Increase In Norepinephrine Levels Research Articles

A mechanistic analysis of the force-frequency relation in non-failing and progressively failing human myocardium.

This review focuses on the role of the myocardial force-frequency relation (FFR) in human ventricular performance and how changes in the FFR can reduce cardiac output and, ultimately, can contribute to altering the stability of the in-vivo cardiovascular system in a way that contributes to the progression of heart failure. Changes in the amplitude, shape, and position of the myocardial FFR occurring in various forms of heart failure are characterized in terms of maximal isometric twitch tension, slope of the ascending limb (myocardial reserve), and position of the peak of the FFR on the frequency axis (optimum stimulation frequency). All three of these parameters decline according to severity of myocardial disease in the following order: non-failing atrial septal defect, non-failing coronary artery disease, non-failing coronary artery disease with diabetes mellitus, failing mitral regurgitation, failing viral myocarditis, failing idiopathic dilated cardiomyopathy. Evidence is presented supporting a sarcoplasmic reticulum Ca-pump based mechanism for this progressive depression of the FFR. Intracellular calcium cycling and concentration and Ca-pump content all diminish in proportion to degree of depression of the FFR. Additional evidence from myocyte culture studies suggests a cause of diminished Ca-pump content is sustained, elevated levels of plasma norepinephrine. A hypothesis is presented to explain the mechanism of myocardial failure and its progression in terms of changes in the cardiovascular feedback control system that are triggered by reduced myocardial reserve. Sustained elevation of plasma norepinephrine levels depresses expression of sarcoplasmic reticulum Ca-pump protein causing depression of the FFR and this causes a compensatory further increase in norepinephrine levels and a further depression of Ca-pump protein.

Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients

To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.

Angiotensin II mediates systemic rebound hypertension after cessation of prostacyclin infusion in sheep.

Prostacyclin (or epoprostenol), an arachidonic acid metabolite, is an effective treatment for patients with primary pulmonary hypertension. Interruption of chronic prostacyclin infusion can result in recurrent symptoms of dyspnea and fatigue. The etiology of this phenomenon is unknown. We hypothesized that sympathoadrenal activation could lead to increased vascular tone after abrupt termination of the infusion. To evaluate this effect, we monitored six chronically instrumented, awake sheep during and after infusion of prostacyclin. Prostacyclin decreased mean arterial pressure (MAP) by 14% and increased cardiac output by 33%. After the infusion ceased, MAP rebounded 23% above baseline, and cardiac output decreased by 28% from peak values within 10 min. We were unable to demonstrate an increase in norepinephrine levels after cessation of prostacyclin, nor did alpha-adrenergic blockade affect postinfusion hemodynamics. However, plasma renin activity increased >10-fold at peak infusion and remained elevated for up to 2 h after discontinuation of prostacyclin. Coinfusion of the angiotensin II-receptor antagonist L-158,809 resulted in complete abrogation of the postcessation rise in MAP. We conclude that renin-angiotensin system activation is primarily responsible for systemic hypertension occurring after abrupt cessation of prostacyclin infusion in sheep and that angiotensin II receptor blockade prevents this response. Our data do not support a role for sympathetic nervous system activation in the systemic pressor response after prostacyclin infusion.

Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats

The antipsychotic, zotepine, as well as possessing affinity for dopamine D 1- and D 2-like receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [ 3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5–1.5 mg kg −1 i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+171.0%) and 240 min (+211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg −1 i.p.), resulted in a smaller, transient increase in NA levels (+72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg −1 i.p.) nor olanzapine (1.0 mg kg −1 i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg −1 i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of +354.3%), whilst local infusion of nisoxetine (1–100 μM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.

Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder

Background: Catecholamines are thought to play a significant role in the pathophysiology of posttraumatic stress disorder (PTSD), but findings in PTSD have been discrepant. Methods: To obtain more information about catecholamine activity in PTSD, we sampled plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations over a 24-hour period in men with PTSD ( n = 15) and major depressive disorder (MDD) ( n = 12), and nonpsychiatric comparison subjects ( n = 13), under unstimulated conditions. Chronobiological analyses were performed to determine possible changes in the circadian and ultradian release of these hormones. Results: Significant group differences were present for mean plasma NE levels ( p = .03), but not MHPG. NE levels were significantly associated with severity of depression in the PTSD group ( p = .002). Therefore, PTSD subjects were further subdivided into those with and without a comorbid secondary depression. Increased NE levels were only present in PTSD subjects who did not have a secondary depression. This study also found no significant group differences on any of the chronobiological parameters. Conclusions: The results clarify that increased NE levels in PTSD may be confined to the subgroup of subjects who do not have comorbid depression, and as such, may help resolve some of the discrepancies in the literature regarding basal catecholamine activity.

Prenatal experience and postnatal stress modulate the adult neurosteroid and catecholaminergic stress responses

Allopregnanolone (3α-hydroxy-5α-regnan-20-one) is a neuroactive steroid recently shown to be involved in the neurochemical stress response via its positive modulation of the GABAA receptor complex. This experiment investigated the effects of postnatal stress (daily maternal separation during the first week of life) on the subsequent adult response to a stressor (10 min forced swim) in Long–Evans rats from one of three prenatal treatment groups (alcohol, pair-fed and control). Indices of stress response were allopregnanolone concentrations in plasma, cortex and hippocampus, and dopamine and norepinephrine concentrations in prefrontal cortex, nucleus accumbens and striatum. Females had higher levels of allopregnanolone than males in both plasma and brain. Prenatal alcohol exposure combined with early maternal separation stress resulted in an increase in the endogenous levels of allopregnanolone in the prefrontal cortex and hippocampus of adult offspring in response to a stressor compared to subjects without a prior history of postnatal stress ; this effect was greater in females. This increased allopregnanolone was also associated with decreased dopamine and norepinephrine levels in the prefrontal cortex. In the prenatal alcohol-exposed offspring, postnatal maternal separation blunted the increase in dopamine levels in the striatum seen in both control groups. Postnatal maternal separation increased norepinephrine levels in the nucleus accumbens regardless of prenatal experience, while in the prefrontal cortex only prenatal diet condition (pair-feeding and alcohol) resulted in lower norepinephrine levels. The results of this experiment suggest that experience, both pre- and postnatal, can have long-term consequences for the developing neurochemical responses to stressors.

EFFECT OF EXERCISE TRAINING ON THE IMPACT OF PREEXERCISE GLUCOSE LOAD IN DIABETIC PATIENTS

1403 Exercise training (ET) improves glucose metabolism in insulin-dependent diabetic (IDDM) patients (Kemmer & Berger, 1983). However, the effect of ET on the impact of preexercise glucose (GL) administration has not been described in IDDM patients. Therefore, the effect of a GL (1g/kg) load, ingested 30 min before exercise, on endurance capacity and on plasma substrate-hormone response were studied in 6 IDDM patients, 12 h post-insulin administration, and 7 control (C) subjects. Exhaustive cycle exercise bouts were performed before and after 6 months of ET (at ≈65% VO2max). ET significantly increased endurance capacity by 10% in IDDM and 30% in C. Preexercise GL load significantly increased endurance in IDDM before ET (100± 12 vs. 85 ± 13 min, P<0.05) and after ET (107 ± 11 vs. 95 ± 10 min; P<0.05). Neither GL load nor ET modified insulin and C-peptide levels during exercise in IDDM. Insulin and C-peptide levels were significantly lower in IDDM compared with C. ET did not change glucose response during exercise in both IDDM and C. However, ET increased norepinephrine levels at exhaustion (1.2 ± 0.2 vs. 0.9 ± 0.2, ng/mol, P<0.05) in IDDM. Finally, GL load inhibited exercise-induced enhancement of epinephrine in both groups, and ET increased epinephrine levels at exhaustion only in IDDM (162 ± 70 vs 104 ± 40, pg/ml, P<0.05). In conclusion: 1) The beneficial effect of preexercise GL administration on endurance capacity was not modified by ET in both IDDM and C; 2) In IDDM, ET did not attenuate the higher glucose levels during exercise following GL administration, and 3) In IDDM patients, ET improves the adrenergic response during prolonged exercise.

Phasic activation of the locus coeruleus enhances responses of primary sensory cortical neurons to peripheral receptive field stimulation

In the present study we examined the effects of phasic activation of the nucleus locus coeruleus (LC) on transmission of somatosensory information to the rat cerebral cortex. The rationale for this investigation was based on earlier findings that local microiontophoretic application of the putative LC transmitter, norepinephrine (NE), had facilitating actions on cortical neuronal responses to excitatory and inhibitory synaptic stimuli and more recent microdialysis experiments that have demonstrated increases in cortical levels of NE following phasic or tonic activation of LC. Glass micropipets were used to record the extracellular activity of single neurons in the somatosensory cortex of halothane-anesthetized rats. Somatosensory afferent pathways were activated by threshold level mechanical stimulation of the glabrous skin on the contralateral forepaw. Poststimulus time histograms were used to quantitate cortical neuronal responses before and at various time intervals after preconditioning burst activation of the ipsilateral LC. Excitatory and postexcitatory inhibitory responses to forepaw stimulation were enhanced when preceded by phasic activation of LC at conditioning intervals of 200–500 ms. These effects were anatomically specific in that they were only observed upon stimulation of brainstem sites close to (>150 μm) or within LC and were pharmacologically specific in that they were not consistently observed in animals where the LC-NE system had been disrupted by 6-OHDA pretreatment. Overall, these data suggest that following phasic activation of the LC efferent system, the efficacy of signal transmission through sensory networks in mammalian brain is enhanced.

Biological effects of prolonged exposure to ELF electromagnetic fields in rats: III. 50 Hz electromagnetic fields.

Groups of adult male Sprague Dawley rats (64 rats each) were exposed for 8 months to electromagnetic fields (EMF) of two different field strength combinations: 5microT - 1kV/m and 100microT - 5kV/m. A third group was sham exposed. Field exposure was 8 hrs/day for 5 days/week. Blood samples were collected for hematology determinations before the onset of exposure and at 12 week intervals. At sacrifice, liver, heart, mesenteric lymph nodes, bone marrow, and testes were collected for morphology and histology assessments, while the pineal gland and brain were collected for biochemical determinations. At both field strength combinations, no pathological changes were observed in animal growth rate, in morphology and histology of the collected tissue specimens (liver, heart, mesenteric lymph nodes, testes, bone marrow), and in serum chemistry. An increase in norepinephrine levels occurred in the pineal gland of rats exposed to the higher field strength. The major changes in the brain involved the opioid system in frontal cortex, parietal cortex, and hippocampus. From the present findings it may be hypothesized that EMF may cause alteration of some brain functions.

Regulation of renal alpha2-adrenoceptor activity in Dahl salt-sensitive rats by dietary sodium changes

The objective of the study was to evaluate the concept that genetically predisposed salt-sensitivity contributes to an increased adrenergic susceptibility and renal alpha 2-adrenoceptor (A2) abnormality in Dahl salt-sensitive hypertensive rats. The results showed: i) After 2 months of Na-loading (8% NaCl) Dahl salt-sensitive (DSS) rats expressed increased sodium and water retention which paralleled gradual development of diastolic hypertension. Low Na diet (0.5% NaCl) does not prevent hypertension but delays its development. ii) The increased activity of the sympathetic nervous system (SNS), in DSS rats corresponded to the development of hypertension and was stimulated by Na-loading. It was assessed by plasma catecholamine levels and heart rate changes. iii) The increased density of renal A2 by 29% was upregulated by high sodium diet, and coupled with increased norepinephrine level by 53%, only in DSS but not in DSR rats. iv) No strain renal A2 and epinephrine differences between DSS and DSR were found in weanling, prehypertensive rats, or in the adult DSS and DSR on low Na diet. By mediating an enhanced receptor-coupled response, such as increased proximal tubular sodium reabsorption during sodium loading, a genetic abnormality of renal alpha 2-adrenoceptors may contribute to some of the pathophysiologic derangements leading to hypertension in Dahl salt-sensitive rats.

Effect of Calcium Antagonists on Plasma Norepinephrine Levels, Heart Rate, and Blood Pressure

To evaluate the effects of calcium antagonists on sympathetic activity in hypertensive patients, a MEDLINE search for English language articles published between 1975 and May 1996 using the terms calcium antagonists, sympathetic nervous system, and catecholamines was conducted. Clinical studies only reporting the effects of calcium antagonists on blood pressure, heart rate, and plasma norepinephrine (NE) levels in patients with hypertension were included. Data were combined and analyzed according to class of calcium antagonist (dihydropyridine vs nondihydropyridine), their duration of action (short-acting [SA] vs long-acting [LA]), and treatment duration. We identified 63 studies involving 1,252 patients. Acutely after single dosing, SA calcium antagonists decreased mean arterial pressure by 13.7 ± 1.1% and increased heart rate by 13.7 ± 1.4% and NE levels by 28.6 ± 2.5%. Change in NE levels correlated with change in heart rate (r = 0.59, p <0.01) and inversely with change in arterial pressure (r = 0.46, p <0.05) in patients taking dihydropyridine calcium antagonists acutely. With sustained therapy, both classes of SA calcium antagonists increased NE levels. Whereas NE levels remained slightly elevated and heart rate unchanged with LA dihydropyridine calcium antagonists, both heart rate and NE levels decreased with LA nondihydropyridine calcium antagonists. SA calcium antagonists stimulate sympathetic activity when given acutely and over the long term, irrespective of their molecular structure. Sympathetic activation is less pronounced with LA dihydropyridine calcium antagonists and decreases with LA nondihydropyridine calcium antagonists. These data offer a possible pathophysiologic explanation for the increase in morbidity and mortality observed in some studies using SA calcium antagonists.

Noradrenergic suppression of synaptic transmission may influence cortical signal-to-noise ratio.

Norepinephrine has been proposed to influence signal-to-noise ratio within cortical structures, but the exact cellular mechanisms underlying this influence have not been described in detail. Here we present data on a cellular effect of norepinephrine that could contribute to the influence on signal-to-noise ratio. In brain slice preparations of the rat piriform (olfactory) cortex, perfusion of norepinephrine causes a dose-dependent suppression of excitatory synaptic potentials in the layer containing synapses among pyramidal cells in the cortex (layer Ib), while having a weaker effect on synaptic potentials in the afferent fiber layer (layer Ia). Effects of norepinephrine were similar in dose-response characteristics and laminar selectivity to the effects of the cholinergic agonist carbachol, and combined perfusion of both agonists caused effects similar to an equivalent concentration of a single agonist. In a computational model of the piriform cortex, we have analyzed the effect of noradrenergic suppression of synaptic transmission on signal-to-noise ratio. The selective suppression of excitatory intrinsic connectivity decreases the background activity of modeled neurons relative to the activity of neurons receiving direct afferent input. This can be interpreted as an increase in signal-to-noise ratio, but the term noise does not accurately characterize activity dependent on the intrinsic spread of excitation, which would more accurately be described as interpretation or retrieval. Increases in levels of norepinephrine mediated by locus coeruleus activity appear to enhance the influence of extrinsic input on cortical representations, allowing a pulse of norepinephrine in an arousing context to mediate formation of memories with a strong influence of environmental variables.

Sympathetic Mediation of Stress and Aggressive Competition: Plasma Catecholamines in Free-living Male Tree Lizards

MATT, K. S., M. C. MOORE, R. KNAPP AND I. T. MOORE. Sympathetic Mediation of Stress and Aggressive Competition: Plasma Catecholamines in Free-living Male Tree Lizards. PHYSIOL BEHAV 61(5) 639–647, 1997.—The sympathetic nervous system and adrenal catecholaminergic tissue act to prepare an animal for “fight or flight” by release of catecholamines into synapses and plasma. However, few studies have measured plasma catecholamines in nonmammalian vertebrates and none have measured them in free-living animals. We report plasma levels of norepinephrine (NE), epinephrine (EPI) and dopamine (DA) in free-living tree lizards ( Urosaurus ornatus) bled in the field: 1) immediately after capture, 2) after 10 minutes of restraint, 3) immediately after a staged territorial encounter and 4) four minutes after the end of a staged territorial encounter. Time to capture and time to bleed after capture were also recorded for each sample. Time to capture had little effect on plasma catecholamines suggesting that plasma catecholamines do not rise during the brief pursuit by the investigator necessary to capture the lizards in the field. In contrast, plasma NE and EPI increased during blood collection. However, this response was very consistent allowing comparisons to be made using analysis of covariance to control for time to bleed. Results indicate that restraint stress caused a large increase in plasma levels of NE, E and DA. Plasma levels of NE and E, but not plasma DA, were also significantly elevated both immediately and 4 minutes after aggressive encounters, although less so than following restraint stress. These studies show that stress and aggression activate the sympatho-adrenal system. This activation could be involved in behavioral changes during aggression, meeting metabolic demands of the encounter, or both.

Brain Catecholamine Systems in Stress

Publisher Summary In the study discussed in this chapter, immunohistochemical, in situ hybridization histochemistry, tract-tracing, and in vivo microdialysis techniques have been used to investigate the participation of the central catecholaminergic (CA) systems in the organization of responses to an acute neurogenic (pain) stress: subcutaneous injection of 0.5 ml of 4% formalin into the hind paw of rats. This single injection produces a local pain that develops immediately after injection and results in four- to fivefold increase in corticosterone and adrenocorticotropic hormone (ACTH) levels in the plasma and a similar increase in norepinephrine levels in the paraventricular nucleus (PVN). Formalin also induced a rapid expression of c-fos and corticotropin-releasing hormones (CRHs) mRNA in the PVN. The possible crossover of the nociceptive spinal afferents to the medullary CA neurons and the crossover of the ascending CA neurons to the PVN were investigated after spinal and medullary surgical hemisections. Hemisection between the spinal cord and the medulla oblongata did not influence formalin-induced elevation of plasma corticosterone and ACTH levels, and strong c-fos immunoreactivity was observed in the medullary CA cell groups and in the PVN bilaterally, as in the sham-operated animals. Hemisection between the medullary CA cell groups and the PVN (unilateral knife cut at the pons-medulla oblongata border) decreased CRH immunoreactivity and CRH gene expression in the PVN ipsilateral to the transection but remained unchanged contralateral to the knife cut. Although, unilateral pontomedullary hemisection reduce TH and CRH immunoreactivity and CRH gene expression in the PVN, it does not influence the high plasma corticosterone and ACTH levels in response to formalin stress. However, acute immobilization stress in hemisected animals is able to induce CRH expression. These findings suggest that in brain stem-hemisected animals, the remaining intact ascending pathways are sufficient to allow normal, or almost normal, activation of the hypothalamopituitary-adrenal axis during stress.

Modulation of catecholamine release by α2-adrenoceptors and I 1-imidazoline receptors in rat brain

The physiological and pharmacological effects of imidazoli(di) ne derivatives, such as Clonidine, have been related not only to the interaction with α 2-adrenoceptors but also to their activity on non-adrenoceptor sites termed imidazoline receptors. The modulation of catecholamine release by imidazoline drugs was studied by monitoring extracellular levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) with microdialysis in cingulate cortex of rats, with or without irreversible α 2-adrenoceptor blockade. NE and DA levels were in the 1 nM range whereas DOPAC and HVA levels were ≅100 nM. NE and DA levels were increased when the uptake blocker desipramine (1 μM) or KCl (100 mm) were added to the perfusion medium. Clonidine induced a dose-dependent (0.3–1.2 mg/kg i.p.) decrease in NE (max 61%) and DA (max 40%) levels that was reversed by the c 2-adrenoceptor antagonist RX821002. After α 2-adrenoceptor irreversible blockade with the alkylating agent 7V-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), [ 3H] clonidine binding to α 2-adrenoceptors was reduced by 94 ± 1%. Under such conditions, clonidine elicited a paradoxical dose-dependent (0.6–2.4 mg/kg i.p.) increase of NE (max 56%) without modifications in DA, DOPAC and HVA levels. The stimulatory effect of clonidine was prevented by the imidazoline receptor antagonist idazoxan (10 mg/kg i.p.) but not by RX821002 (5 mg/kg i.p.). In rats pretreated with EEDQ, cirazoline (I 1/I 2-imidazoline receptor agonist), moxonidine (Iimidazoline receptor agonist), but not guanabenz (I 2-imidazoline receptor agonist) (1.2–2.4 mg/kg i.p.) elicited an increase of NE levels in a similar manner to clonidine (11–82%). Idazoxan also abolished these responses to cirazoline or moxonidine. In contrast to systemic administration, local perfusion of clonidine (10–100 μM) through the microdialysis probe under α 2-adrenoceptor alkylating conditions, did not modify extracellular levels of NE and DA suggesting an indirect mechanism. The results demonstrate that clonidine and related imidazoli(di) ne drugs are able not only to inhibit NE release in rat cerebral cortex involving an α 2-adrenoceptor mechanism, but also to induce a paradoxical NE release through an indirect extracortical mechanism. The findings evidence that the indirect modulation of NE levels by imidazoline drugs is mainly due to a functional activity on I 1-imidazoline receptors.

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.

2240 Cells containing c-fos-like protein in the rat brain after stimulation on the external membrane of the uterus

The concentrations of adrenaline, dopamine and noradrenaline were measured in 3 regions of the domestic chick telencephalon: (a) the Wulst; (b) a medial forebrain sample comprising mainly the intermediate part of the medial hyperstriatum ventrale (IMHV); and (c) a basal forebrain sample comprising mainly paleostriatum augmentatum. There was no significant left/right hemispheric asymmetry in the concentration of any of these catecholamines in any region studied. Adrenaline was undetectable in the Wulst and medial forebrain samples and only trace amounts were found in the basal forebrain samples of 1-day-old, light-reared chicks. Dopamine concentrations of 9.13 ± 1.13 (S.E.M.) ng/g were present in the Wulst, 16.66 ± 2.56 ng/g in the medial forebrain and 121.19 ± 33.06 ng/g in the basal forebrain samples at hatching. These levels did not alter with age or with visual experience of an imprinting stimulus during the first 50 h post-hatch. At hatching, noradrenaline concentrations of 35.83 ± 8.61 ng/g were present in the Wulst, 26.09 ± 3.75 ng/g in the medial forebrain and 53.13 ± 7.85 in the basal forebrain samples. The noradrenaline concentrations in the Wulst and medial forebrain samples increased significantly over the first 50 h post-hatch in dark-reared chicks. Visual experience increased noradrenaline levels in all 3 regions of the telencephalon studied.

Cells containing C-fos-like protein in the rat brain after stimulation on the external membrane of the uterus

The concentrations of adrenaline, dopamine and noradrenaline were measured in 3 regions of the domestic chick telencephalon: (a) the Wulst; (b) a medial forebrain sample comprising mainly the intermediate part of the medial hyperstriatum ventrale (IMHV); and (c) a basal forebrain sample comprising mainly paleostriatum augmentatum. There was no significant left/right hemispheric asymmetry in the concentration of any of these catecholamines in any region studied. Adrenaline was undetectable in the Wulst and medial forebrain samples and only trace amounts were found in the basal forebrain samples of 1-day-old, light-reared chicks. Dopamine concentrations of 9.13 ± 1.13 (S.E.M.) ng/g were present in the Wulst, 16.66 ± 2.56 ng/g in the medial forebrain and 121.19 ± 33.06 ng/g in the basal forebrain samples at hatching. These levels did not alter with age or with visual experience of an imprinting stimulus during the first 50 h post-hatch. At hatching, noradrenaline concentrations of 35.83 ± 8.61 ng/g were present in the Wulst, 26.09 ± 3.75 ng/g in the medial forebrain and 53.13 ± 7.85 in the basal forebrain samples. The noradrenaline concentrations in the Wulst and medial forebrain samples increased significantly over the first 50 h post-hatch in dark-reared chicks. Visual experience increased noradrenaline levels in all 3 regions of the telencephalon studied.

Benzodiazepine prevention of swim stress-induced sensitization of cortical biogenic amines: an in vivo microdialysis study.

In vivo microdialysis was used to determine the effect of diazepam, flumazenil and FG-7142 upon the biogenic amine response to acute and repeated swim stress in the medial prefrontal cortex of the rat. Acute swim stress increased norepinephrine levels, although dopamine and serotonin levels remained stable. Upon re-exposure to swim stress twenty-four hours later, sustained increases (200-300% of baseline) in all three biogenic amines were detected. This enhanced response to re-stress was not seen in rats pretreated with either a benzodiazepine: agonist (diazepam, 2 mg/kg), an antagonist (flumazenil, 10 mg/kg), or an inverse agonist (FG-7142, 10 mg/kg) given prior to the first swim stress. Therefore, the sensitization of biogenic amine response to re-stress may be prevented by compounds which differ in their activity at the benzodiazepine receptor.

Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus

The present study was designed to determine the relationship between the discharge of noradrenergic locus coeruleus (LC) neurons and norepinephrine release in the medial prefrontal cortex, a target of LC projections. The LC was electrically stimulated at varying frequencies and patterns for 20 min and extracellular norepinephrine levels were measured in the medial prefrontal cortex of halothane-anesthetized rats using in vivo microdialysis. Electrical stimulation of the LC at 3–10 Hz with an evenly spaced pattern of pulses (tonic stimulation) increased cortical norepinephrine levels in a frequency-dependent manner, with 5- and 10-Hz stimulation increasing norepinephrine levels by 49 ± 3% and 66 ± 20%, respectively. The LC was also stimulated with bursts of pulses designed to deliver physiologically relevant phasic stimulation using the same number of stimuli in a 20-min period as delivered by tonic stimulation at 3 Hz. Results revealed that norepinephrine levels were significantly higher with phasic stimulation compared to tonic stimulation. The present findings indicate that both frequency and pattern of LC discharge are determinants of norepinephrine terminal release. Additionally, bursts of LC activity, similar to those that occur in behaving animals, may be more effective in increasing terminal norepinephrine release on a per spike basis than tonic increases in activity.