Brain Norepinephrine Concentrations Research Articles

Effects of l-dopa on dopamine and norepinephrine concentrations in rat brain assessed by gas chromatography

A highly specific and sensitive gas chromatographic method has been developed which is capable of determining picogram amounts of dopamine (DA) and norepinephrine (NE) simultaneously. The catecholamines are converted to the N-2,6-dinitro-4-trifluoromethylphenyl, O-trimethylsilyl derivatives, which are analyzed by gas chromatography with electron-capture detection. The method has been applied to the assay of catecholamines in rat brain extracts. One hour after an acute dose (150 mg/kg i.p.) of l-3,4-dihydroxyphenylalanine, the rat brain concentration of DA increased by 130% while the concentration of NE was unchanged.

Effect of 5,7-dihydroxytryptamine on serotonergic control of prolactin secretion and behavior in rats.

The intracisternal administration of 5,7-dihydroxytryptamine (5,7-DHT) to rats resulted in a potentiated response to 5-hydroxytryptophan (5-HTP) when the animals were tested 30 days later. The 5-HTP-induced changes include elevation of serum prolactin, decrease in operant responding, and the magnitude of the "serotonin behavioral syndrome" observed after 5-HTP administration. The serotonin concentration in brains of 5,7-DHT-treated animals reached maximum earlier and remained elevated longer than that of controls following administration of 5-HTP. Brain norepinephrine and dopamine concentration were not affected by 5-HTP in either group of animals. The increase in serum prolactin concentration elicited by administration of the serotonergic agonists quipazine or 5-methoxy-N,N-dimethyltryptamine and by the serotonin uptake inhibitor fenfluramine also was potentiated by pretreating rats with 5,7-DHT. These data suggest that both serotonergic receptor supersensitivity and the absence of presynaptic uptake sites contribute to the enhanced responses to 5-HTP occurring in rats previously treated with 5,7-DHT. The findings further demonstrate that both behavioral and hormonal measures can be used to assess the sensitivity of serotonergic receptors and indicate that 5,7-DHT may be useful in evaluating the role of serotonergic neurons in neuroendocrine function.

The Schizophrenia Syndrome

Six biological variables-platelet monoamine oxidase activity, urine phenylethylamine concentration, brain norepinephrine concentration, abnormalities on computerized tomography, lateralization asymmetries, and the presence or absence of tardive dyskinesia-are used to discriminate possible biological groups of schizophrenic patients. All variables successfully subclassify patients, some into divisions consistent with phenomological, psychosocial, or biochemical descriptions or hypotheses of schizophrenia. None of the measures, however, has sufficiently stood the test of time to be of clinical utility.

Brain norepinephrine, dopamine, and 5-hydroxytryptamine concentration abnormalities and their role in the high seizure susceptibility of epileptic chickens.

Norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) concentrations were determined in cerebral hemispheres, optic lobes, the midbrain pons–medulla, and cerebellum of adult homozygous recessive epileptic chickens during interictal periods and compared with concentrations in their nonepileptic heterozygous hatchmates. Cerebral hemispheres from epileptic fowl contained significantly lower concentrations of 5-HT and DA and higher concentrations of NE than nonepileptics. Elevation of 5-HT with phenelzine, tryptophan, or the combination of phenelzine plus tryptophan had no effect on seizure susceptibility or severity. Treatment with L-3,4-dihydroxyphenylalanine, which increased brain DA, also had no effect on the seizure incidence or severity. Administration of phenoxybenzamine, phentolamine, or propranolol to block adrenergic receptors did not reduce seizure susceptibility.

Determination of brain regional normetanephrine levels by liquid chromatography with electrochemical detection (LC-EC)

1. 1. A liquid chromatography-electrochemical detection (LC-EC) assay for brain normetanephrine (NMN) has been developed which also allows concurrent determination of brain norepinephrine (NE), dopamine (DA) and serotonin (5-HT) concentrations. 2. 2. Tissue samples were prepurified by cation exchange chromatography and the amines then separated by reversed-phase liquid chromatography on an octylsilane stationary phase. 3. 3. This method permits measurement of at least 200 pg of the above amines in brain. 4. 4. The concentrations of NMN in rat and mouse brain regions were found to be in the range of 0.115–0.435 ng/mg protein.

Calcium-sensitive accumulation of norepinephrine in rat cerebral cortex

The accumulation of high and low concentrations of [ 3H]l-norepinephrine has been examined in a crude synaptosomal preparation of rat cerebral cortex in the presence and absence of uptake 1 inhibitors. When uptake 1 was blocked, [ 3H]l-norepinephrine accumulation exhibited very rapid initial rates. It was not inhibited by 10 mM normetanephrine, a potent inhibitor of peripheral uptake 2, but it was inhibited by 10 mM metaraminol. This accumulation was markedly reduced when calcium ions were omitted from the incubation medium, and is named here ‘calcium-sensitive accumulation’ (CSA) to distinguish it functionally from the sodium-dependent, high affinity, uptake 1 process. CSA may be localized in nerve endings since it was found predominantly in the synaptosomal fraction of homogenates subjected to density gradient centrifugation in sucrose or Fn Ficoll-in-sucrose. At high concentration of [ 3H]l-norepinephrine (1.0 μM) and short incubation times, CSA accounted for most of the total accumulation of [ 3H]l-norepinephrine whereas uptake 1 contributed only a small portion. Since extracellular concentrations of brain norepinephrine are thought to reach levels in excess of 1.0 μM, CSA may be a significant factor in noradrenergic neuronal transmission.

Enhanced 5-hydroxytryptamine and dopamine-mediated behavioural responses following convulsions—III the effects of monoamine antagonists and synthesis inhibitors on the ability of electroconvulsive shock to enhance responses

Abstract Repeated electroconvulsive shock (ECS) administration to rats resulted in enhanced 5-hydroxytryptamine 5-HT) and dopamine (DA) mediated behavioural responses. Pretreatment with p -chlorophenylalanine before the course of ECS (over 10 days) abolished the enhancement of 5-HT mediated responses but not the enhancement of DA-mediated responses. Pretreatment of rats just before each ECS with either of the 5-HT antagonists (−)-propranolol (20 mg/kg) or methergoline (5 mg/kg) also abolished the enhancement of 5-HT but not DA-mediated responses. In contrast, pretreatment with haloperidol (0.5 mg/kg) before each ECS did not inhibit the enhancement of 5-HT or DA-mediated responses. α -Methyl p -tyrosine administration during the course of ECS administration abolished both the enhancement of 5-HT and DA-mediated responses. Specific depletion of the brain noradrenaline content by neurotoxin lesioning did not alter the behavioural responses to either the 5-HT agonist quipazine or the dopamine agonist apomorphine. However, following ECS, lesioned animals did not show the enhanced response to these agonists that was seen in the sham operated rats. The data therefore suggest that intact 5-HT synthesis and release is important for ECS to enhance 5-HT mediated responses, but not to enhance DA-mediated responses. Electroconvulsive shock-induced enhancement of DA-mediated responses does not require intact brain DA synthesis, consistent with other published data, and intact brain NA systems ( α -methyl p -tyrosine and lesioning results) are required for ECS to produce enhanced responses of both 5-HT and DA-mediated behavioural resnonses.

Brain noradrenergic responses to training and to amnestic frontal cortex stimulation

Rats were trained in a one-trial inhibitory (passive) avoidance task prior to receiving supraseizure electrical stimulation of frontal cortex, a treatment that results in amnesia. Forebrain and brainstem norepinephrine (NE) concentrations decreased by 23% 10 min after footshock training. Posttraining frontal cortex stimulation resulted in a potentiation of the forebrain NE response (to 31–33% below control values) and in attenuation of the brainstem response (0–5% lower than control values). These results are consistent with previous findings that indicate that good retention performance is predicted by training and treatment conditions that result in approximately a 20% decrease in brain NE content as measured 10 min after training; deviations from this optimal level, presumably reflecting more or less NE release, predict poor retention in comparably trained and treated rats. Thus, memory storage processing appears to be sensitive to many manipulations that alter the endogenous posttraining brain NE response to footshock.

The effects of butacaine hemisulfate on brain and heart catecholamine concentrations of the mouse

Butacaine hemisulfate was tested for possible effects on mouse brain and heart catecholamine concentrations. A single dose (50 mg/Kg) lowered brain dopamine and heart and brain norepinephrine concentrations. Repeated hourly administration for 4 hours markedly lowered brain and heart catecholamines. Butacaine and the reserpine-like drug Ro4-1284 were compared in vitro for effects on accumulation of m-tyramine (m-TA) by mouse striatum. m-TA, a false dopaminergic transmitter, is an MAO substrate and thus depends on granular binding for protection from MAO. There was more than 85% reduction of m-TA accumulation in the presence of butacaine or Ro4-1284 (both at 10−5M). However, in tissues taken from animals previously treated with an MAO inhibitor, neither compound prevented accumulation of m-TA. These observations suggest that butacaine has a weak reserpine-like action at the level of the storage granuale.

Effects of Tricyclic Antidepressants on Tetrabenazine-Induced Depletion of Brain Monoamines In Rats. 1. Norepinephrine

We studied the effects of tricyclic antidepressants on the tetrabenazine (TB)-induced depletion of brain norepinephrine (NE) using rats. The test drugs were generally administered orally 3 hr before and 2 mg/kg of TB or reserpine (RES) administered subcutaneously 2 hr before sacrifice. The TB-induced NE depletion was enhanced by pretreatment with desmethylimipramine (DMI, 25--100 mg/kg), imipramine (IM, 25--100 mg/kg), chlorimipramine (100 mg/kg), maprotyrine (50 mg/kg), amitriptyrine (50--100 mg/kg), chlorpromazine (CPZ, 5--20 mg/kg i.p.,) and amphetamine sulfate (10 mg/kg). DMI partially suppressed TB-induced NE depletion at 0.5 hr after TB administration. The RES-induced NE depletion was not enhanced with these drugs except for amphetamine. DMI, IM, and CPZ suppressed it instead. DMI also enhanced the yohimbine (2 mg/kg)-induced decrease. The brain NE content showed a tendency toward recovery 2 hr after TB administration, but approached the minimal level at 0.5 hr after TB administration or at 2 hr after RES administration in non-treated rats. In pargyline-pretreated rats, TB produced a decrease of brain NE with an increase of normetanephrine, while the action of RES was weaker than that of TB, up to 2 hr. These results suggest that enhancement of the TB-induced brain NE depletion by tricyclic antidepressants reflects the blockage of NE reuptake from the synaptic cleft.

Central mediation of the antihypertensive effect of pargyline in spontaneously hypertensive rats

The monoamine oxidase (MAO) inhibitor pargyline induced a moderate (about 20 mm Hg) but persistent (48 h) decrease of systolic blood pressure in unanesthetized adult spontaneously hypertensive rats (SHR) but not in normotensive rats. The fall of blood pressure correlated with the blockade of norepinephrine (NE) deamination by brain homogenates. After an intracerebroventricular (icv) injection of 6-hydroxydopamine, which lowered brain NE content by about 70%, pargyline was unable to diminish arterial pressure. Blockade of central α-adrenoreceptors by the treatment with phenitolamine (100 μg icv) could either prevent or reverse the fall of blood pressure in SHR induced by pargyline. Moreover, a low dose of pargyline injected directly into the brain lowered arterial pressure. We conclude that the hypotensive action of pargyline in SHR appears to be consequence of NE accumulating at an inhibitory α-adrenoceptor in brain.

The effects of chronic regimens of clorgyline and pargyline on monoamine metabolism in the rat brain.

AbstractThe effects of chronic administration of clorgyline and pargyline on rat brain monoamine metabolism have been examined. The inhibitory selectivity of these drugs towards serotonin deamina‐tion (MAO type A) and phenylethylamine deamination (MAO type B) can be maintained over a 21‐day period by proper selection of low doses of these drugs (0.5‐1.0 mg/kg/24h). The results are consistent with MAO type A catalyzing the deamination of serotonin and norepinephrine and with MAO type B having little effect on these monoamines. Dopamine appears to be dcaminated in vivo principally by MAO type A. Clorgyline administration during a 3‐week period was accompanied by persistent elevations in brain norepinephrine concentrations; serotonin levels were also increased during the first 2 weeks, but returned towards control levels by the third week of treatment. Low doses of pargyline did not increase brain monoamine concentrations, but treatment with higher doses for 3 weeks led to elevations in brain norepinephrine and 5‐hydroxytryptamine; at this time significant MAO‐A inhibition had developed. The changes in monoamine metabolism seen at the end of the chronic clorgyline regimen are not due to alterations in tryptophan hydroxylase activity. At this time tyrosine hydroxylase activity was also unaffected.

The effect of acute carbaryl administration on various neurochemical and blood chemical parameters in the Japanese quail

Carbaryl, a carbamate insecticide which functions primarily as a cholinesterase inhibitor, has been shown to cause alterations in other general neurochemical parameters as well as blood chemical parameters. The present study examines more specifically the effects of a cholinesterase inhibitor on catecholaminergic components within the central and peripheral nervous systems and addresses the idea of a possible relationship between altered neuronal activity and the hormonal activity of the Japanese quail. The injection of carbaryl (30 mg/kg) caused a significant inhibition of acetylcholinesterase activities in the telencephalon and medulla oblongata at 2 hr postinjection but did not affect cerebellum and diencephalon acetylcholinesterase activities. Carbaryl had no effect on endogenous concentrations of regional brain norepinephrine or on its turnover. Endogenous telencephalon dopamine concentrations were significantly elevated at 24 hr postinjection but dopamine turnover was not altered. Carbaryl caused a significant elevation of cardiac norepinephrine concentrations at 48 hr post-injection as well as an increase in cardiac norepinephrine turnover. Endogenous adrenal catecholamine concentrations were not affected by carbaryl administration, yet adrenal catecholamine turnover was accelerated. Plasma glucose and cholesterol concentrations were not altered by the injection of carbaryl. The results indicate that carbaryl has a subtle effect on the neurochemical integrity of the central and peripheral nervous systems of the Japanese quail.

Effect of gamma-glutamyl cycle inhibitors on brain amino acid transport and utilization.

Two inhibitors of the gamma-glutamyl cycle, methionine sulfoximine (MSO) and 2-imidazolidone-4-carboxylic acid (ICA) were administered to C57LB/6J mice. Both agents resulted in a reduced rate of transport of tyrosine from blood to brain and a decreased rate of incorporation of tyrosine from plasma into brain protein. MSO administration also diminished to concentrations of brain tyrosine, dopamine, and norepinephrine. MSO decreased the transport rate of valine by brain as well as the rate of its incorporation into protein when expressed in relation to the plasma specific activity. The results demonstrate a significant role for the gamma-glutamyl cycle in the transport of large neutral amino acids from blood to brain.

Effects of α- and β-adrenergic receptor antagonists on post-trial epinephrine modulation of memory: Relationship to post-training brain norepinephrine concentrations

Rats were trained in a one-trial inhibitory (passive) avoidance task. Each animal received a 30-min pretrial injection of saline, phenoxybenzamine, or propranolol and an immediate post-trial injection of saline or epinephrine. Animals were tested for retention 24 hr later. In the absence of pretreatment with either adrenergic blocking agent, epinephrine enhanced retention of training with low footshock and impaired retention of training with high footshock. Pretrial injections of propranolol, but not phenoxybenzamine, attenuated epinephrine-produced enhancement of retention performance. Conversely, pretrial treatment with phenoxybenzamine, but not propranolol, attenuated epinephrine-produced retention impairment. Post-training brain norepinephrine concentrations were sensitive to the training-treatment conditions; the extent of a transient decrease (maximal 10 min after training) predicted, in most cases, the retention performance observed in comparably trained and treated animals. These findings thus extend and corroborate our previous evidence suggesting that hormonally mediated central noradrenergic activity may underlie retrograde amnesia and enhancement of memory processes. In addition, these findings suggest that memory storage processing may be modulated by normal post-training hormonal and central aminergic responses to training.

Brain biogenic amines and intravenous self-administration of cocaine in rats.

1. The possible involvent of noradrenaline, dopamine, serotonin and 5-hydorxyindoleacetic acid in the behavioural reinforcement produced by invravenous cocaine has been investigated. 2. rats, in Skinner boxes, were allowed to self-administer cocaine through a chronically implanted jugular vein cannula. A consistent response rate in the order of one self-administration every 10 min was observed with a dose of 3.0 mg/kg cocaine hydrochloride per response. 3. Another group of rats was cannulated and injected with a range of one to six such doses of cocaine at 10 min intervals on the basis of the responding rate, established by rats in the Skinner box. At times of 2,5 and 8 min after each dose of cocaine, the rats were decapitated and brain concentrations of noradrenaline, dopamine, serotonin and 5-hydroxyindoleacetic acid were determined. 4. The brain levels of noradernaline exhibited a cyclic pattern of rise and fall after each dose of cocaine, which corresponded in its time base with the time interval between responses established by the rats in the Skinner box.

Posttraining brain norepinephrine concentrations: Correlation with retention performance of avoidance training and with peripheral epinephrine modulation of memory processing

Posttrial epinephrine injections can enhance or impair later retention performance of inhibitory (passive) avoidance training in rats. The findings reported here indicate that the effects on retention of epinephrine injections and of footshock level are closely related to transient posttraining decreases in whole brain norepinephrine concentrations. Posttraining norepinephrine levels, as measured 10 min after training and treatment, predict the later retention performance of groups of rats trained with high or low footshock and, in addition, predict the retroactive effects (enhancement or impairment) of posttrial epinephrine injections. These findings are consistent with the view that hormonal responses to training may modulate memory storage processing. In addition, the results suggest that memory modulation may involve neuroendocrine mechanisms that include the central noradrenergic system.

Evaluation of the effects of nerve growth factor and anti-nerve growth factor on the development of central catecholamine-containing neurons

Intracisternal NGF or anti-NGF has been found to produce no long-term major alterations in central norepinephrine (NE) or dopamine levels when administered to neonatal rats. While NGF and anti-NGF were found to produce significant changes in brain NE content within one week of treatment, changes in central NE were no longer detectable at 30 days of age. Modification of the growth response of the central adrenergic neurons following 6-OHDA treatment was also not affected by NGF or anti-NGF when evaluated 3 weeks after treatment. However, centrally administered anti-NGF did induce a loss of peripheral NE terminals, which was attributed to leakage of the anti-NGF from the central injection site.

Effect of nicotinic acid on catecholamine synthesis in rat brain.

Effect of nicotinic acid on the formation of catecholamine has been studied. Norepinephrine and dopamine concentrations in brain were 30 per cent higher and brain catecholamine formation was 50 per cent higher in the nicotinic acid-supplemented rats than the nicotinic acid-deficient rats. However, these catecholamine levels of the nicotinic acid-deficient rats were recovered by the administration of nicotinic acid. The concentration of brain tyrosine was unaltered after administration of nicotinic acid to the nicotinic acid-deficient rats. Therefore, the changes catecholamine formation by the nicotinic acid supplementation were not due to the difference of tyrosine concentration in the brain which is the precursor for catecholamine biosynthesis. As the difference of catecholamine concentration between the nicotinic acid deficient and the nicotinic acid supplemented group was smaller than that of catecholamine formation of these groups, the turnover of catecholamine was supposed to be decreased in nicotinic acid deficiency.

Alrestatin: gastric acid antisecretory-antiulcer activity in the rat.

Alrestatin sodium (AY-22,284-A) inhibited gastric acid secretion and decreased the volume of gastric juice produced in the pylorus-ligated rat when administered intraperitoneally or perorally. Pentagastrin-induced gastric acid output in the unanesthetized rat was antagonized. The pyloric ligation-induced ulcer formation in the rat was inhibited. Alrestatin sodium did not exhibit an anticholinergic profile. The drug did not block the norepinephrine neuronal uptake mechanism in rat brain or heart; it did not alter the endogenous norepinephrine concentration in the heart and decreased endogeneous brain norepinephrine concentration. Alrestatin sodium is an effective inhibitor of gastric acid secretion and ulcer formation in the rat.