Norepinephrine In Brain Regions Research Articles

Locus Coeruleus Noradrenergic Modulation of Diurnal Corticosterone, Stress Reactivity, and Cardiovascular Homeostasis in Male Rats

Introduction: Activation of the locus coeruleus-noradrenergic (LC-NA) system during awakening is associated with an increase in plasma corticosterone and cardiovascular tone. These studies evaluate the role of the LC in this corticosterone and cardiovascular response. Methods: Male rats, on day 0, were treated intraperitoneally with either DSP4 (50 mg/kg body weight) (DSP), an LC-NA specific neurotoxin, or normal saline (SAL). On day 10, animals were surgically prepared with jugular vein (hypothalamic-pituitary-adrenal [HPA] axis) or carotid artery (hemodynamics) catheters and experiments performed on day 14. HPA axis activity, diurnally (circadian) and after stress (transient hemorrhage [14 mL/kg body weight] or air puff-startle), and basal and post-hemorrhage hemodynamics were evaluated. On day 16, brain regions from a subset of rats were dissected for norepinephrine and corticotropin-releasing factor (CRF) assay. Results: In DSP rats compared to SAL rats, (1) regional brain norepinephrine was decreased, but there was no change in median eminence or olfactory bulb CRF content; (2) during HPA axis acrophase, the plasma corticosterone response was blunted; (3) after hemorrhage and air puff-startle, the plasma adrenocorticotropic hormone response was attenuated, whereas the corticosterone response was dependent on stressor category; (4) under basal conditions, hemodynamic measures exhibited altered blood flow dynamics and systemic vasodilation; and (5) after hemorrhage, hemodynamics exhibited asynchronous responses. Conclusion: LC-NA modulation of diurnal and stress-induced HPA axis reactivity occurs via distinct neurocircuits. The integrity of the LC-NA system is important to maintain blood flow dynamics. The importance of increases in plasma corticosterone at acrophase to maintain short- and long-term cardiovascular homeostasis is discussed.

Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats

Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through region-specific epigenetic activity and catecholamine levels. We hypothesized that stress in adolescence would increase adult trauma vulnerability by impairing extinction-retention, a deficit in PTSD, by (1) altering class IIa histone deacetylases (HDACs), which integrate effects of stress on gene expression, and (2) enhancing norepinephrine in brain regions regulating cognitive effects of trauma. We investigated the effects of adolescent-stress on adult vulnerability to severe stress using the single-prolonged stress (SPS) model in male rats. Rats were exposed to either (1) adolescent-stress (33–35 postnatal days) then SPS (58–60 postnatal days; n = 14), or (2) no adolescent-stress and SPS (58–60 postnatal days; n = 14), or (3) unstressed conditions (n = 8). We then measured extinction-retention, norepinephrine, HDAC4, and HDAC5. As expected, SPS exposure induced an extinction–retention deficit. Adolescent-stress prior to SPS eliminated this deficit, suggesting adolescent-stress conferred resiliency to adult severe stress. Adolescent-stress also conferred region-specific resilience to norepinephrine changes. HDAC4 and HDAC5 were down-regulated following SPS, and these changes were also modulated by adolescent-stress. Regulation of HDAC levels was consistent with the pattern of cognitive effects of SPS; only animals exposed to SPS without adolescent-stress exhibited reduced HDAC4 and HDAC5 in the prelimbic cortex, hippocampus, and striatum. Thus, HDAC regulation caused by severe stress in adulthood interacts with stress history such that seemingly conflicting reports describing effects of adolescent stress on adult PTSD vulnerability may stem in part from dynamic HDAC changes following trauma that are shaped by adolescent stress history.

Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor.

The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex. Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.

Noradrenergic mechanisms in stress and anxiety: I. preclinical studies

There is considerable preclinical evidence for a relationship between noradrenergic brain systems and behaviors associated with stress and anxiety. The majority of noradrenergic neurons are located in the locus coeruleus (pons), with projections throughout the cerebral cortex and multiple subcortical areas, including hippocampus, amygdala, thalamus, and hypothalamus. This neuroanatomical formation of the noradrenergic system makes it well suited to rapidly and globally modulate brain function in response to changes in the environment, as occurs during the presentation of stressors. Stress exposure is associated with an increase in firing of the locus coeruleus and with associated increased release and turnover of norepinephrine in brain regions which receive noradrenergic innervation. Increased firing of the locus coeruleus is also associated with behavioral manifestations of fear, such as arched back and piloerection in the cat. Exposure to chronic stress results in long-term alterations in locus coeruleus firing and norepinephrine release in target brain regions of the locus coeruleus. Norepinephrine is also involved in neural mechanisms such as sensitization and fear conditioning, which are associated with stress. These findings are relevant to an understanding of psychiatric disorders, such as panic disorder and post-traumatic stress disorder (PTSD), the symptoms of which have been hypothesized to be related to alterations in noradrenergic function. © 1996 Wiley-Liss, Inc.

Noradrenergic mechanisms in stress and anxiety: I. preclinical studies

There is considerable preclinical evidence for a relationship between noradrenergic brain systems and behaviors associated with stress and anxiety. The majority of noradrenergic neurons are located in the locus coeruleus (pons), with projections throughout the cerebral cortex and multiple subcortical areas, including hippocampus, amygdala, thalamus, and hypothalamus. This neuroanatomical formation of the noradrenergic system makes it well suited to rapidly and globally modulate brain function in response to changes in the environment, as occurs during the presentation of stressors. Stress exposure is associated with an increase in firing of the locus coeruleus and with associated increased release and turnover of norepinephrine in brain regions which receive noradrenergic innervation. Increased firing of the locus coeruleus is also associated with behavioral manifestations of fear, such as arched back and piloerection in the cat. Exposure to chronic stress results in long-term alterations in locus coeruleus firing and norepinephrine release in target brain regions of the locus coeruleus. Norepinephrine is also involved in neural mechanisms such as sensitization and fear conditioning, which are associated with stress. These findings are relevant to an understanding of psychiatric disorders, such as panic disorder and post-traumatic stress disorder (PTSD), the symptoms of which have been hypothesized to be related to alterations in noradrenergic function.

Developmental and regional changes in brain norepinephrine levels in diabetic C57BL/KsJ mice: effects of estradiol and progesterone

Developmental and diabetes-associated changes in regional brain norepinephrine (NE) concentrations, and the influence of estradiol (E) and progesterone (P) on NE levels, were correlated with changes in blood glucose levels and body weight (obesity) in developing 4–16-week-old C57BL/KsJ ( db / db) mice relative to corresponding age-matched control (+/?) parameters. Regional brain (i.e. amygdala, hypothalamus and medulla) NE levels were determined by high performance liquid chromatography. The ( db / db) mice exhibited overt hyperglycemia and obesity relative to controls between 4 and 16 weeks of age. Hypothalamic NE levels in diabetics were chronically elevated as compared to those of age-matched controls by 8 weeks of age, and remained elevated through 16 weeks of age. Regional amygdaloid and medullary NE concentrations were comparable in (+/?) and ( db / db) groups by 16 weeks. E-treatments normalized ( db / db) hypothalamic NE concentrations to control levels between 8 and 16 weeks of age, but had no effect on amygdaloid or medullary values. In contrast, in 16 week old ( db / db) mice, P-treatments elevated hypothalamic and medullary NE levels compared to controls and expected diabetic levels. These data demonstrate that a marked modification in regional brain NE concentrations occurs in association with the overt expression of the diabetes mutation during development in this species. Observed changes in adrenergic influences in specific CNS loci may be therapeutically modulated by ovarian steroid hormones, especially in the hypothalamic locus which is recognized to possess steroid-concentrating neurons. The observed normalization of regional brain NE concentrations by E-therapy may be causally related to the ovarian steroid-modulation of overt hyperglycemia and diabetes-associated neuronal degeneration in ( db / db) mice.

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.

Differential effects of chronic lead intoxication on circadian rhythm of ambulatory activity and on regional brain norepinephrine levels in rats.

Changes in biochemical mechanisms and amine concentrations in the brain have been manifested in the form of varying disorders and abnormalities in behavior, including motor-activity, which has been proved with a number of psychoactive drugs. It has been reported that increased level of cerebral norepinephrine (NE) has been shown to be associated with motor hyper-activity, and in lead exposed rats. No study is available which could account for the pattern of changes in spontaneous ambulatory responses in an open field situation together with the steady state regional levels of NE in the brain of chronically lead exposed rats. Therefore, it seemed to be worthwhile to study the circadian rhythm of ambulatory activity and its association with NE levels in various brain regions of rats exposed to lead.

Differential effects of DSP-4 administration on regional brain norepinephrine turnover in rats

The effects of DSP-4 on brain NE levels and turnover in rats were investigated in six brain regions: cortex, hippocampus, cerebellum, brainstem, hypothalamus and locus coeruleus. Administration of 50 mg/kg of DSP-4 significantly decreased NE levels in all brain regions; greatest reductions occured in the cortex (86% decrease) and in the hippocampus (91% decrease). Doses of DSP-4 less than 50 mg/kg did not significantly lower NE levels in other brain regions, except within the cerebellum. Levels of the NE metabolite 3-methoxy, 4-hydroxyphenylethylene glycol sulfate (MHPG-SO4) declined in parallel with those of NE, except within the brainstem and the locus coeruleus. NE turnover, expressed as the ratio of the MHPG-SO4 concentration to that of NE, was higher in the cortex and hippocampus than other regions in control animals, and NE turnover significantly increased only in these two areas after the administration of 50 mg/kg of DSP-4 (p<0.01). There were no significant changes in the levels of dopamine and a significant decrease of serotonin only in the striatum. These results indicate that DSP-4 is a neurotoxin with a strong predilection for noradrenergic neurons, that its effects vary according to brain region and that its administration increases NE turnover in those brain regions showing the greatest depletion of NE.

Stimulation of ornithine decarboxylase by histamine or norepinephrine in brain regions of the developing rat: Evidence for biogenic amines as trophic agents in neonatal brain development

Ornithine decarboxylase (ODC) initiates the synthesis of polyamines which play key roles in regulation of cellular development. Intracisternal administration of histamine or norepinephrine to developing rats produced age-dependent stimulation of ODC in brain. In cerebral cortex and pons-medulla, stimulation by norepinephrine was demonstrable at postnatal day 7 and maximum stimulation occured at about day 9. In contrast, cerebellum showed no initial reactivity to norepinephrine but still developed a large peak of response capability by day 9. In all 3 regions, the response declined rapidly thereafter during the period of major synaptogenesis of noradrenergic pathways. With histamine, none of the regions displayed ODC reactivity at 7 days postnatally; stimulation appeared by day 9, peaked at about day 11 and then declined rapidly. Thus, the trophic effect of histamine or norepinephrine toward ODC activity is present or develops postnatally and appears to terminate with synaptogenesis and onset of neurotransmitter properties of the amines.

Increased hypothalamic noradrenergic activity in one-kidney, one-clip renovascular hypertensive rats.

To further define central and peripheral sympathetic nerve activity in the one-kidney and two-kidney, one-clip models of renovascular hypertension, plasma catecholamines and regional brain norepinephrine of these models were compared with the activities of their brain biosynthetic enzymes: tyrosine hydroxylase (TYH) and dopamine-beta-hydroxylase (DBH). Findings in the groups of 20 one-kidney and 17 two-kidney female Wistar rats were compared with those in 10 sham-operated rats. Systolic blood pressure, measured indirectly, and the mean arterial pressure, measured directly from the femoral arteries, verified development of renovascular hypertension in both the one and two-kidney animals. Plasma norepinephrine increased from 248 +/- 46 to 401 +/- 66 pg/ml in the one-kidney group only (p < 0.001). Hypothalamic TYH and DBH activities of the one-kidney animals were 48 and 34% greater than those of the two-kidney animals and 28 and 39% greater than the sham-operated animals. The multiple t-test indicated significant differences between the mean hypothalamic THY of the one- and two-kidney groups and between the hypothalamic DBH of the one-kidney animals and those of the two-kidney and sham groups (alpha = 0.05). Moreover, the mean norepinephrine content of the hypothalamus in the one-kidney animals was 66% greater than that of the two-kidney and sham groups (p < 0.05). These findings suggest that central noradrenergic pathways of the hypothalamus may be involved in the genesis of one-kidney renovascular hypertension.

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.

Ontogeny of the levels of biogenic amines in various parts of the brain and in peripheral tissues in normal and protein malnourished rats

The ontogenetic development of serotonin, 5-hydroxyindoleacetic acid, and norepinephrine in brain regions and in peripheral tissues was examined in normal and protein malnourished rats from birth to age 300 days. The malnourished rats, which received a diet low in protein starting 5 weeks prior to conception, showed significantly elevated brain and peripheral tissue levels of the biogenic amines and 5-hydroxyindoleacetic acid at birth. This is one of the earliest ages at which protein malnutrition has been reported to affect a major biochemical measure in the brain. In malnourished rats, brain concentrations of serotonin and 5-hydroxydoleacetic acid remained elevated at older ages, up to 300 days, with the largest effects (up to 200% increase) occurring in subtelencephalic brain regions. These changes in brain indole levels probably represent a general metabolic alteration of indoleamine metabolism since elevated indole concentrations were also observed in the heart, lung, and stomach. At most ages the increase in brain norepinephrine levels in malnourished rats was less pronounced than for the indoles. Also, no increase in norepinephrine concentration in the peripheral tissues were observed. With respect to norepinephrine concentrations, the brain appears to be more sensitive to the insult of protein malnutrition than do peripheral tissues. The present results demonstrate that rearing rats on a diet low in protein, but adequate in all other respects, significantly elevates the brain amine content at most ages from birth through 300 days of age.

Circadian rhythm in blood and brain biogenic amines and other biochemical changes in rabbits

Concentrations of blood norepinephrine, serotonin and corticosterone, glucose, liver glycogen, and regional brain norepinephrine were measured during a 24 h period in F 1 hybrid rabbits of lines III × III c. Significant diurnal variations in brain norepinephrine occurred in frontal cortex and hypothalamus, but not in the amygdala. There was a minor correlation between brain and systemic norepinephrine concentrations, but further work is necessary to clarify the exact relationship. Generally, it appears that 2 p.m. is the time when most measurements exhibit least activity, while 7 p.m. appears to be the onset of increased activity.

Effect of glucose on hypothalamic feeding centers in deafferented animals.

ARTICLESEffect of glucose on hypothalamic feeding centers in deafferented animalsGS Chhina, BK Anand, B Singh, and PS RaoGS Chhina, BK Anand, B Singh, and PS RaoPublished Online:01 Aug 1971https://doi.org/10.1152/ajplegacy.1971.221.2.662MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Download PDF FiguresReferencesRelatedInformation Cited ByFunctional MRI of human hypothalamic responses following glucose ingestionNeuroImage, Vol. 24, No. 2The lateral hypothalamic area revisited: Ingestive behaviorNeuroscience & Biobehavioral Reviews, Vol. 20, No. 2Developmental and regional changes in brain norepinephrine levels in diabetic C57BL/KsJ mice: effects of estradiol and progesteroneDevelopmental Brain Research, Vol. 89, No. 2Age- and diabetes-associated alterations in regional brain norepinephrine concentrations and adrenergic receptor populations in C57BL/KsJ miceDevelopmental Brain Research, Vol. 51, No. 2Caudal Brainstem Participates in the Distributed Neural Control of FeedingMorphometric analysis of obesity (ob/ob)- and diabetes (db/db)-associated hypothalamic neuronal degeneration in C57BL/KsJ miceBrain Research, Vol. 501, No. 1Central Nervous System Control of Nutrient Homeostasis1 January 2011Caudal Brainstem Integration of Taste and Internal State Factors in Behavioral and Autonomic ResponsesCAUDAL BRAINSTEM CONTRIBUTIONS TO THE INTEGRATED NEURAL CONTROL OF ENERGY HOMEOSTASISFourth ventricular phlorizin dissociates feeding from hyperglycemia in ratsBrain Research, Vol. 341, No. 2Morphometric analysis of medial basal hypothalamic neuronal degeneration in diabetes (db/db) mutant C57BL/KsJ mice: Relation to age and hyperglycemiaDevelopmental Brain Research, Vol. 20, No. 2Glucose utilization by the mouse brain: Influence of age and diabetesDevelopmental Brain Research, Vol. 15, No. 2Diabetes-associated, ventromedial hypothalamic neuronal degeneration in the Chinese hamsterNeuroscience Letters, Vol. 44, No. 3Two types of medial hypothalamic inhibition of lateral hypothalamic rewardBrain Research, Vol. 277, No. 2Diabetes-associated hypothalamic neuronal depopulation in the aging Chinese hamsterDevelopmental Brain Research, Vol. 9, No. 3Insulin Elicits Ingestion in Decerebrate RatsScience, Vol. 221, No. 4606Morphometric evaluation of the hypothalamic-ovarian axis of the ketonuric, diabetic Chinese hamster: Relationship to the reproductive cycleDiabetologia, Vol. 23, No. 3Depopulation of the ventromedial hypothalamic nucleus in the diabetic Chinese hamsterActa Neuropathologica, Vol. 56, No. 1Current evidence for a role of glucose as a regulator of hypothalamic function and caloric homeostasisPsychoneuroendocrinology, Vol. 6, No. 4Reflex insulin secretion due to central hyperglycemia promoted by intracarotid glucose infusion in dogsPhysiology & Behavior, Vol. 23, No. 2The Forebrain Is Not Essential for Sympathoadrenal Hyperglycemic Response to GlucoprivationScience, Vol. 204, No. 4397Huntington’s Disease: Premature Brain Aging with Abnormalities of Chemical Neurotransmitters and Hormonal FunctionIncreased feeding in response to bilateral injection of insulin antibodies in the VMHPhysiology & Behavior, Vol. 19, No. 2Noradrenergic feeding system in monkey hypothalamus is altered by localized perfusion of glucose, insulin, 2-DG and eatingPharmacology Biochemistry and Behavior, Vol. 5, No. 4Effects of insulin injection on responses of olfactory bulb and amygdala single units to odorsBrain Research, Vol. 99, No. 1Effects of glucose on multiple-unit activity of the hypothalamus in female ratsExperimental Neurology, Vol. 49, No. 2Hyperglycemia and inhibition of insulin secretion by 2-deoxy-d-glucose in rats with hypothalamic lesionsPharmacological Research Communications, Vol. 7, No. 2Effect of hypoglycemia induced by insulin on the depth EEG in the chickenGeneral and Comparative Endocrinology, Vol. 23, No. 2Biogenic Amines in the Hypothalamus: Effect of L-DOPA on Human Growth Hormone Levels in Patients with Huntington's ChoreaINCREASED FREQUENCY OF DIABETES MELLITUS IN PATIENTS WITH HUNTINGTON'S CHOREAThe Lancet, Vol. 299, No. 7765 More from this issue > Volume 221Issue 2August 1971Pages 662-667 Copyright & PermissionsCopyright © 1971 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1971.221.2.662PubMed4934668History Published online 1 August 1971 Published in print 1 August 1971 Metrics

Effects of parabiosis of normal with genetically diabetic mice.

Effects of parabiosis of normal with genetically diabetic mice.