Brain Norepinephrine Metabolism Research Articles

Tyr-Trp administration facilitates brain norepinephrine metabolism and ameliorates a short-term memory deficit in a mouse model of Alzheimer's disease.

The physiological actions of orally ingested peptides on the brain remain poorly understood. This study examined the effects of 39 orally administered synthetic Tyr-containing dipeptides on the enhancement of brain norepinephrine metabolism in mice by comparing the concentration of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Although Tyr-Tyr administration increased blood and cerebral cortex (Cx) Tyr concentrations the most, Tyr-Trp increased Cx MHPG concentration the most. The oral administration of Tyr-Trp ameliorated a short-term memory deficit of a mouse model of cognitive dysfunction induced by amyloid beta peptide 25–35. Gene expression profiling of mouse brain using a microarray indicated that Tyr-Trp administration led to a wide variety of changes in mRNA levels, including the upregulation of genes encoding molecules involved in catecholamine metabolism. A comparative metabolome analysis of the Cx of mice given Tyr-Trp or Tyr-Tyr demonstrated that Tyr-Trp administration yielded higher concentrations of Trp and kynurenine pathway metabolites than Tyr-Tyr administration, as well as higher L-dopa levels, which is the initial product of catecholamine metabolism. Catecholamines were not significantly increased in the Cx of the Tyr-Tyr group compared with the Tyr-Trp group, despite a marked increase in Tyr. Presumably, Tyr-Trp administration enhances catecholamine synthesis and metabolism via the upregulation of genes involved in Tyr and Trp metabolism as well as metabolites of Tyr and Trp. These findings strongly suggest that orally ingested Tyr-Trp modulates the brain metabolome involved in catecholamine metabolism and contributes to higher brain function.

P-Chlorophenylalanine antagonism of the analgesia and increase in brain noradrenaline metabolism produced by morphine

Journal Article p-Chlorophenylalanine antagonism of the analgesia and increase in brain noradrenaline metabolism produced by morphine Get access T G Reigle, T G Reigle Department of Pharmacology, School of Pharmacy University of Georgia, Athens, Georgia 30602 U.S.A. Correspondence. Department of Pharmacology, School of Pharmacy University of Georgia, Athens, Georgia 30602 U.S.A. Search for other works by this author on: Oxford Academic Google Scholar W L Barker W L Barker Department of Pharmacology, School of Pharmacy University of Georgia, Athens, Georgia 30602 U.S.A. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 35, Issue 5, May 1983, Pages 324–325, https://doi.org/10.1111/j.2042-7158.1983.tb02945.x Published: 12 April 2011 Article history Received: 03 November 1982 Published: 12 April 2011

Brain monoamines, exercise, and behavioral stress: animal models.

This paper summarizes our studies examining whether changes in levels of brain monoamines after chronic exercise are associated with altered behavioral and endocrine responses to stressors other than exercise. The focus is on using animal models relevant for understanding reports by humans that regular physical activity reduces depression and anxiety. We studied the effects of chronic activity wheel running or treadmill exercise training on levels of norepinephrine (NE) measured in brain cell bodies and terminal regions at rest and after behavioral stress. We also measured brain levels of serotonin, i.e., 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma aminobutyric acid (GABA), which function as both antagonists and synergists with NE. In general, we found that chronic activity wheel running increased NE levels in the pons medulla at rest and protected against NE depletion in locus coeruleus cell bodies after footshock; the concomitant reduction in escape-latency was consistent with an antidepressant effect. Wheel running also decreased the density of GABAA receptors in the corpus striatum while increasing open-field locomotion, consistent with an anxiolytic effect, but had no effect on hypothalamic-pituitary-adrenal cortical response to footshock measured by plasma levels of adrenocorticotropic hormone (ACTH), corticosterone, and prolactin. In contrast, treadmill exercise training increased the metabolism of NE in brain ascending terminal areas for NE, increased the secretion of ACTH after footshock and immobilization stress and had no effect on GABAA receptor density or open field locomotion. The validity of animal models for studying depression and anxiety after forced versus voluntary exercise is discussed. Recommendations are offered for improving the methods used in this area of research.

Effects of angiotensin II on regional brain noradrenaline metabolism in non-stressed and stressed rats.

By measuring levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in various rat brain regions, the effects of angiotensin II (AT II) injected intracerebroventricularly (ICV) were investigated in non-stressed and stressed rats. Immobilization stress with a wire mesh was employed. Immobilization stress induced significant increases in MHPG-SO4 levels in all brain regions examined, i.e., hypothalamus, amygdala, thalamus, midbrain, hippocampus, cerebral cortex and locus coeruleus (LC) region, which suggests that stress increases NA release in these regions. AT II (1 and 10 micrograms), injected ICV 5 min before exposure to stress for 60 min, attenuated stress-induced increases in MHPG-SO4 levels in the hypothalamus, thalamus and amygdala. AT II, injected ICV in non-stressed rats at 65 min before sacrifice, significantly elevated MHPG-SO4 levels in the midbrain, cerebral cortex, thalamus and LC region. These results indicate that the attenuating effect of AT II on stress-induced increases in brain NA release are, in part, related to the reduction of fear and/or anxiety of the animals exposed to stress.

O-116 - Regional brain noradrenaline metabolism to extended exposure to restraint stress in aging rats.

O-116 - Regional brain noradrenaline metabolism to extended exposure to restraint stress in aging rats.

Effects of neurotropin on regional brain noradrenaline metabolism in rats.

By measuring levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in various rat brain regions, we investigated the effects of an extract isolated from vaccinia virus-inoculated and inflamed skin or tissue of rabbits (Neurotropin, NSP), administered acutely or chronically, on regional NA metabolism in stressed and nonstressed rats. An acute administration of NSP at 50 mg/kg significantly elevated MHPG-SO4 levels in the amygdala and cerebral cortex; and 100 mg/kg of the drug significantly increased the metabolite levels in the hypothalamus, amygdala, thalamus, midbrain, cerebral cortex and pons plus medulla oblongata without affecting NA levels. This suggests that acutely injected NSP slightly increases NA release in these brain regions. One hour immobilization stress caused significant increases in MHPG-SO4 levels, which were not affected by pretreatment with either 50 mg/kg or 100 mg/kg of NSP. Chronic injection with NSP daily at either 50 mg/kg or 100 mg/kg for 7 days was without effect on NA metabolism in all brain regions examined. However, increases in MHPG-SO4 levels caused by stress were significantly attenuated in some regions including the hypothalamus, amygdala and midbrain in chronic NSP-treated rats. This indicates that although an acute administration of NSP slightly increases brain NA release, a chronic treatment with NSP rather attenuates increases in NA release caused by immobilization stress in brain regions such as the hypothalamus, amygdala and midbrain. This suggests a possibility that these attenuating effects on stress-induced increases in brain NA release caused by chronic administration of NSP might be related to the stress-reducing or anti-stress properties of NSP.

The effect of chronically administered mianserin, 8-hydroxymianserin and desmethylmianserin on the 'open field' behaviour and brain noradrenaline metabolism in the olfactory bulbectomized rat.

The chronic effects of mianserin and two of its major metabolites on the behaviour of olfactory bulbectomized rats in the 'open field' apparatus were studied. When these compounds were tested at the same dose, only the parent compound was active in attenuating the hypermotility which the bulbectomized rat exhibited under these experimental conditions. Changes in the concentrations of noradrenaline and 3-methoxy-4-hydroxyphenylglycol (MHPG) were also determined in the amygdaloid cortex and mid-brain regions of the sham-operated and lesioned rats. Only mianserin reversed the reduction in the noradrenaline concentration which occurred in the amygdaloid cortex following bulbectomy; the changes in noradrenaline or MHPG in the mid-brain were not correlated with this behavioural effect of mianserin.

O-9 - Characteristics of regional brain noradrenaline metabolism induced by repeated stress in aged rats

O-9 - Characteristics of regional brain noradrenaline metabolism induced by repeated stress in aged rats

Is 3,4-dihydroxyphenylglycol the major route of central norepinephrine metabolism in rat brain?

Central norepinephrine (NE) metabolism was assessed by measuring 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 3,4-dihydroxyphenylethyleneglycol (DHPG) in different rat brain areas after saline or probenecid (300 mg/kg) administration. Under probenecid, results showed an increased accumulation of total MHPG and DHPG, and a clear preponderance of DHPG levels over MHPG in almost all the brain areas examined. Estimation of their formation rates confirmed that in basal conditions DHPG is formed more rapidly. This study supports the notion that, without ruling out the importance of MHPG, brain DHPG may be a useful index of central NE activity.

Reduced Brain Norepinephrine Metabolism in Obese (ob/ob) Mice is Not Normalized by Tyrosine Supplementation

Five-week-old female lean and obese (ob/ob) mice were fed a 20% protein diet (1.1% tyrosine) or a 20% protein diet supplemented with tyrosine (4% tyrosine). On d 4 of supplementation, brain norepinephrine (NE) synthesis rate and brain efflux of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), a major metabolite of NE in mouse brain, were measured after administration of the monoamine oxidase inhibitor pargyline. Control obese mice had a lower rate of NE synthesis and a lower MHPG efflux than lean controls. Tyrosine supplementation elevated brain tyrosine concentration twofold, but had no effect on NE synthesis rate or MHPG efflux in either group. Likewise, tyrosine supplementation for up to 1 mo had no effect on food intake, oxygen consumption or body weight in obese mice and only a transient effect in lean mice, in which oxygen consumption was higher on d 2 and 3 and food intake was higher on d 3 and 4 compared with nonsupplemented lean mice. We conclude that tyrosine availability is not a limiting factor in the reduced brain noradrenergic activity of obese mice.

The oxidation of adrenaline and noradrenaline by the two forms of monoamine oxidase from human and rat brain

The selective monoamine oxidase inhibitors clorgyline and (?)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (?)-noradrenaline and (+),(?)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-hydroxytryptamine and 2-phenethylamine, which are essentially specific substrates for the A- and B-forms, respectively, under the conditions used in this work, were also determined. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. The total MAO activity was found to be highest in the hypothalamus and lowest in the cerebellar cortex. Use of the selective MAO inhibitors clorgyline and (?)-deprenyl also showed adrenaline and noradrenaline to be substrates for both forms of the enzyme in rat brain. In human cerebral cortex and rat brain the two forms were found to have similar K(m)-values and maximum velocities towards adrenaline. These values for the two forms were also found to be similar in human cerebral cortex when noradrenaline was used as the substrate. In contrast MAO-A showed a significantly lower K(m) and a higher maximum velocity towards noradrenaline in rat brain. These results suggest that the rat may not provide a close model of the human for studies on the effects of MAO inhibitors on brain noradrenaline metabolism.

Methylphenidate effects on activity-stress gastric lesions and regional brain noradrenaline metabolism in rats

Methylphenidate (5, 10 or 20 mg/kg/day) or saline were administered to rats in the activity-stress ulcer paradigm. Running-wheel activity and food consumption did not differ among groups. Methylpenidate produced dose-related increases in gastric ulcer severity, decreases in hypothalamic noradrenaline (NA) and increases in 3-methoxy-4-hydroxy-phenylethyleneglycol sulfate (MHPG-SO 4) in the hypothalamus, amygdala, hippocampus and thalamus. These results differ markedly from the effects seen with a related substance, d-amphetamine, and suggest different mechanisms of action for these drugs.

The effects of L-threo-dihydroxyphenylserine on norepinephrine metabolism in rat brain

The effects of L- threo-3,4-dihydroxyphenylserine (DOPS), an artificial precursor of norepinephrine (NE), on NE metabolism in rat brain were investigated. DOPS administration resulted in a significant elevation in cerebral NE and 3-methoxy-4-hydroxyphenylglycol contents, while carbidopa pretreatment completely blocked these increases. After brain NE was depleted by either α-methyl- p-tyrosine (AMPT), fusaric acid, FLA-63, or reserpine, NE restoration by DOPS was observed in rats treated with either fusaric acid or chronic reserpine. No NE restoration was observed after pretreatment with AMPT, FLA-63, or acute reserpine. The results suggest that NE formed after DOPS administration is mainly localized in the brain capillaries. In some NE-depleting conditions, however, DOPS can penetrate the brain parenchyma.

Increased brain norepinephrine metabolism correlated with analgesia produced by the periaqueductal gray injection of opiates

Dose-dependent increases in in 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MOPEG-SO 4), a major metabolite of norepinephrine, were produced in the limbic forebrain and cerebral cortex 30 min after the bilateral injection of morphine into the periaqueductal gray (PAG). These effects were also elicited by similar injections of levorphanol. Highly significant correlations were obtained between the concentrations of MOPEG-SO 4 and the analgesic effect of the opiates and opiate actions were antagonized by systemic naloxone. These results indicate that activation of opiate receptors in the PAG may elicit the involvement of noradrenergic systems in distant brain regions in the mediation of analgesia.

The differential observation of type A and B MAO-containing terminal fibers in the cerebral cortex of the rat

The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-hydroxytryptamine and 2-phenethylamine, which are essentially specific substrates for the A- and B-forms, respectively, under the conditions used in this work, were also determined. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. The total MAO activity was found to be highest in the hypothalamus and lowest in the cerebellar cortex. Use of the selective MAO inhibitors clorgyline and (−)-deprenyl also showed adrenaline and noradrenaline to be substrates for both forms of the enzyme in rat brain. In human cerebral cortex and rat brain the two forms were found to have similar Km-values and maximum velocities towards adrenaline. These values for the two forms were also found to be similar in human cerebral cortex when noradrenaline was used as the substrate. In contrast MAO-A showed a significantly lower Km and a higher maximum velocity towards noradrenaline in rat brain. These results suggest that the rat may not provide a close model of the human for studies on the effects of MAO inhibitors on brain noradrenaline metabolism.

Recovery of stress-induced increases in noradrenaline turnover is delayed in specific brain regions of old rats

Male Wistar rats at 2 and 12 months of age were sacrificed before, immediately following, and at 6 and 24 hours after a 3-hour immobilization stress period. Levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO 4), in eight brain regions and plasma corticosterone levels were fluorometrically determined. Immobilization stress caused significant increases of MHPG-SO 4 levels in all brain regions examined and significant elevations in plasma corticosterone levels in both 2 and 12 month old rats. In 2 month old rats, the MHPG-SO 4 levels in all brain regions returned to control levels within 6 hours after release from the stress. However, in 12 month old rats, the metabolite levels in the hypothalamus, amygdala, pons plus medulla oblongata (pons+med.obl.) and midbrain still remained at significantly increased levels at 6 and 24 hours after the stress. Moreover, in the amygdala of older rats, stress-induced decreases in NA levels persisted even 6 hours after stress. Plasma corticosterone levels also showed significant elevations at 6 and 24 hours after the stress only in 12 month old rats. These results suggest that brain NA metabolism during recovery periods from an acute exposure to a stressful situation is altered by the aging process in such a manner that NA neurons in the hypothalamus, amygdala, pons+med.obl. and midbrain in older rats remain activated by stressful stimuli for prolonged periods of time following release from stress.

P-5) - Changes in brain noradrenaline metabolism in the rats exposed to stress during daytime or nighttime

P-5) - Changes in brain noradrenaline metabolism in the rats exposed to stress during daytime or nighttime

Disposition and metabolism of MHPG in humans: application to studies in depression.

MHPG is formed from norepinephrine metabolized throughout the body; its levels in plasma reflect total norepinephrine metabolism. Over half of the MHPG, is converted to VMA. Less than 20% of MHPG is derived from brain norepinephrine and urinary excretion of this metabolite cannot be used as a measure of brain norepinephrine metabolism. Because unconjugated MHPG is readily diffusable, there is a free exchange of this metabolite among plasma, cerebrospinal fluid, and nerve tissues (including brain and spinal cord). The CSF MHPG levels, after appropriately correction for the plasma contribution of the metabolite, reflect its rate of formation in the central nervous system.

Effects of imipramine on behavior and brain norepinephrine metabolism in tetrabenazine treated rats: comparative study of a single administration with repeated administrations of imipramine.

The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO4) level in the brain was measured. A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO4. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO4. The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO4 in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of alpha-methyl-para-tyrosine (alpha-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO4 increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. Several considerations were given to the above-mentioned results.

Measurement of tritiated norepinephrine metabolism in intact rat brain

A procedure for the study of NE metabolism in the intact rat brain is described. The method involves ventriculocisternal perfusion of the adult male rat with artificial CSF containing [ 3H]NE. Radioactivity in the perfusate associated with NE and its metabolites 3,4-dihydroxymandelic acid (DOMA), 3,4-dihydroxyphenylethyleneglycol (DHPG), 3-methoxy-4-hydroxymandelic acid (VMA), 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), and normetanephrine (NMN) is separated using high-performance liquid chromatography (HPLC). After 80 min the radioactivity in the perfusate reaches an apparent steady-state. Analysis of the steady-state samples shows higher activity in the fractions corresponding to DHPG and MHPG than in those corresponding to DOMA and VMA, confirming glycol formation as the major pathway of NE metabolism in rat brain. Pretreatment with an MAO inhibitor (tranylcypromine) results in a marked decrease in the deaminated metabolites DHPG and MHPG and a concurrent increase in NMN. The results indicate this to be a sensitive procedure for the in vivo determination of changes in NE metabolism.