Endogenous Norepinephrine Levels Research Articles

Potential of an aqueous extract of Lippia multiflora Moldenke (Verbenaceae) in the treatment of anxiety disorders: Possible involvement of serotoninergic transmission

Ethnopharmacological relevance: The leaves and stems of Lippia multiflora Moldenke (Verbenaceae) are used in traditional medicine to treat depression, anxiety and epilepsy. Aim of the study: The present study investigated the anxiolytic-like effects of Lippia multiflora aqueous extracts in experimental models of anxiety. Materials and methods: Elevated plus maze and open field tests were used to evaluate anxiety and exploratory behaviour. The possible mechanism of action of Lippia multiflora were investigated after pretreatment of animal with agonist and antagonist of serotonin receptors, such as: mCPP, a partial agonist at the 5-HT2C receptors; Way-100635, a selective 5-HT1A receptors antagonist; and DOI, the 5-HT2A/2C receptors agonist. The levels of monoamine neurotransmitters were evaluated in the brain. Results: In the elevated plus maze, Lippia multiflora increased the number of entries into and percentage of time in open arms, and reduced rearing, head dipping, and percentage of time in closed arms. These effects were blocked with the agonist and antagonist of serotonin receptors. In the open field, Lippia multiflora increased crossing and reduced rearing and defecation. The endogenous levels of noradrenaline, dopamine and serotonin in the brain homogenates remain comparable to that distilled water-treated animals. Conclusion: It could be concluded that Lippia multiflora aqueous extracts, used in traditional medicine in Cameroon for the treatment of depression, anxiety and epilepsy seemed to possess anxiolytic properties in mice. These effects might be mediated by serotonin receptors, but not by modulation of the levels of monoamine neurotransmitters when the extract is administered once after one hour.

Anesthetic Induction With Etomidate in Cardiac Surgical Patients: A PRISMA-Compliant Systematic Review and Meta-Analysis

This meta-analysis aimed to systematically review the effects of etomidate (ETM) during anesthetic induction on patients undergoing cardiac surgery. Systematic review and meta-analysis. Operating room. Patients undergoing cardiac surgery. ETM or control drugs. PubMed, Cochrane Library, OVID, and EMBASE were searched through August 31, 2020. Primary outcomes included hemodynamic profiles and stress responses. Secondary outcomes included morbidity, mortality, and postoperative recovery. For continuous/dichotomous variables, treatment effects were calculated as weighted mean difference (WMD)/odds ratio (OR) and 95% confidence interval (CI). A database search yielded 18 randomized controlled trials including 1,241 patients. The present meta-analysis demonstrated that ETM-anesthetized patients had lower heart rates (WMD, -3.31; 95% CI -5.43 to -1.19; p = 0.002), higher blood pressures (systolic blood pressure: WMD, 12.02; 95% CI 6.24 to 17.80; p < 0.0001; diastolic blood pressure: WMD, 5.23; 95% CI 2.39 to 8.08; p = 0.0003; mean arterial pressure (MAP): WMD, 8.64; 95% CI 5.85 to 11.43; p < 0.00001), less requirement for vasopressor (OR, 0.26; 95% CI 0.15 to 0.44; p < 0.00001), and more nitroglycerin usage (OR, 14.89; 95% CI 4.92 to 45.08; p < 0.00001) during anesthetic induction. Current meta-analysis also demonstrated that single-dose ETM lowered cortisol levels transiently and did not have a significant effect on endogenous norepinephrine and epinephrine levels and was not associated with increased postoperative inotrope and/or vasopressor requirement. Additionally, the meta-analysis suggested that ETM anesthesia was associated with neither increased mortality nor morbidity, except a higher incidence of transient adrenal insufficiency in ETM recipients. The present meta-analysis suggested that single-dose ETM during anesthetic induction could be associated with more stable hemodynamics, transient and reversible lower cortisol levels, and a higher adrenal insufficiency incidence, but not worse outcomes in cardiac surgical patients.

P-Synephrine, ephedrine, p-octopamine and m-synephrine: Comparative mechanistic, physiological and pharmacological properties.

Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p‐synephrine and p‐octopamine relative to ephedrine and m‐synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p‐synephrine and p‐octopamine as related to ephedrine and m‐synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p‐Synephrine and p‐octopamine exhibit little binding to α‐1, α‐2, β‐1 and β‐2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m‐synephrine. As a consequence, the effects of ephedrine and m‐synephrine cannot be directly extrapolated to p‐synephrine and p‐octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.

Axonal projection-specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons.

The locus coeruleus (LC) contains the majority of central noradrenergic neurons sending wide projections throughout the entire CNS. The LC is considered to be essential for multiple key brain functions including arousal, attention and adaptive stress responses as well as higher cognitive functions and memory. Electrophysiological studies of LC neurons have identified several characteristic functional features such as low-frequency pacemaker activity with broad action potentials, transient high-frequency burst discharges in response to salient stimuli and an apparently homogeneous inhibition of firing by activation of somatodendritic α2 autoreceptors (α2AR). While stress-mediated plasticity of the α2AR response has been described, it is currently unclear whether different LC neurons projecting to distinct axonal targets display differences in α2AR function. Using fluorescent beads-mediated retrograde tracing in adult C57Bl6/N mice, we compared the anatomical distributions and functional in vitro properties of identified LC neurons projecting either to medial prefrontal cortex, hippocampus or cerebellum. The functional in vitro analysis of LC neurons confirmed their mostly uniform functional properties regarding action potential generation and pacemaker firing. However, we identified significant differences in tonic and evoked α2AR-mediated responses. While hippocampal-projecting LC neurons were partially inhibited by endogenous levels of norepinephrine and almost completely silenced by application of saturating concentrations of the α2 agonist clonidine, prefrontal-projecting LC neurons were not affected by endogenous levels of norepinephrine and only partially inhibited by saturating concentrations of clonidine. Thus, we identified a limited α2AR control of electrical activity for prefrontal-projecting LC neurons indicative of functional heterogeneity in the LC-noradrenergic system.

Phytochemical Analysis and Central Effects of Annona Muricata Linnaeus: Possible Involvement of the Gabaergic and Monoaminergic Systems.

Annona muricata Linnaeus (Annonaceae), popularly known as graviola, is used in folk medicine as both sedative and anticonvulsant. This study correlates the neurochemical profile with the behavioral effects of the hydroalcoholic extract from the leaves of Annona muricata (HLEAM) in mice, proposing to elucidate their mechanism of action on the central nervous system. Flavonoids and phenolic compounds were identified and quantified by High Performance Liquid Chromatography (HPLC) method. The acute toxicity (median lethal dose - LD50) was determined by probitos method using the percentage of mortality based on the Hippocratic screen. HLEAM (25, 50 and 100 mg/kg) was tested, intraperitoneally (i.p.), in models of sedation, anxiety, motor coordination, and seizures. The endogenous levels of dopamine, norepinephrine and DOPAC were assayed by reverse-phase HPLC with electrochemical detection. The HPLC analysis of the extract revealed the presence of flavonoids (quercetin, isoquercitrin, quercitrin, rutin, and kaempferol) and phenolics acids (gallic, chlorogenic, ellagic and caffeic acids). The LD50 was 1091.7 mg/kg and Hippocratic screening indicated central nervous system depressant effect. HLEAM presented sedative effects at doses of 25, 50, and 100 mg/kg, as well as anxiolytic and anticonvulsant effects at a dose of 100 mg/kg. In addition, these effects were partially reversed by flumazenil. The monoamines analysis by HPLC showed that HLEAM decreased the level of norepinefrine and dopamine in the mouse brain striatum. Thus, the results indicate a possible interaction of HLEAM with the GABAergic and monoaminergic systems, adding medicinal value to the popular use of the plant for the treatment of behavioral and neurological disorders.

Antidepressant Effects of the Ginsenoside Metabolite Compound K, Assessed by Behavioral Despair Test and Chronic Unpredictable Mild Stress Model.

Depression is a major social and health problem worldwide. Compound K (CK), an intestinal metabolite of panaxadiol ginsenosides, has been demonstrated to possess significant pharmacological effects on the central nervous system (CNS). Here, we set up this study to investigate the antidepressant effect of CK, and to explore the potential mechanisms underlying this activity. The behavioral despair model and chronic unpredictable mild stress (CUMS) model were established in mice or rats, respectively. Forced swimming test (FST), tail suspension test (TST) and locomotor activity were performed in mice, while the open-field test, food consumption and sucrose preference were assessed in rats. To investigate the underlying mechanism, the levels of endogenous noradrenaline, dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites in the prefrontal cortex (PFC) and hippocampus were detected by HPLC coupled with electron detector. The dopamine degradation enzyme (COMT and MAO) expression was measured by western blot. The BDNF and NGF expression were investigated by immunohistochemical staining analysis. The results showed CK (10, 30mg/kg) intragastric administration for 14 days significantly shorten the immobility time in FST and TST, which could be partially reversed by a D1 receptor antagonist Sch23390. For CUMS rats, CK alleviated the depressant-like behaviors, including decreased food consumption, spontaneous locomotor activity and lower sucrose preference, while WAY-100635, a 5-HT1A receptor antagonist, could attenuate this effect. In addition, CK increased the levels of 5-HT, DA and their metabolites in the PFC and hippocampus of CUMS rats, and could reverse overexpression of MAOB in PFC and hippocampus. CK also increased the GSH and GPx activity in the hippocampus and PFC. The IHC results revealed the BDNF and NGF expression were increased in CK-treated rats. The obtained results indicate that CK exhibits antidepressant effects in rodents, which may be due to the regulation of monoamine neurotransmitter concentration, enhancement of antioxidant capacity, as well as increase of neurotrophin expression in the CNS.

Food Restriction is Required to Preserve the Antisteatotic Effects of Central Leptin in the Liver of Middle-Aged Rats.

Aging is a significant risk factor for the development of obesity and hepatic steatosis associated with insulin and leptin resistance. Food restriction (FR) is commonly used for reducing body weight (BW), adiposity, and liver steatosis. Thus, this study aimed to determine whether FR in middle-aged rats can recover the central leptin antisteatotic effects observed in the liver in young animals. Two groups of 4-month-old Wistar rats were fed ad libitum (AL) or were on FR for 3 months. At 7 months of age, both groups were centrally treated with rat leptin (0.2 μg/d, 7 days) or saline. Central leptin reduced food intake and BW, but not the hepatic triglyceride content, in 7-month-old rats fed AL. However, in 7-month-old FR rats, leptin did not affect BW but markedly reduced serum leptin, serum and hepatic triglyceride levels, and the expression of hepatic lipogenic genes. In addition, central leptin decreased serum and hepatic endogenous norepinephrine levels of FR rats, exerting a homeostatic effect beyond its antisteatotic actions. These findings suggest that in middle-aged rats, moderate FR is required for both preserving the antisteatotic actions of central leptin and avoiding excessive weight loss.

Cold adaptive thermogenesis following consumption of certain pungent spice principles: A validation study

Identifying a means to activate or potentiate thermogenic mechanisms through ingestion of dietary compounds have important implications in cold endurance and survival. Although many reports discuss the thermogenic potential of spices, it is surprising that none of the studies verify whether consumption of spices can improve cold endurance. In this study, we have attempted to evaluate if ingestion of certain spices can activate heat-generating mechanisms in the body such that a fall in. core body temperature (CBT) can be delayed or prevented when faced with a cold challenge. Ten commonly used spices in the Indian cuisine were chosen and 70% ethanol extract of the spices were fed orally to male Wistar rats at a dose of 250mg/kg for a period of 7 days. A change in CBT during cold exposure was recorded before and after treatment. At the end of the experiment, plasma norepinephrine and serum free fatty acid levels were estimated. We observed that among the ten spices, treatment with cinnamon and pepper extracts showed significant improvement in comparison to the control group. Based on evidence in literature and the HPLC-MS analysis from our lab, we hypothesized that the effects of the pepper and cinnamon extracts might be due to their piperine and cinnamaldehyde content respectively. However, no improved endurance was observed when they were administered alone. Poor endurance following depletion of endogenous norepinephrine levels using reserpine indicated its involvement in mediating the heat generating processes. However, it is noteworthy that green tea and spice treated animals exhibited a fall in CBT which was lower than their initial fall. In conclusion, our findings provide experimental evidence that ingestion of spices, viz., pepper and cinnamon, might elicit thermogenic responses such that hypothermia can be delayed or prevented upon cold exposure.

Spontaneous intrahepatic haemorrhage: two cases of segmental arterial mediolysis

Segmental arterial mediolysis (SAM) is an under-recognized degenerative vascular disorder with variable clinical presentations. It affects medium to large calibre arteries, typically those arising from the coeliac axis, and its diagnosis is complicated by overlap with other clinical entities like fibromuscular dysplasia. Diagnosis requires histopathological examination of the affected tissue, although radiographic appearances can be suggestive of SAM. We report on two patients presenting with acute rupture of an intrahepatic artery affected by SAM. Both patients ultimately required right hemi-hepatectomy in order to either control ongoing bleeding or for removal of liver rendered ischaemic by intra-arterial embolization. This was achieved safely despite additional SAM lesions present throughout the vasculature. In both cases described, presentation followed recent, unrelated abdominal surgery and we propose a link between these two events. Recent research has identified the potential role of noradrenaline in the development of SAM lesions in greyhounds, with levels of endogenous noradrenaline known to rise in the setting of surgery.

Is There a Place for β-Mimetics in Clinical Management of Neuropathic Pain? Salbutamol Therapy in Six Cases

Is There a Place for β-Mimetics in Clinical Management of Neuropathic Pain? Salbutamol Therapy in Six Cases

Deletion of N-type Ca2+ Channel Cav2.2 Results in Hyperaggressive Behaviors in Mice

Voltage-dependent N-type Ca(2+) channels play important roles in the regulation of diverse neuronal functions in the brain, but little is known about its role in social aggressive behaviors. Mice lacking the alpha1B subunit (Ca(v)2.2) of N-type Ca(2+) channels showed markedly enhanced aggressive behaviors to an intruder mouse in the resident-intruder test. The dorsal raphe nucleus (DRN), which contains serotonin neurons, is known to be involved in aggression in animals. We thus examined the DRN neurons in the Ca(v)2.2-deficient (Ca(v)2.2(-/-)) mice. Microinjection of omega-conotoxin GVIA, an N-type Ca(2+) channel-specific blocker, into the DRN of wild type mice resulted in escalated aggression, mimicking the phenotypes of Ca(v)2.2(-/-). Electrophysiological analysis showed increased firing activity of serotonin neurons with a reduced inhibitory neurotransmission in the Ca(v)2.2(-/-) DRN. Ca(v)2.2(-/-) mice showed an elevated level of arginine vasopressin, an aggression-related hormone, in the cerebrospinal fluid. In addition, Ca(v)2.2(-/-) mice showed an increase of serotonin in the hypothalamus. These results suggest that N-type Ca(2+) channels at the DRN have a key role in the control of aggression.

Abstract P110: Exploratory Study on Mechanism by Which Hypothermia Improves Outcomes of Cardiopulmonary Resuscitation

Introduction : In an earlier report, our group demonstrated that when head cooling was started during CPR, outcomes were improved. We had also reported in a series of studies the adverse effects on ultimate outcomes of adrenergic amines, both á 1 and âadrenergic agonists and improved outcomes withá 1 and âadrenergic blockades. We therefore hypothesized that the benefits of rapid head cooling may at least in part relate to reduced adrenergic stimulation. In a small exploratory study, we therefore measured endogenous plasma concentration of norepinephrine. Methods: Pilot studies were conducted in 7 domestic male pigs weighing 40±5 kg. After 15 minutes of untreated ventricular fibrillation, in 4 animals head cooling was induced with a Rhino Chill device coincident with start of CPR. An additional 3 animals served as identically treated controls without hypothermia. CPR was continued for 5 minutes in both group prior to defibrillation. Endogenous plasma norepinephrine levels were measured at baseline and 5 minutes after start of CPR. Results: None of the control animals were successfully resuscitated, in contrast to 3 of 4 brain cooled animals. Jugular vein temperature was reduced from 38.0°C to 37.0°C in brain cooled animals ( P &lt;0.001). Endogenous norepinephrine levels were greatly increased in comparing to baseline levels and was significantly less in brain cooled animals (153 vs 381 μg/L, P &lt;0.05) Conclusions: The mechanism by which rapid head cooling improves outcome of resuscitation may, at least in part, relate to inhibition of the adverse effects of endogenous adrenergic stimulation.

CE coupled with amperometric detection using a boron‐doped diamond microelectrode: Validation of a method for endogenous norepinephrine analysis in tissue

The level of endogenous norepinephrine (NE) in several tissue types was determined by CE with amperometric detection. We report herein on the method validation by HPLC using both amperometric and coulometric detection (CD). Keys to the method were the use of a diamond microelectrode for detection and off-line SPE for sample preparation. The run buffer was a 250 mM borate solution adjusted to pH 8.8 with potassium hydroxide. The diamond microelectrode exhibited a low and stable background current, and a low peak-to-peak noise < or =0.65 pA at the detection potential of +0.86 V versus Ag/AgCl. For standard solutions, the detector signal (i.e., oxidation current) changed linearly with the NE concentration (r(2) = 0.999) between 60 and 1000 nmol/L with an estimated LOD of 51 nmol/L (S/N = 3) and a response variability of 4.5% (RSD, n = 5). An Oasis MCX sorbent was used for SPE and the procedure produced an NE recovery of 95.1 +/- 5.6% (n = 6) from tissue homogenates. NE levels in the spleen, small intestine, and heart of a normotensive rat were found to be in the range of 0.77-0.97, 0.22-0.32, and 0.29-0.45 microg/g tissue (n = 3), respectively.

Determination of endogenous norepinephrine levels in different chambers of the rat heart by capillary electrophoresis coupled with amperometric detection

Capillary electrophoresis with end-column amperometric detection (CE-EC) was used to determine the regional distribution of norepinephrine (NE) in the hearts of sympathetically innervated (control) and chemically sympathectomized rats. Key features of the method are (i) the sample preparation and clean-up step that involved the application of off-line solid phase extraction (SPE) with a 95% NE recovery and (ii) the use of a diamond microelectrode for detection. NE was quantified in the left and right ventricle, the ventricular septum, and the left and right atrium. The NE concentration in the atria was three to five times higher than in the ventricles and ventricular septum of control rats. Basal NE levels in the left and right ventricle and the ventricular septum were reduced to below the detection limit (0.034 μg/g tissue) in tissues treated with the neurotoxin, 6-hydroxydopamine (6-OHDA), while only a moderate reduction was observed in the left and right atrium. Importantly, the diamond microelectrode provided low and stable background current and low peak-to-peak noise ≤0.65 pA at a detection potential of +0.86 V versus Ag/AgCl. A reproducible electrode response was observed for multiple injections of tissue homogenates with minimal response attenuation due to electrode fouling.

Inhibition of uptake-1 activity in the human heart in a hypernoradrenergic state

Uptake-1, mediated by the cell membrane norepinephrine transporter (NET), constitutes the main route of inactivation of norepinephrine at sympathetic nerve terminals. In vitro, the NET can be saturated with a KM between 0.1 and 1 μmol/L. This study addressed whether endogenous norepinephrine levels can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. patients with pheochromocytoma, a catecholamine-secreting tumor, were imaged by 6-[18F]fluorodopamine positron emission tomography. Above 3 nmol/L (about 500 pg/ml) in antecubital venous plasma, left ventricular myocardial 6-[18F]fluorodopamine-derived radioactivity varied inversely with the logarithm of plasma norepinephrine concentration (R = −0.77, P <0.0001). Treatment of the pheochromocytoma resulted in decreased norepinephrine levels and increased myocardial 6-[18F]fluorodopamine-derived radioactivity. In the liver and left ventricular chamber, there was no significant relationship between 6-]18F]fluorodopamine-derived radioactivity and plasma norepinephrine. Therefore, at sufficiently high plasma concentrations, endogenous norepinephrine competes with sympathetic imaging agents at uptake-1 sites. As a result, this competition could lead to erroneous conclusions of sympathetic denervation, net dysfunction, or, in the case of pheochromocytoma, tumor burden. drawing quantitative conclusions about uptake-1 activity in hypernoradrenergic states should be approached with caution. Clinical Pharmacology & Therapeutics (2004) 75, P54–P54; doi: 10.1016/j.clpt.2003.11.206

Release of neurotransmitters from rat brain nerve terminals after chronic ethanol ingestion: differential effects in cortex and hippocampus.

To gain a better insight into the alterations of brain function after chronic ethanol, we measured the release of various neurotransmitters from nerve terminals of cortex and hippocampus isolated fm rats chronically fed with ethanol. The K+-evoked release of [3H]acetylcholine (ACh), f[H]dopamine (DA), [3H] glutamate(Glu) and [3H]noradrenaline (NA) was determined in superfused synaptosomes of brain cortex and hippocampus from rats exposed to the Lieber-DeCarli alcohol liquid diet for 5 weeks. In cortical synaptosomes, chronic ethanol administration did not affect the release of ACh and of DA, while significantly decreasing the release of Glu and NA. The endogenous levels of NA, DA and their metabolites were unchanged. In hippocampal synaptosomes the only effect of chronic alcohol was an increased release of Glu. It can be concluded that at presynaptic level chronic ethanol alters brain neurotransmitter systems selectively. Glutamatergic and noradrenergic nerve terminals from cortex are more vulnerable than those from hippocampus.

Effect of adrenergic stimulation on Rb(+) uptake in normal and ischemic areas of isolated pig hearts: (87)Rb MRI study.

The role of adrenergic stimulation in Rb(+) uptake in normal and ischemic areas of pig hearts was investigated using an agonist (dobutamine) and an antagonist (S-propranolol). The left anterior descending artery (LAD) in isolated pig hearts was cannulated to maintain adequate perfusion of the LAD bed (2.2-2.8 ml/min/g). Rb(+) loading was initiated by switching perfusion to Rb(+)-containing Krebs-Henseleit (KH) buffer in the presence of 0.1 microM dobutamine, 0.5 microM propranolol, or no drug (control), and the LAD flow was reduced to 10% of the baseline for 120 min. The flow through the LAD was then restored to normal and the drugs were removed. In all groups the rate of Rb(+) uptake obtained from serial (87)Rb images was severely depressed in the ischemic anterior wall relative to that in the normal posterior wall. Dobutamine increased the rate of Rb(+) uptake in the posterior wall (6.3% +/- 1.4% vs. 2.5% +/- 0.25% per minute in control) and did not affect the rate in the anterior wall (0.86% +/- 0.40% vs. 1.14% +/- 0.19% per minute in control). Propranolol did not affect Rb(+) uptake in either of these areas. We conclude that the stimulation of Rb(+) uptake by dobutamine is related to activation of Na(+)/K(+) ATPase and passive Na(+) influx in normal tissue. The lack of any effect of propranolol implies a low level of endogenous norepinephrine during low-flow (LF) ischemia.

Naphazoline-Induced Neuroendocrine Changes: Increases in ANP and cGMP Levels, but Suppression of NE, 3H-NE, and cAMP Levels in Rabbit Eyes

The objective of this study was to determine whether naphazoline, an alpha 2 (α₂)/imidazoline (I₁) agonist, can alter endogenous levels of atrial natriuretic peptide (ANP) and norepinephrine (NE) in aqueous humor and cyclic nucleotide (cAMP, cGMP) accumulation and NE overflow inthe iris-ciliary body (ICB) of the rabbit eye. Topical naphazoline (25, 75, and 250 µg) caused a dose-dependent elevation of the ANP levels (36, 54, and 137 pg/ml, respectively) in aqueous humor. This effect was antagonized by pretreatment with efaroxan, an antagonist of I₁/α₂ receptors. Another α₂/I₁ agonist, moxonidine (75 µg topically), caused significant increases in ANP levels in aqueous humor, whereas other relatively selective α₂-adrenergic receptor agonists, brimonidine (50 µg topically) and oxymetazoline (75 µg topically), did not. In naphazoline (75 µg) pretreated eyes, the NE levels in aqueous humor were attenuated by 36% (from 6.0 to 3.8 pg/ml). Furthermore, naphazoline (1, 10, and 100 µmol/l) caused a dose-related inhibition of NE release from ICBs: 25, 45, and 80%, respectively. The isoproterenol (1 µmol/l) stimulated cAMP accumulation was inhibited 53% by naphazoline (100 µmol/l). In contrast, naphazoline significantly increased the cGMP levels in ICBs. These data demonstrate that naphazoline acts on I₁ receptors to increase ANP and to reduce NE levels in aqueous humor. The former effect could also contribute to elevation of cGMP levels and inhibition of cAMP accumulation in the ICB. Further studies will be required to determine if elevation of ANP levels is a critical component of naphazoline-induced alteration of aqueous humor dynamics.

Increased responsiveness of ventromedial hypothalamic neurons to norepinephrine in obese versus lean mice: relation to the metabolic syndrome.

Studies of the effects of acute and chronic norepinephrine (NE) infusion into the ventromedial hypothalamus (VMH) of rodents indicate important roles for VMH NE activities in the development of the obese-glucose intolerant state. Moreover, elevated endogenous levels of NE and/or its metabolites have been observed in a variety of obese-glucose intolerant animal models. We therefore investigated the VMH neuronal electrophysiologic responsiveness to iontophoretically applied NE in lean-euglycemic and obese-hyperglycemic mice. Additionally, the effect of dopamine agonist treatment (which reduces obesity and hyperglycemia) on VMH responsiveness to NE was examined in obese-hyperglycemic mice. Obese (ob/ob) mice were treated daily for 14 days with either bromocriptine (BC, D2 agonist) (10 mg/kg) plus SKF38393 (SKF, D1 agonist) (20 mg/kg) or vehicle. Lean mice were also similarly treated with vehicle. Twenty-seven hours following the final treatment, mice were anesthetized to obtain electrophysiologic responses of glutamate activated VMH neurons to local NE administration. In all three study groups, NE administration inhibited glutamate evoked neuronal activity in the majority (90%) of recorded neurons. No response to NE was observed in the remaining 10% of neurons. Also within all three groups there existed two patterns of response to NE; a) long duration (>2 min) and low threshold (<20 nA) and b) short duration and high threshold. Relative to lean mice, obese mice exhibited a significant 70% increase in average duration of response, 3-fold increase in percent neurons with long duration of response, and 2-fold increase in percent neurons with low threshold of response. BC/SKF treatment of obese mice significantly reduced the percent VMH neurons with long duration and low threshold of response to NE to resemble the VMH neuronal responsiveness to NE observed in lean mice. Increased VMH responsiveness to NE is part of the endogenous neurophysiology of obese-hyperglycemic ob/ob mice. Taken together with previous findings mentioned above, the present results suggest that this increased VMH responsiveness to NE contributes to the pathophysiology of the obese-hyperglycemic state.

Fluid flow and metasomatism in the genesis of the amphibolites-facies, pelite-hosted Kanmantoo copper deposit, South Australia

Daily treatment of neonatal rats with 1-triiodothyronine for 30 days increased locomotor activity as well as the synthesis and presumably, release of brain norepinephrine, dopamine and 5-hydroxytryptamine. Whereas administration of lithium carbonate (60 mg/kg) to normal rats for 10 days, beginning from the 20th day of age, produced no significant effect, this antimanic drug significantly decreased the observed increase in spontaneous locomotor activity in l-triiodothyronine-treated rats. Lithium treatment in normal rats increased the activity of striatal tyrosine hydroxylase, but produced no significant effect on the endogenous levels of norepinephrine and dopamine in several discrete brain regions examined. Lithium, enhanced deamination of catecholamines as evidenced by increased level of 3,4-dihydroxyphenylacetic acid and monoamine oxidase activity in normal rats. The activity of catechol o-methyltransferase was decreased to 82 and 59% in midbrain and crebral cortex of normal rats, respectively. Furthermore, chronic treatment with lithium increased endogenous levels of tryptophan, tryptophan hydroxylase, 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in normal animals. In contrast to the effects seen in normal rats, admininstration of lithium in l-triiodothyronine-treated animals significantly decreased tyrosine hydroxylase as well as dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid, suggesting that this antimanic drug reduced the synthesis and turnover of dopamine. However, the steady-state levels of norepinephrine were raised in hypothalamus, pons-medulla, midbrain and striatum of lithium-treated hyperthyroid rats. As seen in normal animals, lithium in l-triidothyronine-treated rats increased trytophan, tryptophan hydroxylase and 5-hydroxytryptamine levels, but decreased the concentration of 5-hydroxyindoleacetic acid. The results show that the suppressed behavioral activity seen in lithium-treated hyperthyroid rats may be associated with decreased synthesis of norepinephrine and dopamine in the brain. Finally, the effects exerted by lithium on the brain catecholamine metabolizing system of young hyperthyroid rats were not similar to those seen in normal rats of the corresponding age group.