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Sleep pressure builds during wakefulness, but the mechanisms underlying this homeostatic process are poorly understood. One zebrafish model suggests that sleep pressure increases as a function of global neuronal activity, such as during sleep deprivation or acute exposure to drugs that induce widespread brain activation. Given that the arousal-promoting noradrenergic system is important for maintaining heightened neuronal activity during wakefulness, we hypothesised that genetic and pharmacological reduction of noradrenergic tone during drug-induced neuronal activation would dampen subsequent rebound sleep in zebrafish larvae. During stimulant drug treatment, dampening noradrenergic tone with the α2-adrenoceptor agonist clonidine unexpectedly enhanced subsequent rebound sleep, whereas enhancing noradrenergic signalling with a cocktail of α1- and β-adrenoceptor agonists did not enhance rebound sleep. Similarly, CRISPR/Cas9-mediated elimination of the dopamine β-hydroxylase (dbh) gene, which encodes an enzyme required for noradrenalin synthesis, enhanced baseline sleep in larvae but did not prevent additional rebound sleep following acute induction of neuronal activity. Across all drug conditions, c-fos expression immediately after drug exposure correlated strongly with the amount of induced rebound sleep, but was inversely related to the strength of noradrenergic modulatory tone. These results are consistent with a model in which increases in neuronal activity, as reflected by brain-wide levels of c-fos induction, drive a sleep pressure signal that promotes rebound sleep independently of noradrenergic tone. [ABSTRACT FROM AUTHOR]

Copyright of Nordic Nursing Research / Nordisk Sygeplejeforskning is the property of H. Aschehoug & Co. (W. Nygaard) AS and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Faculty of Pharmacy of Ankara University / Ankara Üniversitesi Eczacilik Fakültesi Dergisi is the property of Ankara University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased frontal-midline theta and alpha power during the EST, whereas occipital alpha power was reduced during both the EST and PLRT. Our findings provide evidence that phasic taVNS systematically modulates behavioral, pupillary, and electrophysiological parameters of LC-NA activity during cognitive processing. Moreover, we demonstrate for the first time that the pupillary light reflex can be used as a simple and effective proxy of taVNS efficacy. These findings have important implications for the development of noninvasive neuromodulation interventions for various cognitive and clinical applications. [ABSTRACT FROM AUTHOR]

The locus caeruleus, which has a tubular anatomical shape in the pons, affects almost the entire central nervous system despite its small size. Locus caeruleus which was first noticed about two centuries ago is the source of noradrenaline and is dark blue due to the neuromelanin pigment contained in its cells. This is why it is called coeruleus (sky blue) in Latin. This group of cells located bilaterally in the pons contains approximately 45.000-50.000 cells. In recent years we have much more information about the locus caeruleus due to developing technology and optogenetic studies, functional magnetic resonance imaging techniques. It is known that this anatomical device plays a key role in user characteristics such as attention, use, and stress. Because oculomotor functions reflect mental fruits, it has been the focus of attention especially for engineers working in the field of ergonomics. In this review study, it is aimed to reveal the anatomical structure, physiological characteristics and clinical importance of the locus caeruleus. [ABSTRACT FROM AUTHOR]

Copyright of Lijecnicki Vjesnik is the property of Croatian Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In this review, we aim to integrate our recent findings on the vasopressin system and its role in social discrimination with other known neuromodulatory mechanisms in the olfactory bulb that are involved in different experimental models of social memory. Behavioral paradigms commonly used to investigate odor-related social memory are individual social memory in rodents, lamb recognition in sheep, and the Bruce effect in female mice. All three cases involve neuromodulation in the main and/or the accessory olfactory bulb, the first centers for olfactory processing. As a large diversity of neuromodulators participate in social memory formation, here, we focus primarily on shared neuromodulatory systems and their physiological effects, in particular, the social neuropeptides, vasopressin and oxytocin, and the arousal-related modulators, acetylcholine and noradrenaline. [ABSTRACT FROM AUTHOR]

Several forms of chronic pain do not respond to the conventional analgesics, such as opioids, but can be treated with antidepressants, such as serotonin and noradrenalin reuptake inhibitors (SNRIs). Recent studies indicate that noradrenalin signalling is a key target for SNRI-induced analgesia in neuropathic pain. SNRIs inhibit chronic pain by blocking reuptake of noradrenalin and subsequent activation of adrenergic receptors on neurons in the dorsal horn of the spinal cord. However, in the nervous system, various subtypes of adrenergic receptors are highly expressed by astrocytes and microglial cells. Activation of these receptors on astrocytes engages complex intracellular signalling pathways and prevents inflammatory changes of microglia, which in turn can affect neuronal activity. Hence, SNRIs-induced modulations of the glial cell physiology can impact neural circuit functions and pain perception. In this review, we summarize our current knowledge on the impact of SNRIs on glial cells and in modulating chronic pain in experimental animal models. [ABSTRACT FROM AUTHOR]

Aim: We aimed to investigate the effects of intravenous glucose administration in the lateral hypothalamic area (LHA) on the levels of noradrenaline, dopamine and their metabolites dihydroxyphenylglycol (DHPG)- dihydroxyphenylaceticacid (DOPAC) by brain microdialysis method. Materials and Methods: Adult male Wistar albino rats in 2 normally fed groups and 2 groups of restricted food intake for 24 hours (saline and glucose administered) were used. Microdialysis procedures were performed on the rats in LHA under anesthesia and samples were collected in 20 minutes. After the first samples were recorded as control, 0.9% saline was administered to the control groups and 50% glucose solution was administered intravenously to the glucose groups at a dose of 1.4 ml/kg. During the next 40 minutes, samples were collected and analyzed on the HPLC-ECD system. One-way ANOVA was used for statistical evaluation. Results: Noradrenaline concentration was higher in fasted rats than in satiated animals at baseline. Noradrenaline levels at the 20th minute were significantly decreased in both fasted-satiated groups compared to control group (p=0.01). There was no statistically significant difference in the 40th minute noradrenaline values and dopamine-DHPG-DOP AC levels compared to control. Conclusion: Systemic glucose administration decreased LHA noradrenaline concentration in fasted and satiated rats. It can be mentioned that noradrenergic neurotransmission in LHA can be modulated by plasma glucose. [ABSTRACT FROM AUTHOR]

The role of stress is important in the etiology of depression which subsequently affects cardiovascular regulation. There has been a lot of evidence of the beneficial effects of melatonin in various cardiovascular pathologies. We examined the effect of chronic melatonin treatment on noradrenaline content, synthesis, transport and degradation in the left atria and ventricle of rats exposed to chronic mild unpredictable stress (CUMS). Our results show that CUMS decreased expression of mRNA TH and NET in the left atria and COMT in the left ventricles, whereas increased MAO-A enzymes in the left ventricles. Melatonin treatment induced a significant increase in gene expression of NET in the atria and a decrease in MAO-A in the ventricle. The observed beneficial effects of enhanced uptake and reduced degradation during melatonin treatment were most probably a compensatory mechanism which protects cardiomyocytes from the deleterious effects of noradrenaline overstimulation. [ABSTRACT FROM AUTHOR]

The objective of the study was to identify brain structures that mediate reward as evidenced by positive reinforcing effects of stimuli on behavior. Testing by intracerebral self‐stimulation enabled monkeys to inform whether activation of ~2900 sites in 74 structures of 4 sensorimotor pathways and 4 modulatory loop pathways was positive, negative or neutral. Stimulation was rewarding at 30% of sites, negative at 17%, neutral at 52%. Virtually all (99%) structures yielded some positive or negative sites, suggesting a ubiquitous distribution of pathways transmitting valence information. Mapping of sites to structures with dense versus sparse dopaminergic (DA) or noradrenergic (NA) innervation showed that stimulation of DA‐pathways was rewarding or neutral. Stimulation of NA‐pathways was not rewarding. Stimulation of association areas was generally rewarding; stimulation of purely sensory or motor structures was generally negative. Reward related more to structures' sensorimotor function than to density of DA‐innervation. Stimulation of basal ganglia loop pathways was rewarding except in lateral globus pallidus, an inhibitory structure in the negative feedback loop; stimulation of the cerebellar loop was rewarding in anterior vermis and the spinocerebellar pathway; and stimulation of the hippocampal CA1 loop was rewarding. While most positive sites were in the DA reward system, numerous sites in sparsely DA‐innervated posterior cingulate and parietal cortices may represent a separate reward system. DA‐density represents concentrations of plastic synapses that mediate acquisition of new synaptic connections. DA‐sparse areas may represent innate, genetically programmed reward‐associated pathways. Implications of findings in regard to response habituation and addiction are discussed. [ABSTRACT FROM AUTHOR]

Abstract The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP. We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients. We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions. Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

Patients with chronic non-malignant pain report impairment of physical and social life along with psychological state affecting their overall quality of life. The purpose of managing pain is to reduce the trauma and improve the patient comfort with better quality of life. Tramadol is a centrally acting weak μ-opioid receptor analgesic and is a racemic mixture of (+)-tramadol and (−)-tramadol enantiomers. Tramadol is used worldwide and is listed in many medical guidelines for pain management. The (+)-tramadol has greater affinity for μ-opioid receptor and provides additional prevention of 5- hydroxy tryptamine reuptake, while the (-)-tramadol is a successful noradrenaline reuptake inhibitor and intensifies its release by activating the auto receptor. Tramadol is prescribed to relieve moderate to severe pain management in patients. Tramadol does not show much serious adverse effects without any dependency potential in therapeutic doses as seen in other opioids, like morphine. Tramadol metabolite M1 also has μ-opioid receptor agonist activity, but it faces poor blood brain barrier permeability. In this review, we report the complete updated status of Tramadol along with its chemistry, synthesis, pharmacology, medicinal uses, adverse effects and its combinations available in the market. We have also covered Tramadol patents so that a complete overview provides a broader perspective for future designing of its derivatives and increase their potential use for pain management in terminal cancer patients.

It remains unclear whether the dopaminergic and noradrenergic systems may be implied in suicide attempt risk. In addition, although the serotonergic system has been extensively studied, no formal meta-analysis has been performed to examine its association with suicide attempt. Using PRISMA methodology, we performed a systematic literature review and random-effects meta-analyses of the differences in cerebrospinal fluid (CSF) levels of 5-HIAA, HVA and MHPG between suicide attempters and individuals who never attempted suicide. We identified 30 studies including 937 suicide attempters and 1128 non-attempters; 29 of them measured CSF levels of 5-HIAA, 22 measured CSF levels of HVA and 14 measured CSF levels of MHPG. CSF levels of 5-HIAA and HVA were significantly lower in suicide attempters than in non-attempters [SMD = −0.43 (95% CI: −0.71 to −0.15; p < 0.01) and SMD = −0.45 (95% CI: −0.72 to −0.19; p < 0.01), respectively]. We did not find a significant association between CSF MHPG levels and suicide attempt. Our analyses relied on a limited number of studies of good quality and most studies included small sample sizes. Both serotonin and dopamine systems may play a role in suicide attempt risk. Our findings suggest that a silo approach to biomarkers should be phased out in favor of the study of multiple systems in parallel and in the same populations to progress in the identification of the biological components independently associated with suicide risk, with the goal of identifying new treatment targets and improving suicide risk prediction. [ABSTRACT FROM AUTHOR]

Glucose provides vital energy for cells and contributes to gene expression. The hypothalamus is key for metabolic homeostasis, but effects of glucose on hypothalamic gene expression have not yet been investigated in detail. Thus, herein, we monitored the glucose-dependent transcriptome in murine hypothalamic mHypoA-2/10 cells by total RNA-seq analysis. A total of 831 genes were up- and 1390 genes were downregulated by at least 50%. Key genes involved in the cholesterol biosynthesis pathway were upregulated, and total cellular cholesterol levels were significantly increased by glucose. Analysis of single genes involved in fundamental cellular signaling processes also suggested a significant impact of glucose. Thus, we chose ≈100 genes involved in signaling and validated the effects of glucose on mRNA levels by qRT-PCR. We identified Gnai1–3, Adyc6, Irs1, Igfr1, Hras, and Elk3 as new glucose-dependent genes. In line with this, cAMP measurements revealed enhanced noradrenalin-induced cAMP levels, and reporter gene assays elevated activity of the insulin-like growth factor at higher glucose levels. Key data of our studies were confirmed in a second hypothalamic cell line. Thus, our findings link extra cellular glucose levels with hypothalamic lipid synthesis and pivotal intracellular signaling processes, which might be of particular interest in situations of continuously increased glucose levels.

The symptomatic treatment of REM sleep behaviour disorder (RBD) is very important to prevent sleep-related falls and/or injuries. Though clonazepam and melatonin are usually considered the first-line symptomatic therapy for RBD, their efficiency has not been proven by randomized clinical trials. The role of dopamine agonists in improving RBD symptoms is controversial, and rivastigmine, memantine, 5-hydroxytryptophan, and the herbal medicine yokukansan have shown some degree of efficacy in short- and medium-term randomized clinical trials involving a low number of patients. The development of potential preventive therapies against the phenoconversion of isolated RBD to synucleinopathies should be another important aim of RBD therapy. The design of long-term, multicentre, randomized, placebo-controlled clinical trials involving a large number of patients diagnosed with isolated RBD with polysomnographic confirmation, directed towards both symptomatic and preventive therapy for RBD, is warranted.

The aim of this work is studying tramadol impacts, within the safe dose (˂400mg/65kg body weight), on neurotransmitters concentrations in the brain and spleen as lymphoid organ compared to the kidney as a nonlymphoid organ and its toxic effect on defined brain regions. The type of mice were used in this work is male Balb/c mice. These mice were divided into adult and young groups. Every age group was divided into three subgroups (n=8 mice); H group consumed 40mg TM/kg daily, D group consumed 20mg TM/kg daily, and control group (C) consumed only water ad libtum. The mice were sacrificed after one month. The brain, spleen and kidney were collected and homogenized to measuring levels of noradrenaline (NE) and acetylcholine (ACH). The histopathological changes were detected only in the cerebellum sections of mice consumed tramadol which showed a decreased number of Purkinje cells and loss of their distinctive shape. While there were no differences in NE level in the kidney, significantly higher NE levels in the brain and spleen of the young and adult mice consumed TM were detected. ACH levels increase significantly in the brain, spleen, and kidney of the young and adult mice consumed TM. All these changes were more severe in the mice consumed high TM concentration. As a conclusion, tramadol consumption has very dangerous impacts on the central and peripheral nervous systems. In addition to its histological effects, it could cause hyperactivity of the parasympathetic system, which could result in a very dangerous impact on all body organs, and hyperactivity of sympathetic nerve system, which could result in many dangerous impacts of our immune system. These impacts happened also when tramadol dose not exceeded than 400mg/daily and increase with an elevation of tramadol dosage. [ABSTRACT FROM AUTHOR]

Pheochromocytomatosis is defined as a multifocal cell dissemination limited to the operatively opened space with no signs of distant metastasis. After primary adrenalectomy due to a pheochromocytoma this is a rare and underrecognized manifestation of a tumor recurrence. Between 2010 and 2019 a total of 5 patients with the presentation of pheochromocytomatosis were treated in this center. Clinical and survival data were compared to 12 patients with a metastasized pheochromocytoma. Patients presenting with pheochromocytomatosis showed a better but not significant overall survival (136.8 vs. 107 months). Furthermore, patients with pheochromocytomatosis presented more often with a noradrenaline secretion type. Tumor recurrence in the pheochromocytomatosis group occurred on average 69.2 months after the initial diagnosis and was therefore much later than in patients with distant metastases from a pheochromocytoma (39 months, p = 0.13). This article outlines this special manifestation of recurrence of a pheochromocytoma based on this patient collective. Besides technical operative aspects there appears to be evidence for tumor-specific factors that promote the development of pheochromocytomatosis. Importantly, it seems that all patients with a pheochromocytoma should receive lifelong aftercare and that patients should be closely monitored during the first 5 years after surgery. [ABSTRACT FROM AUTHOR]

The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson's syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP. We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson's syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients. We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions. Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP. [ABSTRACT FROM AUTHOR]

Dopaminergic deficiency, shown by many studies using functional neuroimaging with Single Photon Emission Computerized Tomography (SPECT) and Positron Emission Tomography (PET), is the most consistent neurochemical feature of rapid eye movement (REM) sleep behaviour disorder (RBD) and, together with transcranial ultrasonography, and determination of alpha-synuclein in certain tissues, should be considered as a reliable marker for the phenoconversion of idiopathic RBD (iRBD) to a synucleopathy (Parkinson’s disease –PD- or Lewy body dementia -LBD). The possible role in the pathogenesis of RBD of other neurotransmitters such as noradrenaline, acetylcholine, and excitatory and inhibitory neurotransmitters; hormones such as melatonin, and proinflammatory factors have also been suggested by recent reports. In general, brain perfusion and brain glucose metabolism studies have shown patterns resembling partially those of PD and LBD. Finally, the results of structural and functional MRI suggest the presence of structural changes in deep gray matter nuclei, cortical gray matter atrophy, and alterations in the functional connectivity within the basal ganglia, the cortico-striatal, and the cortico-cortical networks, but they should be considered as preliminary.

Major depressive disorder (MDD) is the most prevalent mental illness contributing to global disease burden. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the first-line treatment for MDD, but are only fully effective in 30% of patients and require weeks before improvement may be seen. About 30% of SSRI-resistant patients may respond to augmentation or switching to another antidepressant, often selected by trial and error. Hence a better understanding of the causes of SSRI resistance is needed to provide models for optimizing treatment. Since SSRIs enhance 5-HT, in this review we discuss new findings on the circuitry, development and function of the 5-HT system in modulating behavior, and on how 5-HT neuronal activity is regulated. We focus on the 5-HT1A autoreceptor, which controls 5-HT activity, and the 5-HT1A heteroreceptor that mediates 5-HT actions. A series of mice models now implicate increased levels of 5-HT1A autoreceptors in SSRI resistance, and the requirement of hippocampal 5-HT1A heteroreceptor for neurogenic and behavioral response to SSRIs. We also present clinical data that show promise for identifying biomarkers of 5-HT activity, 5-HT1A regulation and regional changes in brain activity in MDD patients that may provide biomarkers for tailored interventions to overcome or bypass resistance to SSRI treatment. We identify a series of potential strategies including inhibiting 5-HT auto-inhibition, stimulating 5-HT1A heteroreceptors, other monoamine systems, or cortical stimulation to overcome SSRI resistance. [ABSTRACT FROM AUTHOR]

Abstract Patients with chronic non-malignant pain report impairment of physical and social life along with psychological state affecting their overall quality of life. The purpose of managing pain is to reduce the trauma and improve the patient comfort with better quality of life. Tramadol is a centrally acting weak μ-opioid receptor analgesic and is a racemic mixture of (+)-tramadol and (−)-tramadol enantiomers. Tramadol is used worldwide and is listed in many medical guidelines for pain management. The (+)-tramadol has greater affinity for μ-opioid receptor and provides additional prevention of 5- hydroxy tryptamine reuptake, while the (-)-tramadol is a successful noradrenaline reuptake inhibitor and intensifies its release by activating the auto receptor. Tramadol is prescribed to relieve moderate to severe pain management in patients. Tramadol does not show much serious adverse effects without any dependency potential in therapeutic doses as seen in other opioids, like morphine. Tramadol metabolite M1 also has μ-opioid receptor agonist activity, but it faces poor blood brain barrier permeability. In this review, we report the complete updated status of Tramadol along with its chemistry, synthesis, pharmacology, medicinal uses, adverse effects and its combinations available in the market. We have also covered Tramadol patents so that a complete overview provides a broader perspective for future designing of its derivatives and increase their potential use for pain management in terminal cancer patients. [ABSTRACT FROM AUTHOR]

The aim of the study was to determine the possible presence of adrenergic receptors in the smooth musculature of small and large intestines of heavy hybrid turkey, using different concentrations of non-selective adrenergic receptor agonists, noradrenaline, under in vitro conditions. The research was carried out on 24 fattening turkeys. Tests of circular and longitudinal layers of muscular duodenum, jejunum, ileum, cecum and colon in the organ isolation apparatus, using different concentrations of noradrenaline hydrogentartarate solution, were tested. The research has established the presence of adrenergic receptors within the smooth musculature of the small and large intestines of fattening turkeys. The effect of the noradrenaline on the longitudinal layer was stronger (P<0.001) than the effect on the circular layer of tunica muscularis in small and large intestines of fattening turkeys. There were also statistically significant differences in the results obtained with regard to the use of different concentrations of noradrenaline. Significant differences in the effects of noradrenaline in different parts of the small and large intestines have also been established. Further research into smooth musculature of the small and large intestines of fattening turkeys is needed, with the use of selective agonists and a and ß receptor antagonists. [ABSTRACT FROM AUTHOR]

Here, we used a range of immunohistochemical stains, focussing on tyrosine hydroxylase and dopamine‐β‐hydroxylase, to show that within the pons of tree pangolins clusters of noradrenergic neurons are present. No noradrenergic neurons were observed in the pontine periventricular gray matter (A6 and A4 groups missing), with all noradrenergic neurons being found within the pontine tegmentum (A7 and A5 groups). The tree pangolin is unique in lacking the locus coeruleus (A6) cell group observed in all vertebrates previously studied; however, noradrenergic axons and terminal networks were found throughout the cerebral cortex. We propose this is achieved through a unique structural reorganization of this system. First, the number of noradrenergic neurons in the compact portion of the subcoeruleus (A7sc) of the tree pangolin is increased, providing a total number of noradrenergic neurons in the pontine tegmentum (A7diffuse, A7sc, A5) that is equivalent to the entire locus coeruleus complex in related species of similar brain mass. Second, the most medially located noradrenergic neurons of the A7sc have dendrites that extend into the ventrolateral periventricular gray matter, in the location where the A6 neurons should have been located, forming a "pseudo A6" region. Third, the topological relationships of this "pseudo A6" region to other neurochemical systems that interact with the A6 neurons, such as the orexinergic, cholinergic, and serotonergic systems, appear to be maintained. Thus, a unique structural plasticity of this region appears to maintain the standard functions of the locus coeruleus complex in this unusual mammalian species. Immunohistochemical staining for tyrosine hydroxylase reveals the absence of the locus coeruleus (A6) within the pontine periventricular gray matter (PVG) in the brain of the tree pangolin. Note the extension of dendrites from the subcoeurleus (A7sc), through the fifth mesencephalic tract (trVmes), into the PVG, to compensate for the absence of cells. [ABSTRACT FROM AUTHOR]

The locus coeruleus (LC) plays a crucial role in modulating several higher order cognitive functions via its widespread projections to the entire brain. We set out to investigate the hypothesis that LC functional connectivity (FC) may fluctuate nonlinearly with age and explored its relation to memory function. To that end, 49 cognitively healthy individuals (19–74 years) underwent ultra high-resolution 7T resting-state functional magnetic resonance imaging and cognitive testing. FC patterns from the LC to regions of the isodendritic core network and cortical regions were examined using region of interest–to–region of interest analyses. Curvilinear patterns with age were observed for FC between the left LC and cortical regions and the nucleus basalis of Meynert. A linear negative association was observed between age and LC-FC and ventral tegmental area. Higher levels of FC between the LC and nucleus basalis of Meynert or ventral tegmental area were associated with lower memory performance from age of 40 years onward. Thus, different LC-FC patterns early in life can signal subtle memory deficits. Furthermore, these results highlight the importance of intact interactions between neurotransmitter systems for optimal cognitive aging. [ABSTRACT FROM AUTHOR]

This study characterizes the impact of increasing-intensity treadmill exercise (iTR) on noradrenergic (NE) and serotonergic (5HT) modulation of neuropathic pain. Following sciatic nerve transection and repair (SNTR) rats developed significant mechanical and thermal hyperalgesia that was partially prevented by iTR performed during the first 2 weeks after injury. Marked decrease in the expression of 5HT 2A and α 1A and β-, but not α 2A adrenergic receptors in the spinal cord dorsal horn was associated to SNTR and recovered by iTR, particularly in lamina II. iTR significantly increased 5HT 2A in periaqueductal grey (PAG), raphe magnus (RM) and dorsal raphe nucleus (DRN), with a pattern suggesting reorganization of serotonergic excitatory interconnections between PAG and DRN. iTR also increased the expression of α 1A in locus coeruleus (LC) and DRN, and β 2 in LC, indicating that exercise enhanced activity of NE neurons, likely by activating autologous projections from DRN and PAG. iTR hypoalgesia was antagonized by blockade of β 2 and 5HT 2A receptors with administration of butoxamine and ketanserin. The neurotoxin DSP4 was injected to induce depletion of NE projections from LC before starting iTR. DSP4 treatment worsened mechanical hyperalgesia, but iTR hypoalgesia was similarly produced. Moreover, 5HT 2A expression in LC further increased after DSP4 injection, all these results suggesting an intrinsic regulation of 5HT and NE activity between PAG, DRN and LC neurons activated by iTR. Finally, iTR significantly reduced microglial reactivity in LC and increased non-microglial BDNF expression, an effect that was reverted by butoxamine, implicating BDNF regulation in central 5HT/NE actions on neuropathic pain. [ABSTRACT FROM AUTHOR]

In the arcuate nucleus of the hypothalamus (ARH) satiety signaling (anorexigenic) pro-opiomelanocortin (POMC)-expressing and hunger signaling (orexigenic) agouti-related peptide (AgRP)-expressing neurons are key components of the neuronal circuits that control food intake and energy homeostasis. Here, we assessed whether the catecholamine noradrenalin directly modulates the activity of these neurons in mice. Perforated patch clamp recordings showed that noradrenalin changes the activity of these functionally antagonistic neurons in opposite ways, increasing the activity of the orexigenic NPY/AgRP neurons and decreasing the activity of the anorexigenic POMC neurons. Cell type-specific transcriptomics and pharmacological experiments revealed that the opposing effect on these neurons is mediated by the activation of excitatory α1A - and β- adrenergic receptors in NPY/AgRP neurons, while POMC neurons are inhibited via α2A – adrenergic receptors. Thus, the coordinated differential modulation of the key hypothalamic neurons in control of energy homeostasis assigns noradrenalin an important role to promote feeding.

Introduction: The concentration of noradrenalin and corticosterone as the two nociception modulators change after fasting or stress situation. The aim of present study was to investigate the effect of food deprivation on formalin-induced nociceptive behaviours and plasma levels of noradrenalin and corticosterone in rats. Methods: Food was withdrawn 12, 24 and 48 h prior to performing the formalin test, but water continued to be available ad libitum. The formalin solution (50 μL, 2%) was injected into plantar surface of hind paw. The nociception responses of the animals during the first phase (1-7 minutes), the inter-phase (8-14), the phase 2A (15-60) and the phase 2B (61-90) was separately evaluated. The plasma concentrations of noradrenalin and corticosterone were measured using specific ELISA and IRA kits, according to manufacturer's instructions. Results: In contrast to the increasing of 48 h food deprived animals during phase 2, the nociceptive behaviours of 12 and 24 h groups decreased through the interphase, phase 2A and phase 2B. The injection of formalin in the normal male rats significantly decreased the plasma level of noradrenalin and corticosterone. Food deprivation for 12 and 24 h increased noradrenalin level significantly in comparison with control group which has caused by fasting induced antinociceptive behaviours. There was no significant change in food deprivation for 48 h group. Food deprivation for 12, 24 and 48 h had no effect on corticosterone level in male rats. Discussion: The present study emphasizes that the acute food deprivation diminished the nociceptive behaviours in the formalin test and show a correlation with increase in plasma noradrenalin level.

Objective To study the anti-depressant effect and mechanism of Peiyuan Jieyu Fang (Tonifying-original Qi Releasing-depression Formula). Methods The reserpine depression model was established by intraperitoneal injection of reserpine (2.5 mg/kg) in mice,acute stress depression model, by forced swimming test (FST) in mice,and chronic stress depression model,by long-term bandage (14 d) and noise in mice. The influences of Peiyuan Jieyu Fang on body temperature, ptosis and rate of overstepping bound in reserpine depression model,and on immobility time of FST in acute stress depression model and chronic stress depression model were observed. The content of brain 5- hydroxytryptamine (5-HT),noradrenalin (NA) and indoleamine-2,3-dioxygenase (ID0) in acute stress depression model, and content of 5-HT and IDO in chronic stress depression model were detected by using enzyme-linked immunosorbent assay (ELISA). The expression of IDO mRNA was detected by using fluorescence quantitative polymerase chain reaction (PCR) in chronic stress depression model. Results The decrease of body temperature was antagonized in all Peiyuan Jieyu Fang groups (abbreviated as high-dose group, mid-dose group and low-dose group) in reserpine depression model (P <0. 01). The ptosis and akinesia induced by reserpine were relieved in high-dose group (P <0.05),and akinesia was relieved in low-dose group (P <0.05). The immobility time of FST was shortened (P <0. 05,P <0.01),and content of 5-HT and NA were significantly increased in acute stress depression model in mid-dose group and low-dose group (P <0. 05, P <0. 01). The immobility time of FST was shortened in varying degrees,content of 5-HT was increased,content of IDO was decreased and IDO mRNA expression was up-regulated in chronic stress depression model in high-dose group,mid-dose group and low-dose group (P < 0. 05). Conclusion Peiyuan Jieyu Fang has some relief effects on depression symptoms induced by reserpine,FST and chronic stress in mice. The mechanism may be related to that Peiyuan Jieyu Fang can increase the content of 5-HT and NA, inhibit IDO activity, and down-regulate IDO mRNA expression. [ABSTRACT FROM AUTHOR]

Objective: We examined the complex relationship between lesion location, symptoms of depression (affective and apathetic), and monoamine dysfunction after stroke.Methods: Magnetic resonance imaging was performed on 48 post-stroke patients that had been assessed for affective and apathetic symptoms using the Hospital Anxiety and Depression Scale and the Apathy Scale, respectively. Noradrenalin (NA), dopamine (DA), their metabolites, and a metabolite of serotonin (5-HT) were measured using 24-h urine samples, and 5-HT and 3-methoxy-4-hydroxyphenylglycol were measured using blood samples. We developed a statistical parametric map that displayed the associations between lesion location and both positive and negative alterations of monoamines and their metabolites.Results: Multivariate analysis indicated that basal ganglia lesions and 5-HT showed relationships with affective symptoms, whereas homovanillic acid was related to apathetic symptoms. Univariate analysis showed no such relationships. However, decreases in NA and DA and increases in NA and DA turnover were related to lesions in the brainstem, whereas increases in NA and DA as well as decreases in NA and DA turnover were related to cortical and/or striatum lesions. 5-HT turnover data showed a pattern opposite to that seen for NA and DA turnover.Conclusions: Monoaminergic neuronal pathways are controlled by both receptor-mediated feedback mechanisms and turnover; thus, depletion of monoamines is not the only cause of depression and apathy. Moreover, the monoamine neuronal network might be divided into two branches, catecholamine (NA and DA) and 5-HT, both of which are anatomically and functionally interconnected and could respectively influence apathetic and affective symptoms of depression. [ABSTRACT FROM AUTHOR]

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Laboratory procedures such as the Trier Social Stress Test or the (Socially Evaluated) Cold Pressor Test have been used to investigate working memory performance under stress. Researchers so far have reported a diverse spectrum of stress effects (including the lack thereof) on working memory tasks. We conducted a systematic review of the effect acute stress on working memory performance in standardized laboratory procedures. An overview of the existing literature suggests that acute stress affects working memory in a time-dependent manner, presumably due to the differing time scales of the main stress-reactive hormones involved. Based on the empirical evidence, we hypothesize that the immediate stress-induced release of noradrenaline decreases working memory performance within the first 10 min post stress. In addition, rapid cortisol effects impair working memory at a later time-interval beginning about 25 min post stress. We outline future research directions which could further explore the implications of our insights, as for example combined pharmacological and naturalistic stressor interventions. • We analyzed prior literature regarding effects of acute stress on working memory. • We observed a bi-modal distribution of negative stress effects in regard to time. • Working memory deficits occurred mainly directly after and 25 + minutes after a stressor. • The first peak in negative stress effects coincides with high central noradrenaline levels. • The second peak in negative stress effects coincides with high central cortisol levels. [ABSTRACT FROM AUTHOR]