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Monoaminergic systems are known to be involved in the pathophysiology of neuropsychiatric disorders and vegetative functions due to their established influence on hypothalamic and subcortical areas. These systems can be modulated by lifestyle factors, especially exercise, which is known to produce several beneficial effects on reproduction, brain health, and mental disorders. The fact that exercise is sensed by the brain shows that muscle-stimulated secretion of myokines allows direct crosstalk between the muscles and the brain. One of such exercise-induced beneficial effects on the brain is exhibited by irisin-a recently discovered PGC-1α-dependent adipo-myokine mainly secreted from skeletal muscle during exercise. Thus, we hypothesized that irisin may affect central monoamine levels and thus play an important role in the muscle-brain endocrine loop. To test this assertion, for 10 weeks, vehicle (deionized water) or 100 ng/kg irisin was injected intraperitoneally once a day to 12 male and 12 female rats after which the levels of monoamines and their metabolites were determined by HPLC-ECD. In the hypothalamic nuclei, irisin significantly decreased dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) (p < 0.05), DOPAC/DA ratio (p < 0.01) and noradrenaline (NA, p < 0.05) levels in the anteroventral periventricular nucleus (AVPV), and DOPAC and NA levels in the medial preoptic area (mPOA) (p < 0.05), having a crucial role in reproduction and sexual motivation, respectively. On the other hand, irisin significantly increased DOPAC levels in the lateral hypothalamic area (LHA) (p < 0.05), which acts as a hunger center, while it significantly decreased the levels of DA, NA, and its metabolite 3,4-dihydroxyphenylglycol (DHPG) in the ventromedial hypothalamic nucleus (VMH) as a known satiety center (p < 0.05). In nucleus accumbens (NaC), irisin significantly reduced 5-hydroxyindoleacetic acid (5-HIAA) levels (p < 0.05), which are implicated in autism spectrum disorder (ASD) physiopathology. It also significantly increased DA levels in this area, thus exhibiting positive effects on depression and sexual dysfunction in men. On the other hand, it significantly decreased serotonin (5-HT) (p < 0.01) and its metabolite 5-HIAA levels in the medial amygdala (MeA) (p < 0.05), indicating that it may play a role in social behaviors. Moreover, it significantly attenuated NA levels in the same subcortical area (p < 0.01), which is directly involved in stress-induced activation of the central noradrenergic system. These findings demonstrate for the first time that irisin induces significant changes in monoamine levels in many hypothalamic nuclei involved in feeding behavior and vegetative functions, as well as in subcortical nuclei related to neuropsychiatric disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Early-life social isolation induces emotional and cognitive dysregulation, such as increased aggression and anxiety, and decreases neuron excitability in the medial prefrontal cortex (mPFC). The noradrenergic system in the mPFC regulates emotion and cognitive function via α 1 or α 2A adrenergic receptors, depending on noradrenaline levels. However, social isolation-induced changes in the mPFC noradrenergic system have not been reported. Here, male Wistar rats received post-weaning social isolation for nine consecutive weeks and were administered behavioral tests (novel object recognition, elevated plus maze, aggression, and forced swimming, sequentially). Protein expression levels in the mPFC noradrenergic system (α 1 and α 2A adrenergic receptors, tyrosine hydroxylase, and dopamine-β-hydroxylase used as indices of noradrenaline synthesis and release) were examined through western blotting. Social isolation caused cognitive dysfunction, anxiety-like behavior, and aggression, but not behavioral despair. Socially-isolated rats exhibited increased protein levels of the α 1 adrenergic receptor, tyrosine hydroxylase, and dopamine-β-hydroxylase in the mPFC; there was no significant difference between the groups in the α 2A adrenergic receptor expression levels. Preferential activation of the α 1 adrenergic receptor caused by high noradrenaline concentration in the mPFC may be involved in social isolation-induced emotional and cognitive regulation impairments. Targeting the α 1 adrenergic receptor signaling pathway is a potential therapeutic strategy for psychiatric disorders with symptomatic features such as emotional and cognitive dysregulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

First, we aimed to investigate ex vivo the effects of ethanol (EtOH) on levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their metabolites in the frontal cortex, hippocampus, and striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Animals were treated intraperitoneally with saline (control) or EtOH (1.0, 2.0, or 3.0 g/kg). Brain samples were collected 60 and 120 min after EtOH injection, and monoamines and their metabolites were measured by HPLC-ECD. We found in both WT and Aldh2-KO mice that 3.0 g/kg EtOH increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the level of 3-methoxytyramine (3-MT). A 2.0 g/kg dose of EtOH also increased HVA, but there was not a consistent effect within the brain regions of Aldh2-KO and WT mice. There were inconsistent findings of genotype differences in the levels of DA, 5-HT, and their metabolites in the brain regions tested. None of the EtOH doses altered NE, DA, 5-HT, or 5-hydroxyindoleacetic acid contents in any of the brain regions studied. Second, we tested whether EtOH-induced increases in DOPAC and HVA are mediated by increased monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) activity. To test this, we used the MAO blocker clorgyline (2.0 and 4.0 mg/kg) and the COMT blocker tolcapone (15 and 30 mg/kg) alone or in combination with EtOH (3.0 g/kg). Clorgyline alone increased 3-MT and decreased DOPAC and HVA levels, whereas tolcapone alone increased DOPAC and decreased 3-MT and HVA levels. Surprisingly, the combination of EtOH with clorgyline (4.0 mg/kg) or tolcapone (30 mg/kg) further decreased 3-MT and increased DOPAC and HVA levels, an effect that reversed the inhibitor-induced decreases in HVA. These results suggest that a high concentration of EtOH can accelerate DA metabolism, as evidenced by the increase in DOPAC and HVA, and this effect is likely a consequence of increased degradation of DA by MAO., (Copyright © 2022 Elsevier B.V. All rights reserved.)

ErbB4 loss-of-function in catecholaminergic neurons induces catecholamine dyshomeostasis. Despite ErbB4's significant role in neuropathology, the signaling pathways that regulate these changes are still widely unknown. In this study, we attempt to identify the downstream pathway of ErbB4 that regulates catecholamine homeostasis. The SH-SY5Y human neuroblastoma cell line was used as the in vitro model for catecholaminergic neurons. Western blotting, enzyme-linked immunosorbent assay, and pharmacological and genetic manipulations by agonist/antagonist or small interference RNA were used to investigate the relationship between ErbB4 and extracellular catecholamines. We confirmed that ErbB4 is abundantly expressed in undifferentiated and retinoic acid-differentiated catecholaminergic cells from the SH-SY5Y cell line. ErbB4 inhibition increase the ratio of phosphorylated p38 to total p38 in SH-SY5Y human neuroblastoma cells. Consistent with previous in vivo observations in mice, ErbB4 deficiency led to increases in extracellular dopamine and norepinephrine levels. However, the resulting increase in extracellular dopamine, but not norepinephrine, could be suppressed by p38 inhibitor SB202190. Our results suggest that both extracellular dopamine and norepinephrine homeostasis could be regulated by ErbB4 in human catecholaminergic cells, and ErbB4 may regulate extracellular dopamine, but not norepinephrine, through the p38 MAPK signaling pathway, thus indicating different regulatory pathways of dopamine and norepinephrine by ErbB4 in catecholaminergic neurons., (Copyright © 2021. Published by Elsevier B.V.)

Cannabidiol (CBD) is a non-psychotomimetic compound derived from Cannabis sativa. Preclinical and clinical studies have shown therapeutic potential of CBD in a variety of disorders. Despite several research efforts on CBD, its antidepressant activity has been poorly investigated and the exact mechanism of action remains unclear. Thus, this study aimed to further explore the mechanism of CBD after chronic administration (7 days). First, the dose level of CBD that is enough to produce antidepressant effects after chronic administration was explored. Second, the changes in key proteins and neurotransmitters through such methods as real-time polymerase chain reaction (RT-PCR), western blotting, and high-performance liquid chromatography-electrochemical detection (HPLC-ECD) were critically studied. Furthermore, correlation between behavioral phenotypes with protein and neurotransmitters was established and the possible mechanism was herein postulated. The results showed that only the high dose CBD 100 mg/kg chronic administration induced antidepressant-like effects in mice subjected to forced swim test. Chronic CBD 100 mg/kg administration resulted in significant increases in serotonin (5-HT) and noradrenaline (NA) levels in the hippocampus (HPC). Similarly, the chronic administration of CBD 30 mg/kg and CBD 100 mg/kg significantly decreased nuclear factor kappa B (NF-κB) expression in the HPC. Moreover, none of the treatments were observed to induce locomotor effects. Thus, we concluded that chronic administration of CBD (100 mg/kg) induced antidepressant-like effects by increasing 5-HT and NA levels in the HPC. These results shed new light on further discovery of the antidepressant effect of CBD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Prolonged exposure to manganese (Mn) may lead to toxic effects on the central nervous system (CNS). The mechanisms underlying neuronal death from exposure to Mn are not well understood but undoubtedly involve inflammatory processes. The aim of this study was to explore the effects of long-lasting intranasal Mn exposure in rats focusing on inflammatory processes and catecholamine (dopamine, norepinephrine) levels in the striatum and hippocampus. It was found that intranasal administration by instillation of MnCl 2 solution once a day for 90 days leads to impaired movement and gait. We also observed that Mn concentration increased in the hippocampus (by 30 %) and in the striatum (by 220 %), dopamine (24 %) and DOPAC (35 %) were reduced in the striatum, and dopamine (190 %) and DOPAC (220 %) levels increased with simultaneously norepinephrine reduction (30 %) in the hippocampus. Observation of cytokine mRNA revealed increased expression of both assayed cytokines (IL-1β and TNF-α) in the hippocampus. There was a 3-fold increase in the expression of IBA-1 mRNA, 2-fold increase in NFκB mRNA, and dramatic reduction in IkB mRNA in the striatum. Taken together, intranasal exposure to a high dose of MnCl 2 induces neuroinflammation and neurotransmission disturbance, but the effects are specific for each studied brain region., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chronic pain manifests in multiple disorders and is highly debilitating. While its pathophysiology is not fully understood, the involvement of the mesocorticolimbic monoaminergic systems have been shown to play a critical role in chronic pain emergence and/or maintenance. In this study, we analyzed the levels of monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in mesocorticolimbic areas - medial prefrontal cortex, orbitofrontal cortex, striatum, nucleus accumbens and amygdala - 1 month after a neuropathic lesion, Spared Nerve Injury (SNI). In SNI animals, were observed a marginal decrease of DA and 5-HT in the striatum and a rightward shift in the levels of NA in the nucleus accumbens. While mesocorticolimbic monoamines might be relevant for chronic pain pathophysiology its content appears to be relatively unaffected in our experimental conditions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase and tryptophan hydroxylase, which are essential enzymes for the biosynthesis of dopamine, norepinephrine, and serotonin. It has been known that BH4 is a labile molecule and easily oxidized. As ascorbic acid (AsA) is an antioxidant that is rich in the brain, alteration in the AsA concentration in the brain may affect the proper metabolism of BH4. Here, we examined the effect of AsA deficiency on the concentration of BH4 using ODS rats, which are defective in the gene for AsA synthesis. Intake of an AsA-deficient diet for 2 weeks in ODS rats resulted in great reductions in the AsA levels up to 7 % in the liver and up to 55 % in the brain compared to animals fed a basal diet containing an adequate amount of AsA. The BH4 concentrations in ODS rats fed an AsA-free diet were decreased to 71 % in the liver and 88 % in the brain of those fed a basal diet. We found that the levels of dopamine, norepinephrine, and serotonin were also decreased compared with the ODS rats fed a basal diet. Our data showed that AsA deficiency can affect the BH4 concentrations in the liver and brain, resulting in decreases in the monoamine levels in the brain. These results suggest the importance of AsA in the pathophysiology of neuropsychiatric and cardiovascular disorders through alteration in the BH4 metabolism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Noradrenergic projections from the nucleus tractus solitarius (NTS) to the hypothalamic paraventricular nucleus (PVN) are involved in nicotine (Nic) dependence. Nic induces hypothalamic norepinephrine (NE) release through N-methyl-d-aspartate receptors (NMDARs) and nitric oxide in the NTS. However, acupuncture attenuates Nic withdrawal-induced anxiety. Therefore, this study investigated the effects of acupuncture on Nic-induced hypothalamic NE release. Rats received an intravenous infusion of Nic (90 μg/kg, over 60 s) and extracellular NE levels in the PVN were determined by in vivo microdialysis. Immediately after Nic administration, the rats were bilaterally treated with acupuncture at acupoint HT7 (Shen-Men) or PC6 (Nei-Guan), or a non-acupoint (tail) for 60 s. Acupuncture at HT7, but not at PC6 or the tail, significantly reduced Nic-induced NE release. However, this was abolished by a post-acupuncture infusion of either NMDA or sodium nitroprusside into the NTS. Additionally, acupuncture at HT7, but not the control points, prevented Nic-induced plasma corticosterone secretion and inhibited Nic-induced increases in the phosphorylation of neuronal nitric oxide synthase (nNOS) and endothelial NOS in the NTS. These findings suggest that acupuncture at HT7 reduces Nic-induced NE release in the PVN via inhibition of the solitary NMDAR/NOS pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Locus coeruleus (LC) noradrenergic neurons afferents release noradrenaline (NA) in the cerebellar cortex for modulating cerebellar neuronal circuitry function. Our previous study found that NA inhibited the spontaneous simple spikes activity of cerebellar Purkinje cells (PC) through activation of molecular layer interneurons (MLIs) in vivo in mice. We here examined the effects of NA on spontaneous complex spikes (CSs) activity of cerebellar PC in urethane-anesthetized mice by electrophysiology recording technique and pharmacological methods. Our results showed that cerebellar surface perfusion of NA significantly reduced the number of spikelets and the area under curve (AUC) of the spontaneous CSs. Application of nonselective adrenergic receptor (AR) antagonist, phentolamine, abolished the NA-induced inhibition of CSs. However applying a nonselective β-AR blocker, propranolol, failed to prevent the NA-induced inhibition of CSs activity. The NA-induced inhibition of CSs activity was not blocked by α1-AR antagonist, prazosin, but it was abolished by α2-AR antagonist, yohimibine. Moreover, application of α2-AR agonist, UK14304 induced a depression of CSs activity and mimicked the NA-induced inhibition of CS activity. These results indicate that NA regulates spontaneous CSs activity of cerebellar PCs via activation of α2-AR in vivo in mice. Our present results suggest that noradrenergic neurons of LC may modulate the outputs of cerebellar PCs via inhibition of CSs activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

While the expression of β 3 -adrenergic receptors is firmly established in adipose, kidney and heart tissue, their expression and function in the brain remains unclear despite their potential role in depression and stress-related disorders. This study aimed to investigate the expression of β 3 -adrenoreceptors and their involvement in the mechanism controlling the resting holding current in layer V medial prefrontal cortex (mPFC) pyramidal neurons in young rats. Applications of the selective β 3 -adrenergic receptor agonists BRL 37344 and SR 58611 A evoked inward currents in the tested neurons. The inward currents evoked by BRL 37344 or noradrenaline (a nonselective physiological adrenergic receptor agonist) were prevented or decreased, respectively, by the selective β 3 -receptor antagonist L-748,337. Western blot and fluorescence immunohistochemistry analyses revealed β 3 -adrenergic receptor protein expression in the mPFC. Thus, based on the results obtained here, functional β 3 -adrenergic receptors are expressed in layer V mPFC pyramidal neurons and their activation evokes inward currents., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The efficiency of the memory system lies not only in its readiness to detect and retrieve old stimuli but also in its ability to detect and integrate novel information. In this review, we discuss recent evidence suggesting that the neural substrates sensitive to detecting familiarity and novelty are not entirely overlapping. Instead, these partially distinct familiarity and novelty signals are integrated to support recognition memory decisions. We propose here that the mediodorsal thalamus is critical for familiarity detection, and for combining novelty signals from the medial temporal lobe cortex with the relative familiarity outputs of computations performed in other cortical structures, especially the prefrontal cortex. Importantly, we argue that the anterior hippocampus has a prominent role in detecting novelty and in communicating this with midbrain and striatal structures. We argue that different types of novelty (absolute or contextual) engage different neurotransmitter systems that converge in the hippocampus. We suggest that contextual or unexpected novelty triggers dopaminergic hippocampal-midbrain coupling and noradrenergic-mediated pupil dilation. In contrast, absolute novelty triggers cholinergic-mediated hippocampal encoding accompanied by diminished pupil dilation. These two, distinct hippocampal encoding mechanisms both lead to later recollection but are sensitive to different types of novelty. We conclude that this neurotransmitter-mediated hippocampal encoding establishes the hippocampus in an encoding mode that briefly prevents the engagement of retrieval., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Substantial behavioral evidence exists to support the idea that the lateral hypothalamus (LH) makes axonal connection with spinally-projecting noradrenergic neurons of the A7 catecholamine cell group in the pons. Through this putative projection, the LH modulates nociception via α 1- and α 2 -adrenoceptors in the dorsal horn. We used double-label immunocytochemistry to demonstrate that axons from the LH labeled with the anterograde tracer biotinylated dextran amine (BDA) appose tyrosine hydroxylase-immunoreactive (TH-ir) neuron profiles in the A7 area. Other pontine areas labeled with BDA included the dorsomedial tegmental area, the pontine reticular nucleus, oral part, the caudal aspect of the dorsal raphe, the periaqueductal grey and the A6 area. To confirm the findings of the brightfield experiment, we used confocal microscopy to identify axons from the LH labeled with the anterograde tracer Fluoro-Ruby co-localized with TH-ir dendrites and cell bodies in the A7 cell group. These findings provide an anatomical substrate for behavioral studies in which stimulation of the LH modifies nociception in the spinal cord via norepinephrine., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We have recently reported that the serotonin (5-HT) projections from the midbrain's raphe nuclei that contains 5-HT cell bodies may play a role both in heat production and in heat loss. The purpose of the present study was to clarify the involvement of 5-HT in the ventral tegmental area (VTA), where 5-HT is suggested to participate in thermoregulation, using the combined methods of telemetry, microdialysis, and high performance liquid chromatography, with a special emphasis on regulation of the body temperature (T b ) in freely moving rats. First, we measured changes in T b , tail skin temperature (T tail ; an index of heat loss), heart rate (HR; an index of heat production), locomotor activity (Act), and levels of extracellular monoamines in the VTA during cold (5°C) or heat (35°C) exposure. Subsequently, we perfused citalopram (5-HT re-uptake inhibitor) into the VTA and measured the thermoregulatory parameters and monoamines release. Although T b , T tail , and HR changed during both exposures, significant changes in extracellular level of 5-HT (138.7±12.7% baseline, p<0.01), but not dopamine (DA) or noradrenaline (NA) were noted in the VTA only during heat exposure. In addition, perfusion of citalopram into the VTA increased extracellular 5-HT levels (221.0±52.2% baseline, p<0.01), but not DA or NA, while T b decreased from 37.4±0.1°C to 36.8±0.2°C (p<0.001),T tail increased from 26.3±0.4°C to 28.4±0.4°C (p<0.001), and HR and Act remained unchanged. Our results suggest that the VTA is a key area for thermoregulation, and 5-HT, but not DA or NA, modulates the heat loss system through action in the VTA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The adult rodent piriform cortex has been reported to harbor immature neurons that express markers associated with neurodevelopment and plasticity, namely polysialylated neural cell adhesion molecule (PSA-NCAM) and doublecortin (DCX). We characterized the expression of PSA-NCAM and DCX across the rostrocaudal axis of the rat piriform cortex and observed higher numbers of PSA-NCAM and DCX positive cells in the posterior subdivision. As observed in the rat piriform cortex, Nestin-GFP reporter mice also revealed a similar gradient of GFP-positive cells with an increasing rostro-caudal gradient of expression. Given the extensive noradrenergic innervation of the piriform cortex and its role in regulating piriform cortex function and synaptic plasticity, we addressed the influence of norepinephrine (NE) on piriform cortex plasticity marker expression. Depletion of NE by treatment with the noradrenergic neurotoxin DSP-4 significantly increased the number of DCX and PSA-NCAM immunopositive cells in the piriform cortex of adult rats. Similarly, DSP-4 treated Nestin-GFP reporter mice revealed a robust induction of GFP-positive cells within the piriform cortex following NE depletion. Genetic loss of NE in dopamine β-hydroxylase knockout (Dbh -/-) mice phenocopied the effects of DSP-4, with an increase noted in PSA-NCAM and DCX positive cells in the piriform cortex. Further, chronic α 2 -adrenergic receptor stimulation with the agonist guanabenz increased PSA-NCAM and DCX positive cells in the piriform cortex of adult rats and GFP-positive cells in the piriform cortex of Nestin-GFP mice. By contrast, chronic α 2 -adrenergic receptor blockade with the antagonist yohimbine reduced PSA-NCAM and DCX positive cells in the piriform cortex of adult rats. Our results provide novel evidence for a role of NE in regulating the expression of plasticity markers, including PSA-NCAM, DCX, and nestin, within the adult mouse and rat piriform cortex., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The corticosterone mouse model is widely used in preclinical research towards a better understanding of mechanisms of major depression. One particular administration procedure is the subcutaneous implantation of corticosterone slow-release pellets. In this report we want to provide basic evidence, regarding behavioral changes, neurotransmitter and -modulator levels and some other relevant biomolecules after hypothalamic-pituitary-adrenal-axis distortion. We show that three weeks of corticosterone pellet exposure robustly induces depressive-like but not anxiety-like behavior in mice, accompanied by a significant decrease in hippocampal brain-derived neurotrophic factor levels, at five weeks after the start of treatment. Furthermore there is an overall decrease in plasma corticosterone levels after three weeks of treatment that lasts up until the five weeks' time point. On the other hand, no differences are observed in total monoamine, glutamate or d-serine levels, nor in glucocorticoid receptor expression, in various depression-related brain areas. Altogether this characterization delivers vital information, supplementary to existing literature, regarding the phenotyping of pellet-induced hypothalamic-pituitary-adrenal-axis disruption in mice following three weeks of continuous corticosterone exposure., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

DSP-4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] is a neurotoxin that depletes norepinephrine. The catecholaminergic system has been implicated in the regulation of blood glucose level. In the present study, the effect of DSP-4 administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on blood glucose level was examined in d-glucose-fed and restraint stress mice models. Mice were pretreated once i.c.v. or i.t. with DSP-4 (10-40μg) for 3days, and d-glucose (2g/kg) was fed orally. Blood glucose level was measured 0 (prior to glucose feeding or restraint stress), 30, 60, and 120min after d-glucose feeding or restraint stress. The i.c.v. or i.t. pretreatment with DSP-4 attenuated blood glucose level in the d-glucose-fed model. Plasma corticosterone level was downregulated in the d-glucose-fed model, whereas plasma insulin level increased in the d-glucose-fed group. The i.c.v. or i.t. pretreatment with DSP-4 reversed the downregulation of plasma corticosterone induced by feeding d-glucose. In addition, the d-glucose-induced increase in plasma insulin was attenuated by the DSP-4 pretreatment. Furthermore, i.c.v. or i.t. pretreatment with DSP-4 reduced restraint stress-induced increases in blood glucose levels. Restraint stress increased plasma corticosterone and insulin levels. The i.c.v. pretreatment with DSP-4 attenuated restraint stress-induced plasma corticosterone and insulin levels. Our results suggest that depleting norepinephrine at the supraspinal and spinal levels appears to be responsible for downregulating blood glucose levels in both d-glucose-fed and restraint stress models., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Activity Regulated Cytoskeleton Associated Protein (Arc) is an immediate early gene that is critical to brain plasticity. In this study, norepinephrine's regulation of Arc expression was examined during different stages of postnatal development. Rats were injected with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective noradrenergic neurotoxin, during preadolescence (PND 0 or 13), adolescence (PND 23 or 48) or adulthood (PND 60). After each DSP4 treatment, brains were harvested later in development and Arc mRNA levels analyzed with in situ hybridization. Rats lesioned with DSP4 during preadolescence showed no differences in Arc level compared to saline treated controls. In contrast, adolescence was a time of changing Arc mRNA response to DSP4. Rats lesioned during early adolescence showed Arc expression increases, while rats lesioned during late adolescence showed dramatic Arc expression decreases. Decreases in Arc level caused by late adolescent DSP4 were similar to those found in lesioned adults. These findings highlight a qualitatively different regulation of Arc expression by norepinephrine according to developmental stage, and indicate that mature regulation is not intact until late adolescence. These data point to important developmental differences in norepinephrine's regulation of brain plasticity. These differences may underlie contrasting psychotropic responses in children and adolescents compared to adults., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The noradrenergic and dopaminergic systems are associated with the motor system and have anatomical and functional connections that have not yet been studied. The present study aimed to examine the specific role of D1 receptors (D1Rs) on noradrenergic and dopaminergic responses in the rat brain. Male Wistar rats were assigned to eight groups to receive systemic injection of a D1R agonist (SKF-38393) at 0, 1, 5 or 10mg/kg or injection of a D1R antagonist (SCH-23390) at 0, 0.25, 0.5 or 1mg/kg. Dopamine (DA) and noradrenaline (NA) levels were measured using high-performance liquid chromatography. Injection of SKF-38393 alone at 1, 5 and 10mg/kg did not alter DA levels in the midbrain, cerebral cortex or pons, while it significantly increased these levels in the striatum (at 1 and 10mg/kg), hippocampus (at 1mg/kg) and cerebellum (at 1 and 5mg/kg). Administration of SKF-38393 at 1, 5, and 10mg/kg decreased the NA levels in the midbrain, pons, hippocampus (except at 1mg/kg) and cortex (except at 5mg/kg), whereas the opposite effect was observed in the striatum. SCH-23390 decreased the DA levels in the cortex (at 0.25 and 0.5mg/kg) and pons (at 0.5mg/kg). In contrast, 0.25, 0.5 and 1mg/kg SCH-23390 increased the DA levels in the cerebellum, whereas no differences from the control levels were observed for the DA levels in the striatum, midbrain and hippocampus. SCH-23390 at 0.5 and 1mg/kg increased the NA levels in the striatum. In contrast, the midbrain, hippocampus, cortex, pons and cerebellum did not exhibit altered NA levels. Our results demonstrate that the activation of D1Rs modulates the response of the noradrenergic system in nearly all of the investigated brain structures; thus, the blockade of D1Rs attenuates the effects induced by D1R activation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Descending noradrenergic inhibition to the spinal cord from the locus coeruleus (LC) is an important endogenous pain-relief mechanism which can be activated by local glutamate signaling. Here we tested whether dysregulation of extracellular glutamate level in the LC induced by down-regulating astroglial glutamate transporter-1(GLT-1) impairs endogenous analgesia. In rats treated with repeated LC injections of GLT-1 selective or non-targeting small interfering RNA (siRNA), a subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity. LC-injected GLT-1 siRNA reduced expression of GLT-1 in the LC (P=0.02), increased basal activity of LC neurons (P<0.01), and increased basal extracellular concentrations of LC glutamate (P<0.01) and spinal noradrenaline (P<0.01), but did not affect mechanical withdrawal thresholds in the hindpaw (P=0.83), compared to non-targeting siRNA. LC-injected GLT-1 siRNA impaired capsaicin-evoked release of LC glutamate and spinal noradrenaline, capsaicin-evoked LC neuronal activation, and NSIA. These results suggest that astroglial GLT-1 is essential to normal LC function and that increased extracellular glutamate by down-regulating GLT-1 impairs evoked LC activity and NSIA, essentially taking the LC "off-line"., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The aim of the study was to investigate the effects and possible underlying mechanism of salidroside (Sal) on lipopolysaccharide (LPS)-induced depression-like behavior in mice. Sal (12 mg/kg and 24 mg/kg) and fluoxetine (20 mg/kg) were administered intragastrically once daily for 5 days. At the 5th day, LPS (0.5 mg/kg) was injected intraperitoneally 30 min after drug administration. Levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in serum were measured by ELISA. Levels of neurotransmitters like norepinephrine (NE) and 5-hydroxytryptamine (5-HT) in the prefrontal cortex were detected by HPLC-MS. Further, brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and Nuclear factor-κB (NF-κB) in hippocampal was determined by western blot analysis. Our data showed that pretreatment with Sal dramatically attenuated LPS-induced inflammatory response, decrease of NE and 5-HT levels in the prefrontal cortex. In addition, Sal increased expression levels of BNDF and TrkB. These results suggested that Sal may play a neuroprotective role through the BDNF/TrkB signaling pathway., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are frequently used for the management of neuropathic pain. Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In the present study, we examined the analgesic effects of duloxetine (SNRI) and amitriptyline (TCA) in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intraperitoneal administration of duloxetine and amitriptyline dose-dependently (3,10 and 30 mg/kg) suppressed hyperalgesia induced by SNL. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and amitriptyline (10 mg/kg, respectively). We further determined NA and 5-HT contents in homogenized samples from the ipsilateral dorsal spinal cord after SNL. Although the NA content in SNL rats 2 weeks after ligation was higher than that in SNL rats 4 weeks after ligation, the analgesic efficacy of duloxetine and amitriptyline was similar between two groups. The present study suggests that NA/5-HT increase in the spinal cord is crucial in the antihyperalgesic effect of duloxetine and amitriptyline. The plastic change of the descending noradrenergic system does not obviously affect the analgesic efficacy of duloxetine and amitriptyline., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The pedunculopontine nucleus (PPN) is connected to spinal, cerebellar and cerebral motor control structures and can be activated with external electrodes. Intrinsic cholinergic neuronal degeneration in the PPN is associated with postural instabilities and gait disturbances (PIGD) in advanced Parkinson's disease (PD). Clinical studies have demonstrated that PPN stimulation may improve PIGD. We investigated this claim and the underlying mechanisms using the 6-hydroxydopamine (6-OHDA) hemilesion model of PD. In this study, gait-related parameters, including the base of support (BOS), stride length, and maximum contact area, were analyzed via CatWalk gait analysis following PPN-low frequency stimulation (LFS) of rats with unilateral 6-OHDA lesions. Additionally, neurotransmitter concentrations in the ventrolateral thalamic nucleus (VL) were measured by microdialysis and liquid chromatography-mass spectrometry (LC-MS). Our data revealed that unilateral 6-OHDA lesions of the medial forebrain bundle (MFB) induced significant gait deficits. PPN-LFS significantly improved the BOS (hindlimb) and maximum contact area (impaired forelimb) scores, whereas no other gait parameters were significantly affected. Unilateral 6-OHDA MFB lesions significantly decreased acetylcholine (ACh) and moderately decreased noradrenaline (NA) concentrations in the VL. PPN-LFS mildly reversed the ACh loss in the VL in the lesioned rats but did not alter the NA levels. Taken together, our data indicate that PPN-LFS is useful for treating gait deficits of PD and that these effects are probably mediated by a rebalancing of ACh levels in the PPN-VL pathway. Thus, our findings provide possible insight into the mechanisms underlying PIGD in PD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Oleoylethanolamide (OEA) is an endocannabinoid analogy that belongs to a family of endogenous acylethanolamides. Increasing evidence suggests that OEA may act as an endogenous neuroprotective factor and participate in the control of mental disorder-related behaviors. In the present study, we investigated the antidepressant- like potential of OEA in mice in comparison with clomipramine (Cp). 50 mice were randomly divided into 5 groups, and treated with a vehicle (0.3% methyl cellulose, 20 mL/kg, p.o.), OEA (2.5, 5-10mg/kg, p.o.), or Cp (10mg/kg, p.o.) for 7 days. The immobility was used to evaluate depressive-like behaviors in tail suspension test (TST) and forced swimming test (FST). ELISA detected changes in cerebral noradrenaline (NE) and serotonin (5-HT) levels. Likewise, in the drug-induced model of depression, OEA was given once daily at 10mg/kg (p.o.) for 7 consecutive days. Then, the mice received reserpine (4 mg/kg, i.p.) and the rectal temperature was measured at different time points. Consequently, head twitch behavior induced by intraperitoneal injection of 5-hydroxy-tryptophan (5-HTP; 300 mg/kg) were determined. The experimental data showed that OEA (2.5-10mg/kg) treatment significantly decreased the immobility as compared to the control group, and OEA (10mg/kg) treatment significantly increased 5-HTP-induced head twitch behavior and reversed reserpine-induced hypothermia and increased cerebral levels of NE and 5-HT. Thus, the antidepressant effects of OEA may be related to regulating central monoamine neurotransmitters., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Previous in vitro binding studies identified a 7-fluoro derivative of marsanidine, a partial α2-adrenoceptor (α2-AR) agonist, to display high affinity and selectivity for α2-AR over α1-AR, imidazoline-1 and imidazoline-2 binding sites. In the present study 7-fluoro-marsanidine is further characterised in vivo to investigate its pharmacological effects on extracellular noradrenaline (NA) levels at frontal cortex in conscious freely moving rats using the technique of in vivo brain microdialysis. Peripheral administration of 7-fluoro-marsanidine via intraperitoneal (i.p.) route at the dose of 0.1mg/kg slightly, but non-significantly, decreased extracellular NA level (maximum by 17% at 20 min) in rat frontal cortex compared to basal level. At a higher dose of 1mg/kg, 7-fluoro-marsanidine reduced cortical NA level (maximum by 73% at 40 min) significantly as compared to basal level between 20 and 80 min. In addition, systemic administration of 7-fluoro-marsanidine at both the doses produced rapid onset of sedation in rats. These data suggest that 7-fluoro-marsanidine is able to cross the blood-brain barrier and, by acting as an α2-AR agonist, reduces extracellular NA levels in rat frontal cortex in a dose related manner. Thus, initial studies indicate 7-fluoro-marsanidine to possess favourable functional properties at α2-AR., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Evodiamine is a major alkaloid compound extracted from the dry unripened fruit Evodia fructus (Evodia rutaecarpa Benth., Rutaceae), which has a variety of pharmacological activities. The present study aims to determine the antidepressant-like effect of evodiamine in a rat model of chronic unpredictable mild stress (CUMS). We identified that evodiamine could reverse the following CUMS-induced behavioural deficits and biochemical changes in rats: the decreases of sucrose preference, number of crossings, 5-HT and NA levels, as well as the increase of immobility time. Evodiamine treatments also ameliorated the corticosterone hypersecretion induced by CUMS. Furthermore, we found that evodiamine was able to up-regulate the expression of brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase B (pTrkB) without altering TrkB. This study suggests potential antidepressant-like effect of evodiamine on CUMS rats, and its underlying mechanisms can be potentially linked to their modulating effects on the monoamine transmitters and BDNF-TrkB signaling in the hippocampus., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Opioids are effective analgesics used clinically for both acute and chronic pain management. However, repeated opioid treatment can induce serious side effects such as nausea, vomiting, drowsiness, respiratory depression, euphoria, dependence, hyperalgesia, and tolerance. The mechanism of noxious information transmission in the central nervous system following dependence is still not clear. Norepinephrine (NE), an important neurotransmitter, participates both in the process of opioid dependence and also pain modulation in the central nervous system. In this study, we examined the role of NE on the evoked discharges of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the nucleus accumbens (NAc) of rats, following the development of morphine dependence. Our results revealed that NE inhibited the evoked discharges of PENs and attenuated the inhibition of PINs, while phentolamine enhanced the evoked discharges of PENs and facilitated the inhibition of PINs. These results indicate that the inhibitory action of NE on pain modulation acts via alpha adrenoceptors in the NAc of morphine-dependent rats., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The social defeat paradigm involves aggressive encounters between Long-Evans (L-E) (resident) and Sprague-Dawley (S-D) (intruder) rats. Successful application of chronic social defeat stress in S-D rats is dependent upon selection of highly aggressive L-E rats. Half of the L-E rats screened for aggression did not meet the criterion for aggression (L-E rats performing a defeat, characterized by the intruder surrendering or acquiring a supine position for at least 3s). The observation of the differences in the level of aggression between age and weight matched L-E rats was quite compelling which led us to the present study. Herein, we measured behavioral differences between aggressor and non-aggressor L-E rats. We analyzed their anxiety-like behavior using open-field and elevated plus maze tests. We also measured aggression/violence-like behavior using two tests. In one, time taken to defeat the intruder S-D rat was recorded. In the second test, time taken to attack a novel object was compared between the two groups. We observed a significant increase in anxiety-like behavior in aggressor rats when compared to the non-aggressive group. Furthermore, time taken to defeat the intruder rat and to attack a novel object was significantly lower in aggressive L-E rats. Biochemical data suggests that heightened anxiety-like behavior and aggression is associated with increased plasma levels of corticosterones and elevated oxidative stress. Significant alterations in dopamine (DA), norepinephrine (NE) and epinephrine (EPI) were observed within the hippocampus, amygdala, and the prefrontal cortex, suggesting potential involvement of dopaminergic and noradrenergic systems in regulation of aggressive behaviors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this study was to validate the effects of tianeptine on serotonergic and noradrenergic neurotransmission in a rat model of neuropathic pain. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague-Dawley rats, and mechanical allodynia was assessed using von Frey filaments. The effects of intrathecally administered tianeptine on mechanical allodynia were assessed. Dihydroergocristine or yohimbine, a serotonergic or α-2 adrenergic receptor antagonists, respectively, were intrathecally administered 10min before tianeptine to investigate its mechanism of action. Additionally microdialysis studies were performed to measure the extracellular levels of serotonin (5-HT) and norepinephrine (NE) in the spinal dorsal horn following tianeptine administration. Intrathecal tianeptine significantly increased the paw withdrawal thresholds in a dose-dependent manner and the antiallodynic effect was antagonized by dihydroergocristine and yohimbine. Microdialysis studies revealed that tianeptine increased the levels of 5-HT and NE in the spinal dorsal horn. These findings suggest that tianeptine may be effective for the management of neuropathic pain and that its analgesic mechanism is exerted by increased levels of 5-HT and NE in the synaptic cleft at the spinal level., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Norepinephrine (NE) is an important neurotransmitter in the brain, and regulates antinociception. However, the mechanism of action of NE on pain-related neurons in the hippocampal CA3 region is not clear. This study examines the effects of NE, phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of rats. Trains of electric impulses applied to the right sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in the hippocampal CA3 region were recorded by using a glass microelectrode. Our results revealed that, in the hippocampal CA3 region, the intra-CA3 region microinjection of NE decreased the pain-evoked discharged frequency and prolonged the discharged latency of PEN, and increased the pain-evoked discharged frequency and shortened discharged inhibitory duration (ID) of PIN, exhibiting the specific analgesic effect of NE. While intra-CA3 region microinjection of phentolamine produced the opposite response. It implies that phentolamine can block the effect of endogenous NE to cause the enhanced response of PEN and PIN to noxious stimulation. On the basis of above findings we can deduce that NE, phentolamine and alpha-adrenoceptor are involved in the modulation of nociceptive information transmission in the hippocampal CA3 region., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Yulangsan polysaccharide (YLSP) has been utilized as a phytomedicine to managing nervous dysfunction in China. Thus, this study aimed to evaluate the potential YLSP-mediated detoxification role against morphine dependence in rats. The results indicated that the morphine dependence model significantly increased withdrawal symptoms, levels of NO and NOS (P<0.05). Furthermore, monoaminergic neurotransmitters, including DA and NE, were detected at elevated levels in the ventral tegmental area (VTA), hippocampus (HIP) and prefrontal cortex (PFC), respectively, while the level of DA was decreased and NE was increased in the nucleus accumbens (NAc). Conversely, YLSP administration significantly reversed naloxone-induced withdrawal symptoms, expression of brain NO and NOS, and monoaminergic neurotransmitters (P<0.05). Interestingly, YLSP shows an even more effective trend in attenuating withdrawal symptoms than does clonidine, although without a significant difference. These findings indicate that YLSP attenuation of the naloxone-induced withdrawal symptoms of morphine dependence may be mediated by regulation of the NO pathway and modulation of monoaminergic neurotransmitters., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

One promising strategy to prevent the chronicity of post-operative pain (POP) is to attenuate acute POP during the early phase by efficacious medications with fewer side effects. Duloxetine, one of the serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors (SNRI), is used to treat a wide range of acute and chronic pain. However, its effect on POP has not been investigated. In the present study, we investigated the anti-hypersensitivity effect of duloxetine using a rat model of POP. The possible involvement of spinal 5-HT2A and α2-noradrenergic receptors were also evaluated by using antagonists for 5-HT2A (ketanserin) or α2-noradrenergic receptors (idazoxan). Finally, with the method of in vivo microdialysis, the increase in spinal NA and 5-HT levels after intraperitoneal (i.p.) delivery of duloxetine were investigated. The results showed that intrathecal (i.t.) or i.p. delivery of duloxetine produced an anti-hyperalgesic effect in a dose-dependent manner. The anti-hypersensitivity effect of duloxetine was partly attenuated by pretreatment with ketanserin or idazoxane. Microdialysis study revealed that 5-HT and NA concentrations at the spinal dorsal horn were increased, peaking at 30min after i.p. injection of 20mg/kg duloxetine. These findings indicate that duloxetine inhibits POP by increasing spinal NA and 5-HT levels and activating spinal 5-HT2A or α2-noradrenergic receptors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Tapentadol is a dual action molecule with mu opioid agonist and norepinephrine (NE) reuptake blocking activity that has recently been introduced for the treatment of moderate to severe pain. The effects of intraperitoneal (i.p.) morphine (10mg/kg), tapentadol (10 or 30 mg/kg) or duloxetine (30 mg/kg), a norepinephrine/serotonin (NE/5HT) reuptake inhibitor, were evaluated in male, Sprague-Dawley rats with spinal nerve ligation (SNL) or sham surgery. Additionally, the effects of these drugs on spinal cerebrospinal fluid (CSF) NE levels were quantified. Response thresholds to von Frey filament stimulation decreased significantly from baseline in SNL, but not sham, operated rats. Duloxetine, tapentadol and morphine produced significant and time-related reversal of tactile hypersensitivity. Duloxetine significantly increased spinal CSF NE levels in both sham and SNL rats and no significant differences were observed in these groups. Tapentadol (10 mg/kg) produced a significant increase in spinal NE levels in SNL, but not in sham, rats. At the higher dose (30 mg/kg), tapentadol produced a significant increase in spinal CSF NE levels in both SNL and sham groups; however, spinal NE levels were elevated for an extended period in the SNL rats. This could be detected 30 min following tapentadol (30 mg/kg) in both sham and SNL groups. Surprisingly, while the dose of morphine studied reversed tactile hypersensitivity in nerve-injured rats, CSF NE levels were significantly reduced in both sham- and SNL rats. The data suggest that tapentadol elicits enhanced elevation in spinal NE levels in a model of experimental neuropathic pain offering a mechanistic correlate to observed clinical efficacy in this pain state., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The role of β-adrenoceptors of the hypothalamic paraventricular nucleus (PVN) in modulation of the baroreflex was investigated in conscious rats. The baroreflex was induced by intravenous injection of phenylephrine, and then the extracellular concentration of norepinephrine in the PVN region determined using microdialysis and high-performance liquid chromatography. Next, the role of the β-adrenoceptor in modulation of the baroreflex was investigated by perfusion of its antagonist or agonist into the PVN using microdialysis. Intravenous injection of phenylephrine increased the norepinephrine concentration in the PVN by 35.83 ± 5.71%. Propranolol (an antagonist of the β-adrenoceptor) significantly decreased the gain of reflex bradycardia, but did not affect the magnitude of blood-pressure increases in the baroreflex, resulting in reduced baroreflex sensitivity. Isoprenaline (an agonist of the β-adrenoceptor) significantly increased the gain of reflex bradycardia without affecting blood-pressure increases, leading to increased baroreflex sensitivity. Our results suggest that norepinephrine in the PVN facilitates the phenylephrine-induced baroreflex via β-adrenoceptors., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

α2-Adrenergic agonists simulate norepinephrine (NE) action on α2 receptors of sympathetic neurons to mediate feedback inhibition of NE release. These agents are used as valuable adjuncts for management of hypertension and for anesthesia. Their action, equivalent to NE on α2 adrenergic receptors, raises the question whether α2 agonists may also target NE transporters (NETs), another major control mechanism for noradrenergic neurotransmission. We thus investigated the effect of α2 agonists on transport of the NE analog, (131)I-metaiodobenzylguanidine (MIBG). Results from this investigation showed that xylazine and dexmedetomidine dose-dependently blocked [(3)H]nisoxetine binding in neuron-like SK-N-SH cells. Furthermore, the agents acutely suppressed cellular MIBG uptake in a dose-dependent manner. This effect was uninfluenced by the α2 antagonist yohimbine, but was completely reversed by drug removal. There was no change in membrane NET density by the agents. Moreover, saturation analysis showed that xylazine and dexmedetomidine significantly increased Km without affecting Vmax, indicating competitive inhibition of MIBG transport. Thus, the α2 adrenergic agonists xylazine and dexmedetomidine, acutely suppress NET function through competitive inhibition of substrate transport, likely by direct interaction on a region that over-laps with the nisoxetine binding site., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

L-DOPA induced extracellular dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the ventromedial hypothalamus (VMH) of chickens were measured by in vivo microdialysis. Several doses of 3,4-dihydroxy-l-phenylalanine (l-DOPA) were administered locally through the microdialysis probe into the VMH of chickens for 10 min. Local perfusion of l-DOPA increased the extracellular levels of DA. The increased DA was dose-related and was significantly higher compared to the baseline and control group. The maximal level of DA was 212% and 254%, respectively, of the baseline following administration of 1 and 2 μg/ml l-DOPA. There were no changes in NE and 5-HT levels from baseline after l-DOPA perfusion. l-DOPA (1 μg/ml) was mixed with Ca(2+)-free Ringer, tetrodotoxin (TTX) (2 μM) and high K(+) and was perfused for 30 min into the chicken VMH. TTX and Ca(2+)-free Ringer's solution inhibited the effectiveness of l-DOPA in increasing DA release. The NE and 5-HT levels were significantly lower than the baseline. After administration of K(+) a significant increase of DA, NE and 5-HT was observed. The microdialysis results are consistent with our objective that l-DOPA induced extracellular DA increases in the VMH in a dose-dependent manner and the released DA, NE and 5-HT within the dialysate were related to neuronal activity., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Heart rate is controlled by stimulatory sympathetic and inhibitory parasympathetic nerves innervating the sino-atrial node and cardiac conduction system. Sympathetic release of norepinephrine (NE) and parasympathetic release of acetylcholine (ACh) are controlled by the central nervous system, and by pre-synaptic inhibition of transmitter release within the atria. An increase in cardiac sympathetic transmission relative to parasympathetic transmission is pathological as it can lead to disturbances in heart rhythm, catecholaminergic toxicity and development of arrhythmias or fibrillation. Mice lacking the p75 neurotrophin receptor (p75(-/-)) have elevated atrial NE but a low heart rate suggesting autonomic dysregulation. Similarly, mice whose sympathetic neurons lack the gp130 cytokine receptor (gp130 KO) have a normal heart rate but enhanced bradycardia after vagal nerve stimulation. What is unclear is whether cardiac autonomic disturbances in these animals reflect systemic alterations in nerve activity or whether localized defects in neurotransmitter stores or release are involved. To examine local stimulus-evoked release of neurotransmitters, we have developed a novel method for simultaneous quantification of both NE and ACh after ex vivo atrial field stimulation. Using HPLC with electrochemical detection for NE, and HPLC with mass spectrometry for ACh, we found that following field stimulation NE release was impaired in p75(-/-) atria while ACh content and release was elevated in gp130 KO atria. Thus, alterations in localized transmitter release from atrial explants are consistent with in vivo deficits in heart rate control, suggesting peripheral alterations in autonomic transmission in these mice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Two experiments were performed to investigate the involvements of ventral and dorsal norepinephrine bundle (VNB and DNB) in a selective norepinephrine reuptake inhibitor (NRI) reboxetine (RBX)-induced locomotion and antidepressant-like effects. Rats in the Experiment 1 received a local brain injection of 6-hydroxydopamine (6-OHDA) or an intraperitoneal injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion their VNB or DNB, respectively. Acute effects of RBX (10 mg/kg, i.p.) on the locomotor activity and the forced swim test (FST) were measured 14 days after the lesion. In Experiment 2, activities of the norepinephrine transporter (NET) and the protein kinase C (PKC) in cortex, hippocampus, and locus coeruleus (LC) were detected by western blot after 14 days chronic RBX treatment. Results showed that the antidepressant-like effect of RBX was blocked in VNB lesion but augmented in DNB lesion, and was not relevant to the RBX-induced hypoactivity. Fourteen-days RBX treatment altered the activities of NET and PKC in LC but not hippocampus or cortex. The possible involvement of VNB and DNB in the RBX-induced antidepressant-like effect is discussed., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Thenorphine is a new potent long-acting partial opioid agonist. In present study, the effect of thienorphine on noradrenalin (NA) in the locus coeruleus (LC) and dopamine (DA) and its metabolites in the nucleus acumbens (NAc) and the striatum were examined in freely moving rats during acute and chronic thienorphine treatment followed by naloxone-precipitated withdrawal using the in vivo microdialysis technique. Acute thienorphine (1.0mg/kg, s.c.) treatment had no effect on the level of NA in the LC and the level of DA in the NAc and the striatum. Chronic thienorphine (1.0mg/kg, s.c.) third per day for continued 5 days treatment followed by naloxone-precipitated (5.0mg/kg, i.p.) had not alter the extracellular NA level in the LC and the extracellular level of DA in the NAc and the striatum, but significantly increased the level of DOPAC in the striatum. These changes are thought to reflect a direct effect of thienorphine on release of NA and DA. Thus thienorphine deserves further study as a new treatment for opioid dependence., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Spinal noradrenaline is thought to play an important role in descending pain inhibitory pathways and the modulation of nociceptive information at the spinal level. Tapentadol is a μ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). We showed previously that tapentadol, in contrast to morphine, elevates levels of noradrenaline, but not serotonin, in the ventral hippocampus of rats. The aim of this study was to examine the effects of tapentadol, morphine and venlafaxine on spinal monoamine levels. Rats were implanted with spinal microdialysis probes. Drugs were administered intraperitoneally, and samples were collected for 3h in isoflurane-anesthetized animals and analysed for monoamine content using HPLC-MS/MS. In terms of area-under-curve (AUC, 0-180 min), tapentadol (4.64-21.5mg/kg) produced a dose-dependent, significant increase in extracellular spinal noradrenaline levels (9275±4346 min% at the highest dose versus -1047±889 min% for vehicle). A maximum increase of 182±32% of baseline was reached 60 min after administration of 10mg/kg tapentadol. Venlafaxine (10mg/kg) produced an effect of similar magnitude. In contrast, tapentadol decreased extracellular spinal serotonin levels (non-significantly compared to vehicle), while venlafaxine increased spinal serotonin to 267±74% of baseline. In contrast to tapentadol and venlafaxine, morphine slightly decreased levels of noradrenaline and serotonin. This study demonstrates that analgesic doses of tapentadol (and venlafaxine), but not morphine, increase spinal noradrenaline levels and that tapentadol is devoid of a relevant serotonergic effect. It supports the suggestion that the NRI component of tapentadol is functionally relevant and contributes to its mechanism of action., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Clinical studies indicate an increased incidence of impaired glucose tolerance in individuals with Parkinson's disease (PD). The mechanisms that underlie this co-morbidity are currently unknown. The purpose of this study was to analyze peripheral glucose tolerance following severe unilateral nigrostriatal dopamine (DA) depletion, and to determine whether central and peripheral insulin signaling was affected in the 6-hydroxydopamine (6-OHDA) middle-aged rat model of PD. Although serum insulin levels differed significantly between the 6-OHDA and sham groups over the course of a glucose tolerance test six weeks post-lesion, no significant effect on glucose tolerance or insulin signaling in skeletal muscle was observed. In contrast, markers of striatal insulin resistance were evident in the rats. These data suggest that while 6-OHDA may affect serum insulin levels and striatal insulin signaling, the unilateral 6-OHDA lesion model does not induce glucose intolerance or peripheral insulin resistance, at least at the six-week post-lesion timepoint., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

It has been well established that aging is the most prominent risk factor for PD. In the MPTP mouse model which has been widely used to study PD, studies have shown that MPTP exhibits its neurotoxic effects on the dopaminergic system in an age-dependent manner. Although it is recognized the serotonergic system is impacted in PD, how aging influences serotonergic neurodegeneration in PD has not been adequately investigated. In the present studies, we examined the long-term effects of MPTP treatment on regional concentrations of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) in the striatum and prefrontal cortex (PFC). We also determined if there are differences in the age-dependent vulnerability of the monoaminergic system to MPTP. In young (3-month-old) mice, MPTP produced significant decreases in striatal DA but no changes in striatal 5-HT and NE three weeks after MPTP treatment. There was partial recovery of striatal DA concentrations 18 months later. This was accompanied by elevated striatal 5-HT. In the PFC, NE was decreased but there was complete recovery 18 months later. By contrast, we observed a long-term decrease in prefrontal 5-HT with no recovery of 5-HT concentrations 18 months after MPTP treatment. Striatal DA and NE but not 5-HT neurons exhibited age-dependent vulnerability to MPTP. Aging had no influence on the neurotoxic effects of MPTP in the PFC. Thus, there is divergence in the response of DA and 5-HT systems to MPTP neurotoxicity., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Occlusal disharmony induced by placing an acryl cap on the lower incisors of rats is perceived as chronic stress. This chronic stress activates corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), resulting in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. The ventral ascending noradrenergic bundles (V-NAB) from the brainstem innervate the PVN. To investigate the relationship between the response of the HPA axis and the V-NAB, we examined changes in extracellular noradrenaline (NA) in the PVN and plasma corticosterone, the final output of the HPA axis, following occlusal disharmony in rats injected with 6-hydroxydopamine (6-OHDA), a specific catecholamine neurotoxin. 6-OHDA microinjection into the V-NAB reduced the magnitude of the responses of extracellular NA in the PVN and the plasma corticosterone to occlusal disharmony. Our results suggest that V-NAB to the PVN are involved in occlusal disharmony-induced activation of the HPA axis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Neurotropin is a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, and used for treatment of neuropathic pain. In the present study, we have determined whether neurotropin could exert antinociceptive action using the central neuropathic pain model that we recently established. Rats were randomly allocated to 3 groups: Sham group (n=20), DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine] group (50mg/kg ip, n=18), and DSP-4+5,7-DHT [5,7-dihydroxytryptamine] group (ip DSP-4 50mg/kg+icv 5,7-DHT 200μg, n=18). In Sham, DSP-4 and DSP-4+5,7-DHT groups, the effects of ip neurotropin (100NU/Kg) on hot-plate latency in rats with no lesion, noradrenergic neuron depletion and both noradrenergic and serotonergic neuronal depletion were studied, respectively. Rats in each group were subdivided equally to 2 subgroups: saline and neurotropin. After completion of the hot-plate tests, each rat was decapitated, the cerebral cortex was dissected from its internal structure for measurement of norepinephrine contents. Hot-plate latency significantly decreased by ∼40% 10 days after ip DSP-4 or after ip DSP-4 and 5,7-DHT. Norepinephrine contents in DSP-4 treated rats (55.6±6.3ng/ng tissue) and DSP-4+5,7-DHT treated rats (35.3±6.3ng/ng tissue) were significantly lower than those in intact rats (131.6±5.7ng/ng tissue, p<0.01). Neurotropin significantly increased the area under the curve (AUC) of the hot-plate latency in the DSP-4 and DSP-4+5,7-DHT groups but not in the Sham group. There was a significant correlation between AUC and norepinephrine contents in saline subgroup (p<0.01, r=0.597) but not in neurotropin subgroup in DSP-4 group. Neurotropin exerted an antinociceptive effect in DSP-4 induced central neuropathic pain. The present data suggest neuronal pathways other than descending inhibitory noradrenergic and serotonergic systems may be involved in neurotropin mediated antinociception., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Tramadol is an atypical opioid with monoamine re-uptake inhibition properties. The aim of the current study was to compare, using in vivo microdialysis, the effect of tramadol on extracellular serotonin (5-HT) and noradrenaline (NA) levels in the rat ventral hippocampus with the effects of the dual 5-HT/NA inhibitors (SNRIs) duloxetine and venlafaxine, the tricyclic antidepressant clomipramine, the selective 5-HT re-uptake inhibitor (SSRI) citalopram, and the selective NA re-uptake inhibitor (NRI) reboxetine. It was found that tramadol, duloxetine and venlafaxine increased extracellular levels of both, 5-HT and NA, in a dose-dependent manner. Clomipramine also increased extracellular 5-HT and NA levels, however not dose-dependently in the tested dose range. Citalopram selectively increased extracellular 5-HT levels. Reboxetine increased extracellular NA levels and also to a minimal degree 5-HT levels. It can be concluded that, albeit less efficacious, the effects of tramadol on serotonergic and noradrenergic neurotransmission resemble those of the dual 5-HT and NA re-uptake inhibitors duloxetine, venlafaxine, and clomipramine, and are different from those of the SSRI citalopram and the NRI reboxetine., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Protoberberine isoquinoline alkaloids including berberine inhibit dopamine biosynthesis and aggravate l-DOPA-induced cytotoxicity in PC12 cells. In this study, the effects of berberine on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in PC12 cells and on unilateral 6-OHDA-lesioned rats were investigated. In PC12 cells, berberine at 10 and 30μM associated with 6-OHDA (10, 20, and 50μM) enhanced cytotoxicity at 48h compared to 6-OHDA alone, indicated by an increase in apoptotic cell death. In addition, treatment with berberine (5 and 30mg/kg, i.p.) for 21 days in 6-OHDA-lesioned rats markedly depleted tyrosine hydroxylase-immunopositive cells in the substantia nigra as compared to berberine-untreated rats. Further, the levels of dopamine and norepinephrine were also significantly decreased by berberine administration (5 and 30mg/kg) in the striatal regions of 6-OHDA-lesioned rats. These results suggested that berberine aggravated 6-OHDA-induced cytotoxicity in PC12 cells, and led to the degeneration of dopaminergic neuronal cells in the substantia nigra of 6-OHDA-lesioned rats. It is, therefore, suggested that the use of long-term l-DOPA therapy with isoquinoline derivatives including berberine may need to be examined for the presence of adverse symptoms., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Recent studies have demonstrated the involvement of the sympathetic nerve system in bone metabolism. We have previously demonstrated the expression of adrenergic receptors in the human osteoblast SaM-1 cell line. The aim of this study was to reveal the function of these receptors in osteoblasts using electrophysiological methods. During whole-cell patch clamp recording, the application of noradrenaline reduced the currents induced by a voltage ramp, and the effect was larger in the positive potential range. Pretreatment with the selective α(1B)-adrenergic receptor antagonist chloroethylclonidine eliminated the inhibitory effect of noradrenaline. Using Cs-based pipette solution to block potassium channels, the inhibitory effect of noradrenaline disappeared. In contrast, the effect was unaffected in the presence of tetraethylammonium (TEA), a potassium channel blocker. These results suggest that noradrenaline suppresses Cs-sensitive and TEA-insensitive potassium channels via the α(1B)-adrenergic receptor in human osteoblasts., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The aim of the present study was to assess the response of serotonin (5-hydroxytryptamine; 5-HT) in the preoptic area and anterior hypothalamus (PO/AH) to thermoregulation during exercise in a warm environment. In addition, it was investigated whether a rapid increase in extracellular 5-HT levels in the PO/AH modifies the thermoregulatory response under the same exercise conditions. Rats were made to run for 120 min at 10 m min(-1) on a treadmill at the ambient temperature of 30 degrees C. Body core temperature (T(core)) was monitored using a biotelemetry system, and tail skin temperature (T(tail)) was simultaneously measured as an index of heat loss response. Microdialysis in combination with HPLC was used to measure concentrations of monoamines in the PO/AH. Both T(core) and T(tail) increased during the first 20 min of exercise and remained stable until the end of the exercise period. Low-intensity exercise did not induce any changes in 5-HT release in the PO/AH, although the levels of norepinephrine and dopamine were increased. Moreover, increased extracellular 5-HT by local perfusion of 1 microM citalopram (selective 5-HT reuptake inhibitor; SSRI) in the PO/AH had no effect on the thermoregulatory response during acute low-intensity exercise in a warm environment. These results suggest that enhanced release of only 5-HT in the PO/AH may not intervene thermoregulation during exercise in a warm environment., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)