NE Levels Research Articles

The Impact of Housing Temperature-Induced Chronic Stress on Preclinical Mouse Tumor Models and Therapeutic Responses: An Important Role for the Nervous System.

In the last 10-15years, there has been a recognition that the catecholamines (norepinephrine, NE, and epinephrine, Epi) released by the sympathetic nervous system under stressful conditions promote tumor growth through a variety of mechanisms. Tumors recruit autonomic nerves during their development and NE is then released locally in the tumor microenvironment (TME). Acting through adrenergic receptors present on a variety of cells in the TME, NE and Epi induce proliferation, resistance to apoptosis, epithelial to mesenchymal transition, metastasis of tumor cells, angiogenesis, and inflammation in the TME. These pre-clinical studies have been conducted in mouse models whose care and housing parameters are outlined in "The Guide for the Care and Use of Laboratory Animals [1]. In particular, the Guide mandates that mice be housed at standardized sub-thermoneutral temperatures; however, this causes a state of chronic cold-stress and elevated levels of NE. Although mice are able to maintain a normal body temperature when kept at these cool temperatures, it is becoming clear that this cold-stress is sufficient to activate physiological changes which affect experimental outcomes. We find that when mice are housed under standard, sub-thermoneutral temperatures (~22°C, ST), tumor growth is significantly greater than when mice are housed at thermoneutrality (~30°C TT). We also find that the anti-tumor immune response is suppressed at ST and this immunosuppression can be reversed by housing mice at TT or by administration of propranolol (a β-adrenergic receptor antagonist) to mice housed at ST. Furthermore, at ST tumors are more resistant to therapy and can also be sensitized to cytotoxic therapies by housing mice at TT or by treating mice with propranolol. The implications of these observations are particularly relevant to the way in which experiments conducted in preclinical models are interpreted and the findings implemented in the clinic. It may be that the disappointing failure of many new therapies to fulfill their promise in the clinic is related to an incomplete preclinical assessment in mouse models. Further, an expanded understanding of the efficacy of a therapy alone or in combination obtained by testing under a wider range of conditions would better predict how patients, who are under various levels of stress, might respond in a clinical setting. This may be particularly important to consider since we now appreciate that long term outcome of many therapies depends on eliciting an immune response.It is clear that the outcome of metabolic experiments, immunological investigations and therapeutic efficacy testing in tumors of mice housed at ST is restricted and expanding these experiments to include results obtained at TT may provide us with valuable information that would otherwise be overlooked.

3T3-L1 cells and perivascular adipocytes are not equivalent in amine transporter expression.

Rat perivascular adipose tissue (PVAT) stores, takes up, and releases norepinephrine (NE; Ayala-Lopez et al. (2014) Pharmacol Res Perspect 2, e00041). We hypothesized that 3T3-L1 adipocytes would exhibit similar behaviors and, thus, could serve as a model for PVAT adipocytes. However, basal levels of NE were not detected in 3T3-L1 adipocytes. While incubation of 3T3-L1 adipocytes with exogenous NE increased their cellular NE content, the mRNA expression of several NE transporters [e.g., norepinephrine transporter (NET)] were not detected in these cells. Similarly, we observed expression of the vesicular monoamine transporter 1 (VMAT1) in 3T3-L1 adipocytes by qRT-PCR and immunostaining, but stimulation of the cells with tyramine (100 μm) did not cause a significant release of NE. These studies support that 3T3-L1 adipocytes are not an adequate model of perivascular adipocytes for studying NE handling.

Atomic parameters for the transition of Ne I relevant in nuclear physics

We calculated the magnetic dipole hyperfine interaction constants and the electric field gradients of and levels of Ne I by using the multiconfiguration Dirac–Hartree–Fock method. The electronic factors contributing to the isotope shifts were also estimated for the transition connecting these two states. Electron correlation and relativistic effects including the Breit interaction were investigated in detail. Combining with recent measurements, we extracted the nuclear quadrupole moment values for 20Ne and 23Ne with a smaller uncertainty than the current available data. Isotope shifts in the transition based on the present calculated field- and mass-shift parameters are in good agreement with the experimental values. However, the field shifts in this transition are two or three orders of magnitude smaller than the mass shifts, making rather difficult to deduce changes in nuclear-charge mean-square radii. According to our theoretical predictions, we suggest using instead transitions connecting levels arising from the 2p53s configuration to the ground state, for which the normal mass shift and specific mass shift contributions counteract each other, producing relatively small mass shifts that are only one order of magnitude larger than relatively large field shifts, especially for the transition.

Naproxen, a Nonsteroidal Anti-Inflammatory Drug, Can Affect Daily Hypobaric Hypoxia-Induced Alterations of Monoamine Levels in Different Areas of the Brain in Male Rats.

Goswami, Ananda Raj, Goutam Dutta, and Tusharkanti Ghosh. Naproxen, a nonsteroidal anti-inflammatory drug can affect daily hypobaric hypoxia-induced alterations of monoamine levels in different areas of the brain in male rats. High Alt Med Biol. 17:133-140, 2016.-The oxidative stress (OS)-induced prostaglandin (PG) release, in hypobaric hypoxic (HHc) condition, may be linked with the changes of brain monoamines. The present study intends to explore the changes of monoamines in hypothalamus (H), cerebral cortex (CC), and cerebellum (CB) along with the motor activity in rats after exposing them to simulated hypobaric condition and the role of PGs on the daily hypobaric hypoxia (DHH)-induced alteration of brain monoamines by administering, an inhibitor of PG synthesis, naproxen. The rats were exposed to a decompression chamber at 18,000 ft for 8 hours per day for 6 days after administration of vehicle or naproxen (18 mg/kg body wt.). The monoamine levels (epinephrine, E; norepinephrine, NE; dopamine, DA; and 5-hydroxytryptamine, 5-HT) in CC, CB, and H were assayed by high-performance liquid chromatography (HPLC) with electrochemical detection, and the locomotor behavior was measured by open field test. The NE and DA levels were decreased in CC, CB, and H of the rat brain in HHc condition. The E and 5-HT levels were decreased in CC, but in H and CB, they remained unaltered in HHc condition. These DHH-induced changes of monoamines in brain areas were prevented after administration of naproxen in HHc condition. The locomotor behavior remained unaltered in HHc condition and after administration of naproxen in HHc condition. The DHH-induced changes of monoamines in the brain in HHc condition are probably linked with PGs that may be induced by OS.

Curcumin reverses neurochemical, histological and immuno-histochemical alterations in the model of global brain ischemia

Curcumin, a curcuminoid from Curcuma longa, presents antioxidant and anti-inflammatory actions and, among pathological changes of cerebral ischemic injury, inflammation is an important one. The objectives were to study the neuroprotective action of curcumin, in a model of global ischemia. Male Wistar rats (sham-operated, ischemic untreated and ischemic treated with curcumin, 25 or 50 mg/kg, p.o.) were anesthesized and their carotid arteries occluded, for 30 min. The SO group had the same procedure, except for carotid occlusion. In the 1st protocol, animals were treated 1 h before ischemia and 24 h later; and in the 2nd protocol, treatments began 1 h before ischemia, continuing for 7 days. Twenty four hours after the last administration, animals were euthanized and measurements for striatal monoamines were performed, at the 1st and 7th days after ischemia, as well as histological and immunohistochemical assays in hippocampi. We showed in both protocols, depletions of DA and its metabolites (DOPAC and HVA), in the ischemic group, but these effects were reversed by curcumin. Additionally, a decrease seen in 5-HT contents, 1 day after ischemia, was also reversed by curcumin. This reversion was not seen 7 days later. On the other hand, a decrease observed in NE levels, at the 7th day, was totally reversed by curcumin. Furthermore, curcumin treatments increased neuronal viability and attenuated the immunoreactivity for COX-2 and TNF-alpha, in the hippocampus in both protocols. We showed that curcumin exerts neuroprotective actions, in a model of brain ischemia that are probably related to its anti-inflammatory activity.

Effects of Electroacupuncture on Pain Threshold of Laboring Rats and the Expression of Norepinephrine Transporter and α2 Adrenergic Receptor in the Central Nervous System.

To observe the effects of electroacupuncture on pain threshold of laboring rats and the expression of norepinephrine transporter and α2 adrenergic receptor in the central nervous system to determine the mechanism of the analgesic effect of labor. 120 pregnant rats were divided into 6 groups: a control group, 4 electroacupuncture groups, and a meperidine group. After interventions, the warm water tail-flick test was used to observe pain threshold. NE levels in serum, NET, and α2AR mRNA and protein expression levels in the central nervous system were measured. No difference in pain threshold was observed between the 6 groups before intervention. After intervention, increased pain thresholds were observed in all groups except the control group with a higher threshold seen in the electroacupuncture groups. Serum NE levels decreased in the electroacupuncture and MP groups. Increases in NET and α2AR expression in the cerebral cortex and decreases in enlarged segments of the spinal cord were seen. Acupuncture increases uptake of NE via cerebral NET and decreases its uptake by spinal NET. The levels of α2AR are also increased and decreased, respectively, in both tissues. This results in a decrease in systemic NE levels and may be the mechanism for its analgesic effects.

Formulating diets containing corn distillers dried grains with solubles on a net energy basis: Effects on pig performance and on energy and nutrient digestibility

ABSTRACT A field-scale study was conducted to determine whether formulating diets containing corn, soybean meal, soybean oil, and corn dried distillers grains with solubles (C-DDGS) on an equal NE basis would affect pig performance. Two additional experiments were conducted to determine the DE and ME of these same diets (Exp. 2) and the same C-DDGS sample (Exp. 3) used in Exp. 1 to generate data to support results obtained from the field trial. In Exp. 1, 3 barns, each containing 48 pens and 20 pigs per pen (2,880 pigs) were used. Diets were formulated to contain 0, 10, 20, and 30% C-DDGS, with calculated dietary NE and standardized ileal-digestible Lys being equal across all C-DDGS levels. The NE values (kcal/kg as is) used in feed formulation were corn, 2,557; soybean meal, 1,960; soybean oil, 7,544; and C-DDGS, 2,284. Diets were additionally formulated to meet or exceed the amino acid and mineral needs according to the NRC (2012) recommendations. There were no differences ( P ≥ 0.10) noted for pig ADG, ADFI, or G:F among pigs fed the different C-DDGS levels when evaluated on d 28 (36 replications per treatment) or on d 39 (24 replications per treatment due to scale calibration error in one barn). In addition, there was no effect of dietary treatment on DP ( P ≥ 0.10), suggesting that the estimates of NE used for feed formulation were relatively accurate. When the complete diets were fed to pigs in metabolism crates (Exp. 2), apparent total-tract digestibility of DM, ether extract, NDF, and phosphorus, and dietary DE and ME, increased with increasing C-DDGS levels ( P ≤ 0.05). In Exp. 3, the ME in the C-DDGS used in Exp. 1 and 2 was determined to be 3,682 kcal/kg of DM, which was similar to the formulated value of 3,702 kcal of ME/kg of DM. Overall, the data suggest that the NE levels used for corn, soybean meal, soybean oil, and C-DDGS were relatively accurate given that pig performance and DP were unaffected by C-DDGS inclusion level. Differences in apparent total-tract digestibility of dietary DM, ether extract, NDF, and phosphorus could be directly related to digestibility differences in these nutrients, C-DDGS compared with corn, soybean meal, and soybean oil. These results support the formulating of diets on a NE basis, which is especially important in using alternative feedstuffs in swine feed formulation.

Effect of 2 net energy feeding programs in combination with ractopamine on grow-finish pig growth performance and carcass characteristics

ABSTRACT Crossbred barrows were blocked by BW (28.4 kg) and allocated to 1 of 4 treatments (10 pens per treatment, 5 per pen) in a 2 × 2 factorial arrangement, with 2 NE levels [control vs. low (LE)] and with or without 7.5 mg/kg ractopamine hydrochloride (RAC) during the last 21 d of the 105-d feeding trial. The objectives were (1) to evaluate the BW growth, energy intakes, and energetic efficiency of high growth barrows fed high and low energy density diets during the grow-finisher phases, and (2) to evaluate the effect of feeding RAC when pigs were fed either high and low energy diets. Control diets were based on corn, soybean meal, corn DDGS, and LE diets were created by adjusting inclusion rates of soybean hulls and wheat middlings. Diets were formulated on an equal standardized ileal digestible Lys:NE basis within phase, and RAC diets had increased amino acid concentrations compared with non-RAC diets. From d 0 to 84, control pigs had greater ( P P P P P P P P P

Abstract 17400: Catecholamine Release Triggered by Epicardial Absolute Refractory Period Stimulation Augments Global Left Ventricular Function

Background: Biventricular epicardial (Epi) pacing can augment left ventricular (LV) function in heart failure. We postulated that these beneficial effects could involve catecholamine release from local autonomic nerve activation. This hypothesis was tested by applying Epi pacing stimuli during the muscle’s absolute refractory period (ARP) thereby activating intrinsic nerves without altering activation sequence. Methods: Anesthetized farm pigs (n=5) were instrumented with a LV high-fidelity pressure transducer, left atrial and LV Epi pacing electrodes, and sonomicrometer segment length (SL) gauges placed proximal and distal to the LV stimulation site. A small catheter was placed into the great cardiac vein adjacent to the LV pacing site for blood sampling. During atrial pacing at constant rate, 3 electrical pulses (0.8ms, 2-3x threshold volts) were applied to the LV Epi electrodes during the ARP. An experimental run consisted of baseline measurements, with 10 minutes of stimulation followed by 5 minutes of recovery repeated 3 times before and with ß- receptor blockade (BB, metoprolol, 5 mg). Coronary venous blood was sampled at baseline and at 5 and 10 minutes of stimulation for norepinephrine analysis (NE by ELISA). Results: ARP stimulation produced a significant increase in coronary venous NE levels (p< 0.01) accompanied by a significant 10-15% increase in LV dP/dt max (p< 0.01). Segment length vs. LV pressure loop area proximal to the stimulus site was significantly decreased (29.8 ± 10.9 mmHg*mm) compared to baseline (92.6 ± 8.2 mmHg*mm) but was unchanged at the distal site. BB abolished the changes in segment function and blocked the increase in LV dP/dt despite continued NE release. Conclusion: These results demonstrate that ARP EPI pacing induces NE release and augments global LV function. This effect may contribute to the beneficial effect of biventricular Epi pacing in some patients with heart failure.

Beta-adrenoreceptor blockade abolishes atomoxetine-induced risk taking

RationaleClinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. MethodsThis study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the ‘small/certain’ lever guaranteed a single food pellet, and pressing the ‘large/risky’ lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. ResultsAtomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co-administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co-administration of alpha1-adrenoreceptor antagonist, prazosin, did not. ConclusionsAtomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor.

Plasma Norepinephrine and Dopamine Levels in Prepubertal Male Children with Attention-Deficit Hyperactivity Disorder do not Change with 8 Weeks of Methylphenidate Treatment

ABS TRACT: Plasma norepinephrine and dopamine levels in prepubertal male children with attention-deficit hyperactivity disorder do not change with 8 weeks of methylphenidate treatment Objectives: The aim of this study was to determine plasma norepinephrine and dopamine levels at baseline and after 8 weeks of stimulant treatment in pre-pubertal male children with ADHD. Methods: The study group consisted of 50 children (6-12 years old) diagnosed with ADHD. The control group comprised students from a primary school within the epidemiological catchment area of the clinic and was matched for class and age to the ADHD patients. The Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL) was used to diagnose ADHD and allowed comorbidities. Mental retardation was ruled out with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and impaired functioning. We evaluated disorder severity at the time of assessment using the Clinic Global Impression Scale (CGI). The DuPaul ADHD Rating Scale-IV (ARS) was also used. All patients were treatment-naive. The parents were advised to use OROS methylphenidate daily with no drug holidays during weekends. No rescue medications (immediate-release methylphenidate) were allowed. The dose started at 18 mg and was titrated to 54 mg in 4 weeks to yield average doses of 1 mg/kg/ day. Baseline and endpoint plasma DA and NE were measured. Results: Baseline plasma NE and DA levels had no statistically significant differences between ADHD patients `and controls (232.0±67.3 versus 232.2±65.3 pg/mL and 169.3±48.4 versus 186.9±40.5 pg/mL). Plasma NE levels in all ADHD subgroups decreased with 8 weeks of stimulant treatment, while changes in DA levels were more complex. Plasma DA levels decreased with treatment in the ADHD-inattentive subgroup but were elevated in the hyperactive/impulsive and combined subgroups. There were no statistically significant differences between ADHD subgroups for these variables. Endpoint NE levels were correlated with endpoint DA levels. There were no statistically significant differences between ADHD subgroups. Plasma NE levels were not related to symptom severity or treatment response. In contrast, baseline DA levels were negatively correlated with ARS total scores. Conclusions: We found no statistically significant differences between plasma levels of NE and DA in a prepubertal male sample with ADHD and controls. Plasma DA and NE levels were correlated at both baseline and the endpoint. Although there was a signal that baseline DA levels may correlate with ADHD symptoms as evaluated via ARS, this was not true for endpoint analyses. Because this negative correlation disappeared after treatment, this finding about baseline DA levels may also be evaluated as an early treatment neuromarker. The negative results could also be explained by our focus on plasma. The recent consensus is that urinary levels of NE and DA may be more informative in patients with ADHD and that concurrent evaluation of multiple neurotransmitter systems (i.e., neuropeptide Y and NE) may be more informative. Further studies may benefit from concurrent measurements of plasma and urinary levels of catecholamines and their metabolites.

Abstract 035: Differential Sodium-evoked Activation of Pvn Magnocellular vs. Parvocellular Neurons in Rats Lacking Central GαI<SUB.2 Proteins Contributes to Sustained Elevations in Blood Pressure

Aim: To determine the role of brain Gαi 2 proteins in mediating sodium-evoked PVN neuronal activation and blood pressure regulation in conscious rats. Methods: 24-h intracerebroventricular scrambled (SCR) or Gαi 2 oligodeoxynucleotide (ODN; 25μg/5μl)-pretreated conscious Sprague-Dawley rats were monitored for changes in MAP in response to HS (IV 3M NaCl; 0.14 ml/100g). Rats were sacrificed at control (C), 10, 40, or 100-min post-HS for PVN cFos IHC and analysis of plasma AVP and NE. Separate groups received a V 1a receptor antagonist (IV; 10 μg/ml/kg) 5-min prior to HS. Results: No difference was observed in sodium-evoked peak change in MAP and MAP remained elevated at 100-min in Gαi 2 but not SCR ODN rats (MAP 100-min post-HS [mmHg] SCR 134±2 vs Gαi 2 146±3, P<0.05). Significant increases in the number of Fos + PVN magnocellular neurons were observed post-HS in SCR and Gαi 2 ODN groups ([Fos + cells] SCR C 3±1 vs 100-min 31±5; Gαi 2 C 2±0 vs 100-min 26±4, P <0.05). A rapid increase in circulating AVP was observed at 10-min in both SCR (plasma AVP [pg/mL] C 12.2±1.6 vs 10-min 62.8±6.9, P <0.05) and Gαi 2 ODN (plasma AVP [pg/mL] C 12.1±1.5 vs 10-min 67.7±7.7 P <0.05) groups and returned to control levels at 40- and 100-min. SCR ODN rats exhibited significant increases in the number of Fos + PVN parvocellular neurons ([Fos+ cells] C 15±1 vs 100-min 67±4, P <0.05) and a significant suppression in circulating NE post-HS (plasma NE [nmol/L] C 44.1±4.9 vs 10-min 17.4±3.9, P <0.05). Gαi 2 ODN rats exhibited significantly less Fos + parvocellular neurons compared to SCR ODN rats (100-min [Fos+ cells] SCR 67±4 vs Gαi 2 30±2, P <0.05) and failed to suppress circulating NE ( P >0.05). V 1a receptor blockade prevented a HS-evoked increase in MAP in SCR ODN rats while Gαi 2 ODN rats exhibited elevated MAP (MAP 100-min [mmHg] SCR 125±2 vs Gαi 2 135±0, P <0.05). Conclusion: Brain Gαi 2 proteins are required to mediate sodium-evoked parvocellular sympathetic, but not magnocellular vasopressinergic, responses to maintain physiological blood pressure regulation. A significant component of blood pressure control in this setting is regulated by the sympathetic nervous system, as supported by the attenuated activation of PVN parvocellular neurons and a failure to suppress circulating levels of NE in Gαi 2 ODN rats.

Black berry juice attenuates neurological disorders and oxidative stress associated with concurrent exposure of aluminum and fluoride in male rats

The objective of this study was to assess the protective effect of black berry juice (BBJ) on the neurological disorders and oxidative stress induced by co-exposure to ALCL3 and NaF in male albino rats. Administration of either AlCl3 (200 mg/kg bw) or NaF (10 mg/kg bw) or both of them caused a significant increase in serum and brain TL, TC, TG as well as serum LDLC and VLDLC levels while serum HDLC level was decreased significantly. Additionally, brain neurotransmitter (DA and 5-HT) levels, AChE, Na-K ATPase activity and ATP values were decreased significantly but NE level was increased in rats administered Al or F alone or in combination. Moreover, a significant increase in brain MDA, NO, H2O2 and free radical enzyme (xanthine oxidase (XO)) and a significant decrease in the level of TAC, SOD and GSH were recorded in AlCl3 or NaF intoxicated rats. In addition, the levels of serum Na, Ca, Cu and zinc (Zn) were significantly diminished, while the level of K was significantly increased. However ALCL3 appears to enhance the neurotoxic hazards caused by NaF. On the other hand, the administration of BBJ (1.6 g/kg bw) showed a marked neuroprotective effect against the biochemical abnormalities that occurred and oxidative stress of the brain induced by co-exposure to AlCl3 and NaF. So, it can be concluded that the consumption of BBJ might be useful for alleviating the neurological disorders and oxidative stress associated with concurrent exposure of ALCL3 and NaF indicating its free radical scavenging and potent antioxidant activity.

Effects of angelica naphtha on the withdrawal signs and norepinephrine release in morphine-dependent rats

Objective To explore the effects of angelica naphtha on the withdrawal signs and norepinephrine neurotransmitter in morphine-dependent rats. Methods 72 SD rats were randomly divided into control group, model group, clonidine group and three angelica naphtha groups(80, 40 and 20 mg/kg) . Rats were received gradualy increasing doses of morphine to produce physical dependence.Withdrawal symptoms were evaluated by Ryuta Tomoji score.The level of norepinephrine and normetanephrine(NMN) were tested by enzyme-linked immunosorbent assay(ELISA). Results The scores of withdrawal signs were (4.00± 3.29), (30.13±4.41), (18.96±4.43), 26.04±4.13), (22.33±4.60) and (19.00±3.47), respectively.The morphine withdrawal signs were reduced by angelica naphtha in a dose-dependent manner(P<0.01), also significantly reduced the level of NE and NMN and the ratio of NMN/NE in the nucleus ceruleus and prefrontal cortex(all P<0.01). Conclusion Angelica naphtha alleviates the withdrawal symptoms in morphine-dependent rats, which may be related to the inhibition of excessive turnover of norepinephrine neurotransmitters in the nucleus ceruleus and prefrontal cortex. Key words: Angelica naphtha; Morphine withdrawal; Norepinephrine; Rats

Phase-delay in the light–dark cycle impairs clock gene expression and levels of serotonin, norepinephrine, and their metabolites in the mouse hippocampus and amygdala

ObjectiveA number of animal studies have implicated circadian clock genes in the regulation of mood, anxiety, and reward. However, the effect of misalignment of the environmental light–dark and internal circadian clock on the monoamine system is not fully understood. In the present study, we examined whether an abnormal light–dark schedule would affect behavior-, circadian clock–, and monoamine-related gene expressions, along with monoamine contents in the amygdala and hippocampus of mice. MethodsMice were subjected to an 8-hour phase delay in the light–dark cycle (Shift) every two days for four weeks, and locomotor activity was continuously measured. We examined the circadian expression of clock genes (Per1, Per2, and Bmal1) and genes of the NE/5HT uptake transporters (Net and Sert). In addition, the levels of NE/5HT and their metabolites MHPG/5HIAA were analyzed in the amygdala and hippocampus. ResultsLocomotor activity showed a free-running phenotype with a longer period (>24 hours) and showed misalignment between the light–dark and inactive–active cycles. The amplitude of the day–night fluctuation of Bmal1 expression was reduced in the amygdala and hippocampus of light–dark–shifted mice. Net gene expression in the Shift group showed different profiles compared with the Control group. In addition, NE and 5HT levels in the amygdala of the Shift group increased during the active period. ConclusionsThe present results suggest that misalignment of the internal and external clocks by continuous shifting of the light–dark cycle affects the circadian clocks and monoamine metabolism in the amygdala and hippocampus of mice.

Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats

Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5–20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.

Population of 2p 54p levels of Ne in the afterglow of discharge in helium with small admixtrue of neon

The processes of population of 3p1, 3p3, 3p6, and 3p9 levels (in Paschen’s notation) of neon atom has been studied by spectroscopic methods during the decay period of plasma produced in helium containing small concentrations of neon ([Ne]/[He] ≈ 10–5). Based on the comparative analysis of temporal variation of the intensities of NeI spectral lines of 2p54p → 2p53s and 2p54d → 2p53p transitions, it is established that the formation of exited Ne(2p54p) atoms in the afterglow is related to the dissociative recombination (DR) of homo- and heteronuclear ions and electrons via reactions HeNe+ + e → Ne(2p54p) + Ne and Ne2+ e → Ne(2p54p) + Ne. The relative contributions of these processes to the rate of population of various Ne(3pj) states depend on the energies of 3pj levels. The upper 3p1 level lying above the ground state of Ne2+(v = 0) ion is populated almost entirely due to the DR of HeNe+ heteronuclear ions. The DR of Ne2+ ions and electrons significantly contributes to \(\Gamma _{3p_j }^{Ne_2^ + }\) flux in population of low-lying 3p3, 3p6, and 3p9 levels; \(\Gamma _{3p_j }^{Ne_2^ + }\) value increases with decreasing energy of 3pj level.

Regression analysis to predict growth performance from dietary net energy in growing-finishing pigs.

Data from 41 trials with multiple energy levels (285 observations) were used in a meta-analysis to predict growth performance based on dietary NE concentration. Nutrient and energy concentrations in all diets were estimated using the NRC ingredient library. Predictor variables examined for best fit models using Akaike information criteria included linear and quadratic terms of NE, BW, CP, standardized ileal digestible (SID) Lys, crude fiber, NDF, ADF, fat, ash, and their interactions. The initial best fit models included interactions between NE and CP or SID Lys. After removal of the observations that fed SID Lys below the suggested requirement, these terms were no longer significant. Including dietary fat in the model with NE and BW significantly improved the G:F prediction model, indicating that NE may underestimate the influence of fat on G:F. The meta-analysis indicated that, as long as diets are adequate for other nutrients (i.e., Lys), dietary NE is adequate to predict changes in ADG across different dietary ingredients and conditions. The analysis indicates that ADG increases with increasing dietary NE and BW but decreases when BW is above 87 kg. The G:F ratio improves with increasing dietary NE and fat but decreases with increasing BW. The regression equations were then evaluated by comparing the actual and predicted performance of 543 finishing pigs in 2 trials fed 5 dietary treatments, included 3 different levels of NE by adding wheat middlings, soybean hulls, dried distillers grains with solubles (DDGS; 8 to 9% oil), or choice white grease (CWG) to a corn-soybean meal-based diet. Diets were 1) 30% DDGS, 20% wheat middlings, and 4 to 5% soybean hulls (low energy); 2) 20% wheat middlings and 4 to 5% soybean hulls (low energy); 3) a corn-soybean meal diet (medium energy); 4) diet 2 supplemented with 3.7% CWG to equalize the NE level to diet 3 (medium energy); and 5) a corn-soybean meal diet with 3.7% CWG (high energy). Only small differences were observed between predicted and observed values of ADG and G:F except for the low-energy diet containing the greatest fiber content (30% DDGS diet), where ADG and G:F were overpredicted by 3 to 6%. Therefore, the prediction equations provided a good estimation of the growth rate and feed efficiency of growing-finishing pigs fed different levels of dietary NE except for the pigs fed the low-energy diet containing the greatest fiber content.

Ameliorative effects of physcion 8-O-β-glucopyranoside isolated from Polygonum cuspidatum on learning and memory in dementia rats induced by Aβ1–40

Context: Polygonum cuspidatum Sieb. Et Zucc. (Polygonaceae) has been traditionally used in folk medicine to treat various diseases.Objective: This study investigates the ameliorative effects of physcion 8-O-β-glucopyranoside (PSG) isolated from P. cuspidatum on learning and memory in dementia rats induced by Aβ1–40.Materials and methods: Dementia rats were prepared by intracerebroventricular injection of Aβ1–40. PSG (5, 10, 20, and 40 mg/kg/d, for 5 d) was administered orally. Ameliorative activity of PSG in dementia rats was evaluated by the Morris water maze (MWM) test, and its mechanisms were explored by evaluating AchE activity, levels of DA, NE, and 5-HT in hippocampus, and drebrin protein expressions in hippocampus.Results: Our results indicated that PSG (5, 10, 20, and 40 mg/kg/d) significantly inhibited the prolonged latency in dementia rats (p < 0.05), and inhibitory rates were 16.5, 22.7, 33.0, and 44.8% after 5 d of learning, indicating that PSG improves learning and memory of dementia rats. Furthermore, PSG significantly decreased AchE activity (10, 20, and 40 mg/kg/d; p < 0.05), increased 5-HT (20 and 40 mg/kg/d, p < 0.05), NE (10, 20, and 40 mg/kg/d; p < 0.05), and DA levels (5, 10, 20, and 40 mg/kg; p < 0.05) in the hippocampus. Additionally, PSG obviously decreased the Aβ contents in hippocampus (10, 20, and 40 mg/kg/d; p < 0.05), and up-regulated drebrin protein expressions (5, 10, 20, and 40 mg/kg/d; p < 0.05).Conclusions: PSG can significantly enhance learning and memory in Aβ1–40-induced dementia rats, and the mechanisms may be related to increase levels of Ach, 5-HT, NE, and DA, decrease Aβ contents, and up-regulation of drebrin proteins in hippocampus.

Biochemistry of primary headaches: role of tyrosine and tryptophan metabolism.

The pathogenesis of migraine as well as cluster headache (CH) is yet a debated question. In this review, we discuss the possible role of the of tyrosine and tryptophan metabolism in the pathogenesis of these primary headaches. These include the abnormalities in the synthesis of neurotransmitters: high level of DA, low level of NE and very elevated levels of octopamine and synephrine (neuromodulators) in plasma of episodic migraine without aura and CH patients. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward an increased decarboxylase and reduced hydroxylase enzyme activities. The metabolic shift of the tyrosine is favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity present in migraine. In addition we present biochemical studies performed in chronic migraine and chronic tension-type headache patients to verify if the same anomalies of the tyrosine and tryptophan metabolism are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine metabolism are present only in CM patients (very high plasma levels of DA, NE and tryptamine). Tryptamine plasma levels were found significantly lower in both CM and CTTH patients. In view of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.