect of tyrosine when administered to pregnant rats on tyrosine and noradrenaline brain levels in the fetus was investigated. In the first experiment noradrenaline (NA) was detected in the fetal brain by day 13 of development. NA levels increased from days 13 to 19. Administration of tyrosine to the mother raises both tyrosine and NA levels in the fetal brain. The increase in tyrosine was similar on days 13, 15, 17 and 19 of pregnancy. However, the increase of NA was more pronounced on days 17 and 19 than on days 13 or 15. Tyrosine and NA enhancement was detected 30 min after tyrosine administration, persisted for at least 2 h and disappeared completely 6 h after its administration. Both tyrosine and NA increase are tyrosine dose-related. The present studies suggest that there are no important barriers for tyrosine transport between the maternal blood and the fetal brain. Furthermore, during prenatal life the rate of NA synthesis is regulated by tyrosine brain concentration and therefore maternal intake of tyrosine is an important factor for noradrenaline synthesis regulation in the fetal brain. The possible functional significance of noradrenaline brain increase after tyrosine administration are unknown. However, the NA modification could be the cause of the persistent behavioral modification that we have found in adult rats whose mothers were treated with tyrosine during pregnancy.

Brain norepinephrine levels after BCG stimulation of the immune system

Brain norepinephrine, dopamine and serotonin levels were determined in right and left hemisphere from female C 3H/He mice 13 days after their immune system was stimulated by an intraperitoneal injection of bacillus Calmette-Guérin (BCG) (10 7 bacilli/mouse). Increased norepinephrine levels were observed in both hemispheres but significantly only in the right one. No concomitant variations in dopamine or serotonin levels were detected. Furthermore, norepinephrine levels in the right hemisphere appeared to be correlated with the ability of lymphocytes to proliferate after concanavalin A stimulation. The modulation of the immune system by the brain neocortex has been previously shown to be lateralized. Here we show that the information from the immune system towards the central nervous system also appears to be expressed in a lateralized manner.

Behavioural and neurochemical effects of antipamezole, a novel α2-adrenoceptor antagonist

The effects of antipamezole (MPV-1248), a novel selective and specific α 2-adrenoceptor antagonist, were studied on monoamine metabolism in rat brain and CSF. In addition, the ability of the drug to antagonize the behavioural and neurochemical effects of two α 2-adrenoceptor agonists, detomidine and medetomidine, was assessed. Atipamezole, 0.03–3.0 mg/kg, had no gross behavioral effects on the rats. Above 3 mg/kg, the rats showed increased vocalization and some hostility, rapid breathing and piloerection. The drug caused dose-dependent, rapid and relatively long-lasting increase in the central turnover of noradrenaline (NA) as reflected by increases in the levels of the major metabolites of NA in brain and CSF and an increase in the depleting effect of α-methyl-para-tyrosine on brain NA levels. An increase in the turnover of serotonin (5-HT) in brain was indicated by a decrease in the concentration of 5-HT and a corresponding increase in the level of its metabolite, 5-hydroxyindoleacetic acid. Atipamezole was able to antagonize the sedative, hypothermic and neurochemical effects of two potent α 2-agonists, detomidine and medetomidine. These results give support for the characterization of atipamezole as a potent antagonist at central α 2-adrenoceptors with a rapid onset of action.

Brain norepinephrine and convulsions in the genetically epilepsy-prone rat: Sex-dependent responses to Ro 4-1284 treatment

Seizure predisposition in the Genetically Epilepsy-Prone Rat (GEPR) is at least partially dependent on central nervous system noradrenergic deficits. We have previously shown that moderate seizure GEPRs (GEPR-3) experience an increase in seizure severity after receiving Ro 4-1284, a monoamine vesicle inactivating drug. We are now reporting the effect of this drug on severe seizure GEPRS (GEPR-9). Motives for this study were: (a) to determine the effects of further depletion of innately deficient monoaminergic stores on seizure latencies and (b) to investigate whether a previously documented seizure severity difference between the sexes is related to the defective monoaminergic system in these subjects. GEPR-9s with known seizure history were tested for latency to onset of running phase and convulsion 45 minutes after Ro 4-1284 or saline administration. Brain norepinephrine levels were also determined. Ro 4-1284 caused severe depletion of monoamines in all brain areas assayed in both sexes of GEPR-9s and also caused a reduction in the latencies for onset of running and convulsion. The drug-induced norepinephrine depletion across the brain areas surveyed was significantly greater in females than in their male littermates. These observations prompt us to postulate that noradrenergic neurons in female GEPR-9s are functionally different from those in males and that this difference is detected in the differential effectiveness of Ro 4-1284 between the two sexes. Also, the influence of gonadal hormones on seizure predisposition and on the neurochemical actions of Ro 4-1284 may be different in GEPR-9 males and females.

Alterations of fetal brain biogenic amine metabolites by maternal ethanol exposure

1. 1. Pregnant Sprague-Dawley rats treated chronically with ethanol (3 g/kg daily for the last third of pregnancy) had decreased placental weights at birth ( ca 23%). 2. 2. Whole fetal brain levels of HVA and 5-HIAA were similarly decreased 32 and 38%, respectively. 3. 3. MHPG levels were also marginally reduced (i.e. 15% decline). 4. 4. In the presence of a potent type A MAO inhibitor (harmaline, 10 mg/kg maternal weight 2 hr before fetal delivery) co-treatment with ethanol was found to result in a 60% elevation of whole fetal brain norepinephrine levels. 5. 5. Other biogenic amines and metabolites were not altered by ethanol treatment.

Brain norepinephrine levels and regulation of catecholamine turnover in the rat heart

Brain norepinephrine levels and regulation of catecholamine turnover in the rat heart

Reexamination of the relationship between alcohol preference and brain monoamines in inbred strains of mice including senescence-accelerated mice

The relationship between voluntary alcohol consumption and brain monoamine levels was studied in the inbred strains of C57BL/6N, C57BL/6J, A/J, BALB/cA, CBA/N, C3H/He and DBA/2cr mice; the congeneric mouse strain, B10.Br/Sg, and the senescence accelerated mouse (SAM P1, SAM P2). The C57BL strains exhibited a high alcohol preference whereas the other strains exhibited a low alcohol preference. A clear positive relationship was found between alcohol intake (g/kg/day) and brain norepinephrine level (r=0.683, p<0.05), and a clear negative relationship between alcohol intake and brain serotonin level (r=−0.628, p<0.05). The content of brain dopamine was not clearly correlated with alcohol intake (r=−0.206, p>0.05). These findings suggest that in mice voluntary alcohol preference is influenced by brain norepinephrine and serotonin levels genetically.

Studies on the central action of L-threo-3,4-dihydroxyphenyl-serine (L-threo-DOPS) in FLA-63-treated mice

In order to clarify the central action of L-threo-DOPS, the effect of benserazide on behavioral and biochemical changes by L-threo-DOPS in FLA-63-treated mice was studied. L-threo-DOPS in combination with nialamide markedly increased both the locomotor activity and the concentrations of the brain, heart and kidney norepinephrine (NE) in the FLA-63-treated mice. Benserazide at low doses did not alter either the rise of the brain NE level or the increase in locomotor activity, whereas it significantly inhibited the rise of the heart and kidney NE levels. Benserazide at a high dose significantly inhibited all of them. These results suggested that the increase in locomotor activity might be mediated via activation of the central noradrenergic neurons system by L-threo-DOPS.