Noradrenergic Pathways Research Articles

Structural Scaffolds as Anti- Alzheimer Agents.

Understanding the cognitive and behavioral aspects of Alzheimer's disease- related dementia is surely a sturdy task to deal with. In recent years, a broad search for novel anti-Alzheimer agents has been continuously conducted. The malfunctioning of various neurotransmitter systems and the accumulation of abnormal proteins in the brain are the two key characteristics of this disorder. This is supported by a growing amount of evidence. Some Pharmacophoric groups/combinations exhibit potential neuroprotective activity. This study aims to compile the most recent and interesting target/target combinations/ pharmacophoric combinations to cure Alzheimer's disease. We concentrated our efforts to find the ability of certain pharmacophoric elements to interfere with various enzymatic and/or receptor systems or to work as neuroprotective agents. These pharmacophoric elements may be proved to be promising leads for future multi-target anti-Alzheimer drug discovery programs. Anticholinesterase drugs were mentioned as the best treatment thus far. Additionally, impairments in the serotonergic, GABAergic, noradrenergic, dopaminergic, and glutaminergic and a few other pathways have all been linked to memory, speech, behavioral and other alterations in Alzheimer's disease. This includes the study of workable pharmacophoric groups/combinations, receptors/ enzymatic systems and related hypotheses to find the promising therapeutic lead compounds which could work as future anti-Alzheimer drugs. We discuss future work that would improve our understanding of this Disease.

The anxiolytic-like activity of water-soluble Moringa oleifera Lam. lectin is mediated via serotoninergic, noradrenergic, and dopaminergic neurotransmission

Lectins are carbohydrate-binding proteins that exhibit several biological activities, including modulatory effects on the central nervous system. In this study, we evaluated whether the water-soluble lectin from Moringa oleifera seeds (WSMoL) exhibits an anxiolytic-like effect when intraperitoneally administered to mice at 1, 2, or 4 mg/kg. The combined effects of WSMoL and diazepam (0.5 mg/kg) were also investigated. The animals were subjected to the open field test (OFT) followed by the elevated plus maze (EPM) test. The involvement of monoaminergic signaling in WSMoL activity was evaluated by administering relevant receptor antagonists. To determine whether the effects depended on the carbohydrate recognition domain (CRD), WSMoL CRD was blocked by casein treatment. WSMoL at all doses significantly reduced (22%–48%) the number of rearing responses in the OFT. In the EPM test, the lectin significantly reduced (30%–40%) the time spent in closed arms (1, 2, and 4 mg/kg), and increased the time spent in open arms (4 mg/kg) by 35%. In both the OFT and EPM, WSMoL (1 mg/kg) displayed anxiolytic-like effects when co-administered with diazepam. The effect of WSMoL depended on its CRD, since blockage with casein neutralized its anxiolytic-like effect. Pretreatment with ketanserin, yohimbine, and SCH 23390 inhibited WSMoL anxiolytic-like activity in the EPM, revealing a crosstalk between activity of WSMoL and monoaminergic signaling. However, these antagonists did not interfere with animal performances in the OFT. In conclusion, WSMoL exerts an anxiolytic-like effect via the serotoninergic, noradrenergic, and dopaminergic pathways, and this effect is dependent on its CRD.

External stimulation of the trigeminal nerve activates noradrenergic pathways in healthy volunteers, a pupillometry study.

External stimulation of the trigeminal nerve activates noradrenergic pathways in healthy volunteers, a pupillometry study.

Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments

BackgroundGuanfacine is a α2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer’s disease.Methods/designNorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer’s disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is the change in cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include the change in additional cognitive measures of attention (Tests of Attention: Trails A and B, digit-symbol substitution, Test of Everyday Attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory). From July 2020, observation of change following cessation of treatment is also being assessed.DiscussionThere is strong evidence for early noradrenergic dysfunction in Alzheimer’s disease. The NorAD trial aims to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment.Trial registrationClinicalTrials.govNCT03116126. Registered on 14 April 2017EudraCT: 2016-002598-36

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

BackgroundThe noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury.MethodsThe Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro–adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated.ResultsActivation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice.ConclusionThese findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

Repeated vagus nerve stimulation produces anxiolytic effects via upregulation of AMPAR function in centrolateral amygdala of male rats

Repeated vagus nerve stimulation (rVNS) exerts anxiolytic effect by activation of noradrenergic pathway. Centrolateral amygdala (CeL), a lateral subdivision of central amygdala, receives noradrenergic inputs, and its neuronal activity is positively correlated to anxiolytic effect of benzodiazepines. The activation of β-adrenergic receptors (β-ARs) could enhance glutamatergic transmission in CeL. However, it is unclear whether the neurobiological mechanism of noradrenergic system in CeL mediates the anxiolytic effect induced by rVNS. Here, we find that rVNS treatment produces an anxiolytic effect in male rats by increasing the neuronal activity of CeL. Electrophysiology recording reveals that rVNS treatment enhances the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated excitatory neurotransmission in CeL, which is mimicked by β-ARs agonist isoproterenol or blocked by β-ARs antagonist propranolol. Moreover, chemogenetic inhibition of CeL neurons or pharmacological inhibition of β-ARs in CeL intercepts both enhanced glutamatergic neurotransmission and the anxiolytic effects by rVNS treatment. These results suggest that the amplified AMPAR trafficking in CeL via activation of β-ARs is critical for the anxiolytic effects induced by rVNS treatment.

New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease.

There is clear, early noradrenergic dysfunction in Alzheimer's disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms. Despite the strong evidence of noradrenergic involvement in Alzheimer's, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof‐of‐principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin‐sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone. Here, we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer's disease.

Distinct brainstem to spinal cord noradrenergic pathways inversely regulate spinal neuronal activity.

Brainstem to spinal cord noradrenergic pathways include a locus coeruleus origin projection and diffuse noxious inhibitory controls. While both pathways are traditionally viewed as exerting an inhibitory effect on spinal neuronal activity, the locus coeruleus was previously shown to have a facilitatory influence on thermal nocioception according to the subpopulation of coerulean neurons activated. Coupled with knowledge of its functional modular organisation and the fact that diffuse noxious inhibitory controls are not expressed in varied animal models of chronicity, we hypothesized a regulatory role for the locus coeruleus on non-coerulean, discrete noradrenergic cell group(s).We implemented locus coeruleus targeting strategies by microinjecting canine adenovirus encoding for channelrhodopsin-2 under a noradrenaline-specific promoter in the spinal cord (retrogradely labelling a coeruleospinal module) or the locus coeruleus itself (labelling the entire coerulean module). Coeruleospinal module optoactivation abolished diffuse noxious inhibitory controls (two-way ANOVA, P < 0.0001), which were still expressed following locus coeruleus neuronal ablation.We propose that the cerulean system interacts with, but does not directly govern, diffuse noxious inhibitory controls. This mechanism may underlie the role of the locus coeruleus as a ‘chronic pain generator’. Pinpointing the functionality of discrete top-down pathways is crucial for understanding sensorimotor modulation in health and disease.

Safe use of opioids

Background: Opioids are effective analgesics for cancer pain and refractory non-cancer pain. Although they are essential medication, problematic issues on aberrant behavior and adverse events have rapidly emerged as social problems in Korea. This study aimed to describe the mechanisms, efficacy, and adverse events, especially how to deal with opioid dependency.Current Concepts: Opioid-induced aberrant behavior includes physical and psychological dependences (addiction), abuse, and diversion (giving prescribed opioids to another person). Most physicians are unfamiliar with how to handle patients presenting these problematic issues. Physical and psychological dependences develop through different pathophysiologic mechanisms, i.e., noradrenergic and dopaminergic pathways, respectively. Motivational enhancement therapy, psychosocial support, substitution therapy with buprenorphine, and adjunctive medications, including alpha-2 adrenergic agonist, antidepressants, and non-steroidal antiinflammatory drugs, are the mainstay of treatment for opioid dependency. Constipation, nausea/vomiting, drowsiness/sedation, delirium, itching sensation, voiding difficulty, dry mouth, opioid-induced hyperalgesia, and respiratory depression are well-known physical side effects of opioid consumption.Discussion and Conclusion: Research on the development history, epidemiology of opioid dependency, and its treatment are warranted to avoid an opioid crisis in Korea. Above all, thorough knowledge for physicians and patients is urgently needed.

Impulse control disorders, dopamine dysregulation syndrome and sex dysfunction in Parkinson's disease.

Hypersexuality (HS), characterized by an aberrant, compulsive and inappropriate sexual drive, is an underreported and undermanaged complication of the treatment with dopamine agonists in patients with Parkinson's disease (PD). HS is part of the spectrum of impulse control disorders (ICDs). The failure to control these addictive behaviors is distressing for the patient and it is associated with important consequences. Reports of the prevalence of HS showed different results, due to the lack of standardized diagnostic criteria, but also due to the embarrassment or guilt feelings that patients experience regarding their sexual behaviors. Overall, it is considered that HS may occur in 1.92-22.8% of PD patients and the main risk factors involved could be male sex and genetic susceptibility. The pathophysiology of HS is unknown, but several degenerative mechanisms were proposed, involving dopaminergic, serotoninergic and noradrenergic pathways in cerebral regions responsive for planning and rewarding. There are no standardized tools for the assessment of HS in PD patients; however, several scales and questionnaires were developed with the aim of screening and rating the severity of ICDs, including HS. The management of HS is challenging. Discontinuation or reducing the dopaminergic treatment was effective in some cases, but it might lead to worsening of the motor function. A multidisciplinary approach is mandatory to manage the other associated aspects, such as psychological and social consequences of HS.

Chapter 7 - Breathing during sleep

The depth, rate, and regularity of breathing change following transition from wakefulness to sleep. Interactions between sleep and breathing involve direct effects of the central mechanisms that generate sleep states exerted at multiple respiratory regulatory sites, such as the central respiratory pattern generator, respiratory premotor pathways, and motoneurons that innervate the respiratory pump and upper airway muscles, as well as effects secondary to sleep-related changes in metabolism. This chapter discusses respiratory effects of sleep as they occur under physiologic conditions. Breathing and central respiratory neuronal activities during nonrapid eye movement (NREM) sleep and REM sleep are characterized in relation to activity of central wake-active and sleep-active neurons. Consideration is given to the obstructive sleep apnea syndrome because in this common disorder, state-dependent control of upper airway patency by upper airway muscles attains high significance and recurrent arousals from sleep are triggered by hypercapnic and hypoxic episodes. Selected clinical trials are discussed in which pharmacological interventions targeted transmission in noradrenergic, serotonergic, cholinergic, and other state-dependent pathways identified as mediators of ventilatory changes during sleep. Central pathways for arousals elicited by chemical stimulation of breathing are given special attention for their important role in sleep loss and fragmentation in sleep-related respiratory disorders.

Transcriptomic profiling in mild cognitive impairment using peripheral blood gene co‐expression networks

AbstractBackgroundIn an effort towards AD prodromal risk assessment, precision medicine and biomarker development, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data by constructing gene‐coexpression networks from differentially expressed genes between normal controls and MCI subjects.MethodData from the ImaGene study (Imaging and Genetics Biomarkers study of Alzheimer’s Disease, ImaGene) was used. This included 160 subjects clinically diagnosed with amnestic MCI (n=70), non‐amnestic MCI (n=38) and normal controls (n=52) (Table 1). Quantile‐normalized and log‐transformed mRNA levels were obtained from peripheral blood. In a preliminary analysis we selected 2062 genes (out of HOW MANY) which were significantly differentially expressed between normal controls and MCI (two sample t‐test, pfdr&lt;0.05). Gene‐coexpression networks were built by creating correlation matrices of the differentially expressed mRNA values. Network backbones were then built using the shortest path computation to remove redundancy and identify important edges. Hierarchical clustering was performed on the co‐expression matrix to identify important communities or clusters within the network. We identified the strongest cluster associated with amnestic MCI phenotype (pfdr&lt;0.0001) by using the first principal component of the cluster as the eigen gene. The genes within the cluster and edges within the backbone were investigated.ResultUpon backbone computation, the number of edges compared to original correlation matrix were significantly reduced (Figure 1). Hierarchical clustering yielded 42 clusters of genes. One cluster (eigen gene) had the strongest association with amnestic MCI phenotype (r=0.45, pfdr&lt;0.0001). This cluster consisting of 46 genes warrants further investigation for specific function and interactions with other nodes in the cluster backbone. Two of the driver genes ADRA1A and ARHGAP4 were involved in noradrenergic receptor signaling pathway and PDGF signaling pathway, both of which are dysregulated in AD pathogenesis.ConclusionA large noisy transcriptomic data was reduced to a critical number of mRNA measures from peripheral blood. The backbone method pruned the gene coexpression network significantly. The cluster analysis identified a set of genes which had highly significant association with amnestic MCI. This approach can also help build models for risk assessment, gene therapy and help identify novel therapeutic targets/ dysregulated pathways.

The Role of the Noradrenergic System in Eating Disorders: A Systematic Review.

Noradrenaline (NE) is a catecholamine acting as both a neurotransmitter and a hormone, with relevant effects in modulating feeding behavior and satiety. Several studies have assessed the relationship between the noradrenergic system and Eating Disorders (EDs). This systematic review aims to report the existing literature on the role of the noradrenergic system in the development and treatment of EDs. A total of 35 studies were included. Preclinical studies demonstrated an involvement of the noradrenergic pathways in binge-like behaviors. Genetic studies on polymorphisms in genes coding for NE transporters and regulating enzymes have shown conflicting evidence. Clinical studies have reported non-unanimous evidence for the existence of absolute alterations in plasma NE values in patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN). Pharmacological studies have documented the efficacy of noradrenaline-modulating therapies in the treatment of BN and Binge Eating Disorder (BED). Insufficient evidence was found concerning the noradrenergic-mediated genetics of BED and BN, and psychopharmacological treatments targeting the noradrenergic system in AN. According to these data, further studies are required to expand the existing knowledge on the noradrenergic system as a potential target for treatments of EDs.

Understanding the Pathophysiology of Tourette’s Syndrome: A Review

Tourette’s syndrome (TS) is a neuropsychiatric and neurodevelopment disease typified by deterioration of motor and vocal tics which leads to neuropsychiatric symptoms and impaired motor activities manifestation. Several lines of study indicate the interplay of genetic and environmental factors to be involved in this complex neuropsychiatric syndrome. Approximately 1% people are affected worldwide from this syndrome. In this review, a concise outline presented on the classification, its clinical features and neuropsychiatric co-morbidities linked with this syndrome. This paper also highlights the neurochemistry, dysfunction of (Cortioc-Striato-Thalamo-Cortical) CSTC circuits in TS and an overview on the management approach towards the prevention of TS. Regardless of the major improvements in the understanding of exact cellular and molecular basis of TS, the various evidence indicate that the various neurotransmitter such as dopamine, glutamate, gamma- aminobutyric acid (GABA), serotonin, noradrenergic, cholinergic system, serotonergic system and histaminergic pathways play a major role in pathogenesis of TS. Several research indicates that the dysfunction of CSTS circuits occurred in this complex syndrome These areas of research have contributed to the therapeutic approach towards the management of TS and also provide the basis for future progress of the therapeutic strategies. Thus, tics generated in TS, which affect the social and academic life of patients and disruptive or troubling the family of patients. Patients existing with this syndrome have to face difficulties integrating into social life and coping with day to day basis activities, as a consequence of the syndrome.

Activation of locus coeruleus to rostromedial tegmental nucleus (RMTg) noradrenergic pathway blunts binge-like ethanol drinking and induces aversive responses in mice

There is strong evidence that ethanol entails aversive effects that can act as a deterrent to overconsumption. We have found that in doses that support the development of a conditioned taste aversion ethanol increases the activity of tyrosine hydroxylase (TH) positive neurons in the locus coeruleus (LC), a primary source of norepinephrine (NE). Using cre-inducible AAV8-ChR2 viruses in TH-ires-cre mice we found that the LC provides NE projections that innervate the rostromedial tegmental nucleus (RMTg), a brain region that has been implicated in the aversive properties of drugs. Because the neurocircuitry underlying the aversive effects of ethanol is poorly understood, we characterized the role of the LC to RMTg circuit in modulating aversive unconditioned responses and binge-like ethanol intake. Here, both male and female TH-ires-cre mice were cannulated in the RMTg and injected in the LC with rAVV viruses that encode for a Gq-expressing designer receptor exclusively activated by designer drugs (DREADDs) virus, or its control virus, to directly control the activity of NE neurons. A Latin Square paradigm was used to analyze both 20% ethanol and 3% sucrose consumption using the “drinking-in-the-dark” (DID) paradigm. Chemogenetic activation of the LC to RMTg pathway significantly blunted the binge-ethanol drinking, with no effect on the sucrose consumption, increased the emission of mid-frequency vocalizations and induced malaise-like behaviors in mice. The present findings indicate an important involvement of the LC to RMTg pathway in reducing ethanol consumption, and characterize unconditioned aversive reactions induced by activation of this noradrenergic pathway.This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients

IntroductionIn dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations. MethodsConcentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites. ResultsA significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (rs = −0.3, p < 0.01), depression (rs = −0.3, p < 0.01) and fatigue (rs = −0.2, p = 0.04). ConclusionThis study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.

Lateral hypothalamus-projecting noradrenergic locus coeruleus pathway modulates binge-like ethanol drinking in male and female TH-ires-cre mice

A growing body of literature implicates noradrenergic (NE) signaling in the modulation of ethanol consumption. However, relatively few studies have detailed specific brain pathways that mediate NE-associated binge-like ethanol consumption. To begin to fill this gap in the literature, male and female C57BL6/J and TH-ires-cre mice underwent pharmacological and chemogenetic testing, respectively, in combination with “drinking in the dark” procedures to model binge-like consumption of ethanol or sucrose solutions. First, we showed that intraperitoneal administration of the NE reuptake inhibitor, reboxetine, blunted binge-like ethanol intake in C57BL6/J mice. Chemogenetic activation of locus coeruleus (LC) tyrosine hydroxylase (TH)-expressing neurons blunted binge-like ethanol intake regardless of sex. Chemogenetic activation of LC projections to the lateral hypothalamus (LH), a region implicated in ethanol consumption, blunted binge-like ethanol drinking without altering sucrose intake in ethanol-experienced or ethanol-naïve mice. In C57BL/6 J mice, LH-targeted microinfusion of an α1-adrenergic receptor (AR) agonist blunted binge-like ethanol intake across both sexes, while LH infusion of a β-AR agonist blunted binge-like ethanol intake in females exclusively. Finally, in mice with high baseline ethanol intake both an α1- AR agonist and an α-2 AR antagonist blunted binge-like ethanol intake. The present results provide novel evidence that increased NE tone in a circuit arising from the LC and projecting to the LH reduces binge-like ethanol drinking in mice, and may represent a novel approach to treating binge or heavy drinking prior to the development of dependence.This article is part of the special Issue on “Neurocircuitry Modulating Drug and Alcohol Abuse”.

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans

BackgroundTranscutaneous stimulation of the external ear is thought to recruit afferents of the auricular vagus nerve, providing a means to activate noradrenergic pathways in the central nervous system. Findings from human studies examining the effects of auricular stimulation on noradrenergic biomarkers have been mixed, possibly relating to the limited and variable parameter space explored to date. ObjectiveWe tested the extent to which brief pulse trains applied to locations of auricular innervation (canal and concha) elicit acute pupillary responses (PRs) compared to a sham location (lobe). Pulse amplitude and frequency were varied systematically to examine effects on PR features. MethodsParticipants (n = 19) underwent testing in three separate experiments, each with stimulation applied to a different external ear location. Perceptual threshold (PT) was measured at the beginning of each experiment. Pulse trains (∼600 ms) consisting of different amplitude (0.0xPT, 0.8xPT, 1.0xPT, 1.5xPT, 2.0xPT) and frequency (25 Hz, 300 Hz) combinations were administered during eye tracking procedures. ResultsStimulation to all locations elicited PRs which began approximately halfway through the pulse train and peaked shortly after the final pulse (≤1 s). PR size and incidence increased with pulse amplitude and tended to be greatest with canal stimulation. Higher pulse frequency shortened the latency of PR onset and peak dilation. Changes in pupil diameter elicited by pulse trains were weakly associated with baseline pupil diameter. Conclusion(s): Auricular stimulation elicits acute PRs, providing a basis to synchronize neuromodulator release with task-related neural spiking which preclinical studies show is a critical determinant of therapeutic effects. Further work is needed to dissociate contributions from vagal and non-vagal afferents mediating activation of the biomarker.

Hypertension in Prenatally Undernourished Young-Adult Rats Is Maintained by Tonic Reciprocal Paraventricular-Coerulear Excitatory Interactions.

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular–coerulear excitatory interactions in prenatally undernourished young-adult rats.

Psychiatric Considerations in Pediatric Chronic Pain

Features| May 2021 Psychiatric Considerations in Pediatric Chronic Pain Souraya Torbey, MD; Souraya Torbey, MD Search for other works by this author on: This Site PubMed Google Scholar Gaëlle Rached, MD, MSc; Gaëlle Rached, MD, MSc Search for other works by this author on: This Site PubMed Google Scholar Dimitri Fiani; Dimitri Fiani Search for other works by this author on: This Site PubMed Google Scholar M-Irfan Suleman, MD, FAAP, FASA M-Irfan Suleman, MD, FAAP, FASA Search for other works by this author on: This Site PubMed Google Scholar ASA Monitor May 2021, Vol. 85, 25–26. https://doi.org/10.1097/01.ASM.0000751508.64877.83 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Search Site Citation Souraya Torbey, Gaëlle Rached, Dimitri Fiani, M-Irfan Suleman; Psychiatric Considerations in Pediatric Chronic Pain. ASA Monitor 2021; 85:25–26 doi: https://doi.org/10.1097/01.ASM.0000751508.64877.83 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll PublicationsASA Monitor Search Advanced Search Topics: chronic pain, pediatrics, psychiatry, pain Chronic pain can greatly affect a patient's daily functioning and significantly impact health-related quality of life (Pain 2005;119:1-4). Undertreated or untreated chronic pain in children can be especially burdensome to families by disrupting routines, restricting the child's daily activities, and increasing risk of long-term disability (Paediatr Drugs 2002;4:737-46). Therefore, it is not unusual for chronic pain to be highly comorbid with psychiatric disorders. This association is mediated by significant overlap in biological pathways. First, central and peripheral noradrenergic (NA) and serotoninergic (5-HT) pathways are affected in both pain and mood disorders (Prog Neuropsychopharmacol Biol Psychiatry 2018;87B:290-7; J Psychiatry Neurosci 2001;26:21-9). A pathway involving serotonergic neurons in the dorsal raphe nucleus has been implicated in chronic pain as well as depression (Nat Neurosci 2019;22:1612-4). Both NA and 5-HT brainstem-spinal descending systems... © 2021 American Society of Anesthesiologists (ASA), All Rights Reserved.2021 You do not currently have access to this content.