Noradrenergic Neurotransmitter Systems Research Articles

Exploring the Intersection of Narcolepsy and Attention Deficit Hyperactivity Disorder: Similarities, Differences, and Clinical Implications

Narcolepsy and attention deficit hyperactivity disorder (ADHD) are distinct neurobiological conditions characterized by overlapping symptoms, including excessive daytime sleepiness and cognitive dysfunction. Despite their differences in etiology and pathophysiology, recent studies have highlighted a potential association between the two disorders, with a significant prevalence of ADHD symptoms observed in narcolepsy patients. This narrative review explores the similarities and differences between narcolepsy and ADHD, focusing on their shared symptomatology, neurobiological mechanisms, challenges in diagnosis, and treatment implications. While both disorders exhibit disruptions in dopaminergic and noradrenergic neurotransmitter systems, differential diagnosis remains challenging due to overlapping clinical presentations. Polysomnography findings, such as appearance of sleep onset rapid eye movements in narcolepsy patients, provide important distinctions that enable accurate diagnosis. Treatment strategies often involve stimulant medications for symptom management; however, nonpharmacological interventions, such as cognitive behavioral therapy, have been shown to have the potential to improve patient outcomes. Clinicians must consider the possibility of coexisting narcolepsy in ADHD patients and vice versa to ensure appropriate treatment selection and optimal patient care. Further research is needed to refine diagnostic criteria, elucidate the complex interplay between the two disorders, and develop personalized therapeutic approaches. A multidisciplinary approach involving sleep specialists, neurologists, psychiatrists, and psychologists is essential to address the diverse biopsychosocial needs of patients with concurrent narcolepsy and ADHD.

Ultrasound-Induced Prenatal Stress: New Possibilities for Modeling Mental Disorders

The development of animal models of mental disorders is an important task since such models are useful for studying the neurobiological mechanisms of psychopathologies and for trial of new therapeutic drugs. One way to model pathologies of the nervous system is to impair fetal neurodevelopment through stress of the pregnant future mother, or prenatal stress (PS). The use of variable frequency ultrasound (US) in rodents is a promising method of imitating psychological stress, to which women in modern society are most often subjected. The aim of our study was to investigate the effect of PS induced by exposure to variable frequency ultrasound (US PS) throughout the gestational period on the adult rat offspring, namely, to identify features of behavioral alterations and neurochemical brain parameters that can be associated with certain mental disorders in humans, to determine the possibility of creating a new model of psychopathology. Our study included a study of some behavioral characteristics of male and female rats in the elevated plus maze, open-field test, object recognition test, social interaction test, sucrose preference test, latent inhibition test, Morris water maze, forced swimming test, acoustic startle reflex, and prepulse inhibition tests. We also determined the activity of the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems in the hippocampus and frontal cortex by HPLC-ED. Concentration of norepinephrine, dopamine, DOPAC, serotonin, and HIAA, as well as DOPAC/dopamine and HIAA/serotonin ratios were determined. A correlation analysis of behavioral and neurochemical parameters in male and female rats was performed based on the data obtained. The results of the study showed that US PS altered the behavioral phenotype of the rat offspring. US PS increased the level of anxious behavior, impaired orientation-research behavior, increased grooming activity, decreased the desire for social contacts, shifted behavioral reactions from social interaction to interaction with inanimate objects, impaired latent inhibition, and decreased the startle reflex. US PS activated the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems of the rat frontal cortex and hippocampus. A correlation between neurochemical and behavioral parameters was revealed. Our study showed that US PS leads to a certain dysfunction on behavioral and neurochemical levels in rats that is most closely associated with symptoms of schizophrenia or autism. We hypothesize that this could potentially be an indicator of face validity for a model of psychopathology based on neurodevelopmental impairment.

Brainstem glucose metabolism predicts reward dependence scores in treatment-resistant major depression.

It has been suggested that individual differences in temperament could be involved in the (non-)response to antidepressant (AD) treatment. However, how neurobiological processes such as brain glucose metabolism may relate to personality features in the treatment-resistant depressed (TRD) state remains largely unclear. To examine how brainstem metabolism in the TRD state may predict Cloninger's temperament dimensions Harm Avoidance (HA), Novelty Seeking (NS), and Reward Dependence (RD), we collected 18fluorodeoxyglucose positron emission tomography (18FDG PET) scans in 40 AD-free TRD patients. All participants were assessed with the Temperament and Character Inventory (TCI). We applied a multiple kernel learning (MKL) regression to predict the HA, NS, and RD from brainstem metabolic activity, the origin of respectively serotonergic, dopaminergic, and noradrenergic neurotransmitter (NT) systems. The MKL model was able to significantly predict RD but not HA and NS from the brainstem metabolic activity. The MKL pattern regression model identified increased metabolic activity in the pontine nuclei and locus coeruleus, the medial reticular formation, the dorsal/median raphe, and the ventral tegmental area that contributed to the predictions of RD. The MKL algorithm identified a likely metabolic marker in the brainstem for RD in major depression. Although 18FDG PET does not investigate specific NT systems, the predictive value of brainstem glucose metabolism on RD scores however indicates that this temperament dimension in the TRD state could be mediated by different monoaminergic systems, all involved in higher order reward-related behavior.

Neuroimmunology of depression.

Depression is one of the leading causes of disability worldwide and a major contributor to the global burden of disease, yet the cellular and molecular etiology of depression remain largely unknown. Major Depressive Disorder (MDD) is associated with a variety of chronic physical inflammatory and autoimmune disorders, and mood disorders may act synergistically with other medical disorders to worsen patient outcomes. Here, we outline the neuroimmune complement, explore the evidence for altered immune system function in MDD, and present some of the potential mechanisms by which immune cells and molecules may drive the onset and course of MDD. These include pro-inflammatory signaling, alterations in the hypothalamic-pituitary-adrenal axis, dysregulation of the serotonergic and noradrenergic neurotransmitter systems, neuroinflammation, and meningeal immune dysfunction. Finally, we discuss the interactions between current antidepressants and the immune system and propose the possibility of immunomodulatory drugs as potential novel antidepressant treatments.

Locus coeruleus: a new look at the blue spot.

The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.

State-dependent modulation of sympathetic firing by α1-adrenoceptors requires constitutive PKC activity in the neonatal rat spinal cord.

The central adrenergic and noradrenergic neurotransmitter systems diffusively affect the operation of the spinal neural network and dynamically gauge central sympathetic outflow. Using in vitro splanchnic nerve-thoracic spinal cord preparations as an experimental model, this study examined the intraspinal α1-adrenoceptor-meidated modulation of sympathetic firing behaviors. Several sympathetic single-fiber activities were simultaneously recorded. Application of phenylephrine (Phe, an α1-adrenoceptor agonist) increased, decreased or did not affect spontaneous firing. A log-log plot of the change ratios of the average firing rates (AFR) versus their basal AFR displays a linear data distribution. Thus, the heterogeneity in α1-adrenoceptor-mediated responses is well described by a power law function. Phe-induced power-law firing modulation (plFM) was sensitive to prazosin (Prz, an α1-adrenoceptor antagonist). Heparin (Hep, a competitive IP3 receptor blocker) and chelerythrine (Che, a protein kinase C inhibitor) also caused plFM. Phe-induced plFM persisted in the presence of Hep; however, it was occluded by Che pretreatment. Pair-wise analysis of single-fiber activities revealed synchronous sympathetic discharges. Application of Phe, Hep or Che suppressed synchronous discharges in fiber pairs with apparent correlated firing (ACF) and induced or potentiated synchronous discharges in those without or with minimal ACF. Thus, the basal activities of the sympathetic preganglionic neurons participate in determining the responses mediated by the activation of α1-adrenoceptors. This deterministic factor, which is intrinsic to spinal neural networks, helps the supraspinal adrenergic and noradrenergic systems differentially control their widely distributed neural targets.

Endurance exercise‐induced and mental fatigue and the brain

What is the topic of this review? It provides an overview of the recent papers linking brain neurotransmission with exercise-induced and/or mental fatigue. What advances does it highlight? The noradrenergic neurotransmitter system hastens central fatigue during prolonged exercise, a finding that coincides with a faster rate of increase in the rating of perceived exertion. 2) Mental fatigue affects several neurotransmitter systems, with presumably an important role for dopamine and adenosine, in multiple brain regions such as the prefrontal cortex and the anterior cingulate cortex. In sports and exercise science, fatigue is an elusive concept that has important implications in performance during exercise. It has been described in many ways (tiredness, exhaustion, lethargy or weariness) and describes a physical and/or mental state of being tired and lack of energy. Exercise-induced fatigue can be defined as an acute impairment of exercise performance, and a distinction has been made between peripheral and central fatigue. Mental fatigue can be defined as a psychobiological state caused by prolonged exertion that has the potential to reduce cognitive performance and exercise performance. Recent studies have given clear indications that brain catecholamines are involved in the onset of fatigue during endurance exercise. Evidence is provided indicating that the noradrenergic neurotransmitter system hastens central fatigue, a finding that coincides with a faster rate of increase in the rating of perceived exertion. Brain neurotransmission is also suggested to play an important role in mental fatigue. Several neurotransmitter systems might be implicated (with the most important role for dopamine and adenosine) in multiple brain regions, such as the prefrontal cortex and the anterior cingulate cortex, and the summation of these alterations might explain the impairment in endurance performance in a mentally fatigued state. Obviously, we have to keep in mind that fatigue is a very complex construct and that, besides brain neurochemistry, several other factors play a role in its onset.

A Physiological Marker of Recognition Memory in Adults with Autism Spectrum Disorder? - The Pupil Old/New Effect.

This study investigated the pupil Old/New effect in individuals with Autism Spectrum Disorder (ASD) and typical development (TD). Participants studied verbal and visual meaningful and meaningless materials in black and white on a computer screen. Pupil sizes were measured while participants performed a Remember (episodic memory with context)/Know (semantic memory, no context) recognition memory test. ASD compared to TD individuals showed significantly reduced recognition rates for all materials. Both groups showed better memory for visual compared to verbal (picture superiority effect) and meaningful compared to meaningless materials. A pupil size ratio (pupil size for test item divided by baseline) for old (studied) and new (unstudied) materials indicated larger pupils for old compared to new materials only for the TD but not the ASD group. Pupil size in response to old versus new items was positively related to recognition accuracy, confirming that the pupil Old/New effect reflects a memory phenomenon in the ASD group. In addition, this study suggests an involvement of the noradrenergic neurotransmitter system in the abnormal hippocampal functioning in ASD. Implications of these findings, as well as their underlying neurophysiology, will be discussed in relation to current theories of memory in ASD. Autism Res 2020, 13: 627-640. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Most measures of memory in Autism Spectrum Disorder (ASD) depend on verbal answers. In addition to these verbal answers, this study measured the size of the participants' pupil in response to studied and unfamiliar materials revealing memory difficulties in ASD. Measuring pupil size works nonverbally, outside of conscious awareness and forms the basis of studies on less verbal persons with ASD. Mechanisms and brain regions underlying memory differences in ASD are discussed.

O7.6. META-ANALYSIS OF EFFICACY OF COGNITIVE ENHANCERS FOR PATIENTS WITH SCHIZOPHRENIA-SPECTRUM DISORDERS

BackgroundCognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and should therefore be one of the main treatment targets. Pharmacological enhancement of cognition has been a main field of research in the last decades, investigating almost all neurotransmitter systems and reporting positive as well as negative findings. The pathophysiology of cognitive dysfunctions in schizophrenia is complex and many different neurotransmitter systems are involved. This quantitative review provides an overview of studies of pharmacological agents targeting neurotransmitter systems relevant for cognitive deficits in schizophrenia.MethodsIn our systematic search we included pharmacological agents targeting glutamatergic, cholinergic, serotonergic, dopaminergic, GABAergic and noradrenergic neurotransmitter systems, and also a miscellaneous group of agents, including modafinil/armodafinil. We evaluated the effects of cognitive enhancers on overall cognitive functioning as well as on seven cognitive domains, including attention/vigilance, processing speed, reasoning, verbal learning and memory, visual learning and memory, working memory, and verbal fluency.ResultsIn total, 93 studies with 5630 patients were suitable for inclusion in the meta-analysis. The mean sample size was 28.73 (SD=27.13, range=4–203), mean age of the participants was 44.15 years (SD=6.36, as reported by 91 study samples), 68.54% of the sample were men (as reported by 87 study samples), and average illness duration was 15.57 years (SD=6.47, as reported by 63 study samples). Combining all cognitive enhancers across different neurotransmitter systems for the effect on overall cognitive functioning resulted in fifty-one study samples, with a total of 3635 patients. Cognitive enhancers showed a small but significant positive effect size of 0.10 over placebo treatment (p=.023; 95%CI=0.01 to 0.18). Overall, cognitive enhancers showed no positive effects as compared to placebo for the separate domains. When analysing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small but significant effect size on overall cognitive functioning (Hedges’ g=0.19, p=.01), as well as on working memory (Hedges’ g=0.13, p=.04). A sub-analysis of acetylcholinesterase inhibitors (AChEI) within cholinergic system showed a small effect on working memory (Hedges’ g=0.26, p=.03). No other positive effects of cognitive enhancers as compared to placebo were revealed.DiscussionThe current meta-analysis showed very few favorable effects of cognitive enhancers for patients with schizophrenia spectrum disorders. The overall analysis showed small difference between cognitive enhancers and placebo. Most studies were on agents acting on the glutamatergic and the cholinergic system. There is some evidence of positive effects on cognitive functioning for agents acting on glutamatergic system and acetylcholinesterase inhibitors within cholinergic system. There is still a major lack of studies involving agents acting on other systems. Important issues such as dose, treatment duration, including a younger population and subtyping heterogeneous samples should be taken into account for future studies.

Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease.

Lewy body disorders, including Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterized by profound central and peripheral monoaminergic dysfunction. To investigate whether these alterations depend on dementia status, we measured cerebrospinal fluid (CSF) and serum monoamine and metabolite levels across subgroups of the cognitive spectrum, and evaluated their marker potential afterwards. In total, 153 subjects were included, of which 43 healthy controls (HC), 28 PD patients with normal cognition (PD-NC), 26 patients with PD and mild cognitive impairment (PD-MCI), 18 PDD patients, and 38 DLB patients. The levels of monoamines and metabolites in paired CSF and serum samples were analyzed applying reversed-phase high-performance liquid chromatography with electrochemical detection. Firstly, when comparing subgroups, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were found lowest in HC and PD-NC groups and significantly higher in PDD/DLB patients. In addition, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels differed significantly between HC and PD-MCI/PDD, and DLB patients (P≤0.001), but not between HC and PD-NC patients. Secondly, when performing logistic regression, it was shown that particularly CSF/serum MHPG levels and the serum MHPG to noradrenaline (NA) ratio effectively differentiated between HC and (non-)pooled PD subgroups (AUC = 0.914-0.956), and PDD and DLB patients (AUC = 0.822), respectively. Furthermore, CSF 5-HIAA was the most discriminative parameter to differentiate between PD-NC and PD-MCI (AUC = 0.808), and, PD-NC and PDD subgroups (AUC = 0.916). Our data revealed that especially alterations of the noradrenergic neurotransmitter system could distinguish between Lewy body disorder subtypes, pinpointing CSF/serum MHPG and NA as potential stage markers across the cognitive spectrum.

An Analysis of the Behavioral and Neurochemical Effects of Himantane on the Dynamics of the Ethanol-Induced Hyperlocomotor Response in DBA/2 Mice

We studied the effect of himantane (N-(2-adamantyl)-hexamethyleneimine hydrochloride) on the ethanol-induced hyperlocomotor response in DBA/2 mice. It was found that himantane (20.0 mg/kg, i.p.) per se did not affect the spontaneous locomotor activity but weakened the stimulation of the behavior caused by ethanol (2.0 g/kg, intraperitoneally) after its preliminary single systemic administration. In ex vivo experiments where we evaluated the effect of himantane on the level of monoamines and their metabolites after acute ethanol administration it was shown that himantane has a predominant effect on dopamine and noradrenergic neurotransmitter systems in the striatum in the absence of effects on the serotonergic system.

High dose methylphenidate in the treatment of freezing of gait in advanced Parkinson’s disease

BackgroundFreezing of gait (FoG) is one of the most incapacitating symptoms of Parkinson’s disease (PD) and has been linked to imbalances in the dopaminergic and noradrenergic neurotransmitter systems. Methylphenidate blocks the reuptake of these neurotransmitters, increasing their extracellular concentrations in the striatum and prefrontal cortex. This quantitative pooled analysis was aimed at determining the efficacy and safety of high dose methylphenidate in the treatment of FoG, motor and non-motor symptoms in advanced PD. MethodsElectronic databases were searched for randomized, double-blind, placebo-controlled trials examining the efficacy and safety of methylphenidate (0.8–1.0 mg/kg/day) in FoG. Fixed effects analysis with mean difference of number of freezing episodes was used as primary outcome. Secondary outcomes included Unified Parkinson Disease Rating Scale (UPDRS) Part III score, Montgomery-Asberg Depression Rating Scale (MADRS) score, Epworth Sleepiness Scale (ESS) score and incidence of adverse events. ResultsTwo studies were included with a total of 92 patients. High dose methylphenidate was able to reduce the number of freezing episodes with a MD −1.52 (95% CI −2.91, −0.11, p = .03). However, the drug was not able to offer significant improvement in terms of UPDRS Part III score in the “off” (MD −1.87; 95% CI −6.42, 2.69, p = .40) and the “on” state (MD 1.38; 95% CI −2.91, −0.11, p = 0.54), MADRS Score (MD −0.38, 95% CI −2.37, 1.60, p = .35) and ESS Score (MD −1.09, 95% CI −3.44, 1.26, p = .68). A small but statistically significant proportion of patients given high dose methylphenidate reported nausea, vomiting, and gastritis (MD 4.86, 95% CI 1.15, 20.56, p = .03) ConclusionHigh dose methylphenidate can only marginally, however significantly reduce the number of freezing episodes in patients with advanced PD with a MD −1.52 (95% CI −2.91, −0.11, p = .03).

P.8.b.005 - Evaluating stigmatic attitudes towards mentally ill patients and their underlying factors in Hungary

Freezing of gait (FoG) is one of the most incapacitating symptoms of Parkinson’s disease (PD) and has been linked to imbalances in the dopaminergic and noradrenergic neurotransmitter systems. Methylphenidate blocks the reuptake of these neurotransmitters, increasing their extracellular concentrations in the striatum and prefrontal cortex. This quantitative pooled analysis was aimed at determining the efficacy and safety of high dose methylphenidate in the treatment of FoG, motor and non-motor symptoms in advanced PD.Electronic databases were searched for randomized, double-blind, placebo-controlled trials examining the efficacy and safety of methylphenidate (0.8–1.0 mg/kg/day) in FoG. Fixed effects analysis with mean difference of number of freezing episodes was used as primary outcome. Secondary outcomes included Unified Parkinson Disease Rating Scale (UPDRS) Part III score, Montgomery-Asberg Depression Rating Scale (MADRS) score, Epworth Sleepiness Scale (ESS) score and incidence of adverse events.Two studies were included with a total of 92 patients. High dose methylphenidate was able to reduce the number of freezing episodes with a MD −1.52 (95% CI −2.91, −0.11, p = .03). However, the drug was not able to offer significant improvement in terms of UPDRS Part III score in the “off” (MD −1.87; 95% CI −6.42, 2.69, p = .40) and the “on” state (MD 1.38; 95% CI −2.91, −0.11, p = 0.54), MADRS Score (MD −0.38, 95% CI −2.37, 1.60, p = .35) and ESS Score (MD −1.09, 95% CI −3.44, 1.26, p = .68). A small but statistically significant proportion of patients given high dose methylphenidate reported nausea, vomiting, and gastritis (MD 4.86, 95% CI 1.15, 20.56, p = .03)High dose methylphenidate can only marginally, however significantly reduce the number of freezing episodes in patients with advanced PD with a MD −1.52 (95% CI −2.91, −0.11, p = .03).

The relation of vitamin D, metabolic risk and negative symptom severity in people with psychotic disorders

People with psychotic disorders have an increased metabolic risk and their mean life expectancy is reduced with circa 28 years (Olfson et al., 2015).Predictors of this increased metabolic risk are genetic predisposition (Liu et al., 2013), lifestyle factors such as unhealthy diet, physical inactivity and smoking (Bobes et al., 2010), and the side effects of antipsychotic medication (Werner and Covenas, 2014;Chadda et al., 2013). Low vitamin D status might also contribute to an increased metabolic risk (Ginde et al., 2009;Kendrick et al., 2009;Kilkkinen et al., 2009;Ford et al., 2009) and all-cause mortality by promoting atherosclerosis, hypertension, inflammation and activation of the renin-angiotensin system (Wang et al., 2012;Garland et al., 2014;Lee et al., 2008). Also, one review demonstrated cardiovascular mortality rates in the general population were higher during winter than in summer (Zittermann et al., 2005). Vitamin D interacts with dopaminergic, cholinergic and noradrenergic neurotransmitter systems, which have all been implicated in Schizophrenia Research 195 (2018) 513–518 ⁎ Corresponding author at: University Medical Center Groningen, University Center for Psychiatry, Rob Giel Research center, P.O. Box 30.001 (CC72), 9700 RB Groningen, The Netherlands. E-mail addresses: j.bruins@lentis.nl (J. Bruins), f.jorg@umcg.nl (F. Jorg), e.r.v.d.heuvel@tue.nl (E.R. van den Heuvel), a.a.bartels@umcg.nl (A.A. Bartels-Velthuis), e.corpeleijn@umcg.nl (E. Corpeleijn), f.a.j.muskiet@umcg.nl (F.A.J. Muskiet), g.h.m.pijnenborg@rug.nl (G.H.M. Pijnenborg), r.bruggeman@umcg.nl (R. Bruggeman). experiencing psychotic symptoms (Eyles et al., 2013). When vitamin D is low, dopamine signalling in the brain appears to decrease (Eyles et al., 2013;Cui et al., 2015;Cui et al., 2013;Groves et al., 2014), which in its turn could lead to more severe negative symptoms of psychosis (Buchanan et al., 2007). Indeed, several studies found that vitamin D insufficiency was strongly associated with negative symptoms of psychosis (Graham et al., 2015;Yuksel et al., 2014;Cieslak et al., 2014;Ottesen Berg et al., 2010). Vitamin D is thus associated with both metabolic risk and negative symptom severity. Negative symptoms have also been shown to interfere with patients' ability to be physically active and make healthy lifestyle choices, which can increase their metabolic risk (Bergqvist et al., 2013). Negative symptom severity may therefore mediate the association between low vitamin D and increased metabolic risk in people with a psychotic disorder. Vitamin D is mostly produced in the skin by exposure to ultravioletB radiation in sunlight (Brown et al., 1999;Holick, 2007). Absorption of vitamin D and levels of circulation differ among individuals and can be influenced by determinants such as latitude, season, time of day, skin color (Holick et al., 2011), bodyweight, age, calcium intake (Zittermann et al., 2014), diet and genetics (Mazahery and von Hurst, 2015). Vitamin D shows a natural fluctuation throughout the year, with vitamin D insufficiency more likely to occur during winter than in summer (Rosecrans and Dohnal, 2014). A recent study suggests seasonality may also affect clinical symptoms of schizophrenia, although the underlying mechanism is unknown (Byrne et al., 2015). In this study we aim to investigate whether vitamin D levels are associated with metabolic risk in people with psychotic disorders and whether this effect was mediated by negative symptoms. We hypothesize that vitamin D levels may influence the severity of metabolic disturbances and negative symptoms. As vitamin D levels naturally fluctuate throughout the seasons (Rosecrans and Dohnal, 2014), we examine whether metabolic risk and negative symptom severity follow a similar seasonal fluctuation pattern. Furthermore, we investigate whether the http://dx.doi.org/10.1016/j.schres.2017.08.059 0920-9964/© 2017 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres severity of metabolic risk and negative symptoms differ between patients using and patients not using vitamin D supplementation. In this cross-sectional study, seasonal patterns and differences with regard to supplementation may indicate an interdependent and potentially causal connection between vitamin D, metabolic risk and negative symptom severity

Effect of Stimulation of Neurotransmitter Systems on Heart Rate Variability and β-Adrenergic Responsiveness of Erythrocytes in Outbred Rats.

We studied heart rate variability and β-adrenergic responsiveness of erythrocytes and changes in these parameters in response to single administration of β-adrenoblocker propranolol (2 mg/kg) in outbred male rats against the background of activation of the noradrenergic, serotonergic, and dopaminergic neurotransmitter systems achieved by 4-fold injections maprotiline (10 mg/kg), 5-hydroxytryptophan (50 mg/kg) combined with fluoxetine (3 mg/kg), and L-DOPA (20 mg/kg) with amantadine (20 mg/kg), respectively. Stimulation of the noradrenergic system moderately enhanced the heart rhythm rigidity and β-adrenergic responsiveness of erythrocytes. In addition, it markedly augmented the moderating effect of subsequently administered propranolol on LF and VLF components in the heart rate variability and reversed the effect of propranolol on β-adrenergic responsiveness of erythrocytes. Stimulation of the serotonergic system dramatically decreased all components in the heart rate variability and pronouncedly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol slightly restored all components in the heart rate variability and decreased β-adrenergic responsiveness of erythrocytes to the control level. Stimulation of the dopaminergic system made the heart rate more rigid due to decrease of all components in the heart rate variability; in addition, it slightly but significantly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol produced no significant effects on all components in the heart rate variability and on β-adrenergic responsiveness of erythrocytes. Stimulation of noradrenergic, serotonergic, and dopaminergic neurotransmitter systems produced unidirectional and consorted effects on heart rate variability and β-adrenergic responsiveness of erythrocytes, although the magnitudes of these effects were different. Probably, the changes in the heart rate variability in rats with stimulated neurotransmitter systems results from modification of the cellular sensitivity in peripheral organs to adrenergic influences. However, the differences in the reactions to β-adrenoblocker attest to specificity of the mechanisms underlying the changes in membrane reception and adrenergic pathways in every experimental model employed in this study.

Tourette Syndrome: Complementary Insights from Measures of Cognitive Control, Eyeblink Rate, and Pupil Diameter.

Some individuals with Tourette syndrome (TS) have severe motoric and vocal tics that interfere with all aspects of their lives, while others have mild tics that pose few problems. We hypothesize that observed tic severity reflects a combination of factors, including the degree to which dopaminergic (DA) and/or noradrenergic (NE) neurotransmitter systems have been affected by the disorder, and the degree to which the child can exert cognitive control to suppress unwanted tics. To explore these hypotheses, we collected behavioral and eyetracking data from 26 patients with TS and 26 controls between ages 7 and 14, both at rest and while they performed a test of cognitive control. To our knowledge, this is the first study to use eyetracking measures in patients with TS. We measured spontaneous eyeblink rate as well as pupil diameter, which have been linked, respectively, to DA and NE levels in the central nervous system. Here, we report a number of key findings that held when we restricted analyses to unmedicated patients. First, patients’ accuracy on our test of cognitive control accounted for fully 50% of the variance in parentally reported tic severity. Second, patients exhibited elevated spontaneous eyeblink rates compared to controls, both during task performance and at rest, consistent with heightened DA transmission. Third, although neither task-evoked pupil dilation nor resting pupil diameter differed between TS patients and controls, pupil diameter was positively related to parentally reported anxiety levels in patients, suggesting heightened NE transmission in patients with comorbid anxiety. Thus, with the behavioral and eyetracking data gathered from a single task, we can gather objective data that are related both to tic severity and anxiety levels in pediatric patients with TS, and that likely reflect patients’ underlying neurochemical disturbances.

Elevated Norepinephrine may be a Unifying Etiological Factor in the Abuse of a Broad Range of Substances: Alcohol, Nicotine, Marijuana, Heroin, Cocaine, and Caffeine

A wide range of commonly abused drugs have effects on the noradrenergic neurotransmitter system, including alterations during acute intoxication and chronic use of these drugs. It is not established, however, that individual differences in noradrenergic signaling, which may be present prior to use of drugs, predispose certain persons to substance abuse. This paper puts forth the novel hypothesis that elevated noradrenergic signaling, which may be raised largely due to genetics but also due to environmental factors, is an etiological factor in the abuse of a wide range of substances, including alcohol, nicotine, marijuana, heroin, cocaine, and caffeine. Data are reviewed for each of these drugs comprising their interaction with norepinephrine during acute intoxication, long-term use, subsequent withdrawal, and stress-induced relapse. In general, the data suggest that these drugs acutely boost noradrenergic signaling, whereas long-term use also affects this neurotransmitter system, possibly suppressing it. During acute withdrawal after chronic drug use, noradrenergic signaling tends to be elevated, consistent with the observation that norepinephrine lowering drugs such as clonidine reduce withdrawal symptoms. Since psychological stress can promote relapse of drug seeking in susceptible individuals and stress produces elevated norepinephrine release, this suggests that these drugs may be suppressing noradrenergic signaling during chronic use or instead elevating it only in reward circuits of the brain. If elevated noradrenergic signaling is an etiological factor in the abuse of a broad range of substances, then chronic use of pharmacological agents that reduce noradrenergic signaling, such as clonidine, guanfacine, lofexidine, propranolol, or prazosin, may help prevent or treat drug abuse in general.

Adrenergic neurotransmitter system transporter and receptor genes associated with atomoxetine response in attention-deficit hyperactivity disorder children

Atomoxetine, a selective inhibitor of the norepinephrine transporter, exerts its therapeutic effect for attention-deficit hyperactivity disorder (ADHD) by increasing the concentration of synaptic norepinephrine. The objective of this study was to evaluate the association of the genetic variants of multiple genes of the noradrenergic neurotransmitter system with atomoxetine response. One hundred and eleven ADHD children and adolescents were enrolled in a prospective, open-label study of atomoxetine for 8-12weeks. The dose was titrated to 1.2-1.4mg/kg per day and maintained for at least 4weeks. The primary efficacy measure was the investigator-rated ADHD Rating Scale-IV. Two categorical evaluations of treatment effects (defined as response and remission) were used. Twelve SNPs in SLC6A2, ADRA2A, and ADRA1A were genotyped to analyze their association with response or remission status. rs3785143 in SLC6A2 was associated with responder status (nominal P=0.0048; corrected by multiple test, P=0.0416; OR 2.66, 95% confidence interval (CI) 1.35-5.26). rs2279805 of SLC6A2 was nominally significantly associated with the remission status. (P=0.0221, OR 2.32, 95% CI 1.13-4.75, multiple test P=0.2130). The GG haplotype of rs1800544 and rs553668 in ADRA2A achieved nominal significance for association with non-remission (P=0.0219, OR 2.82, 95% CI 1.16-6.85, multiple test, P=0.2076). The results of this study suggest that DNA variants of both SLC6A2 and ADRA2A in the adrenergic neurotransmitter system might alter the response to atomoxetine, though further replication study in larger sample for validation of these findings is still needed.

Imaging beyond the striatonigral dopaminergic system in Parkinson's disease.

Parkinson 's disease (PD) is characterized by progressive loss of dopaminergic neurons in the nigrostriatal pathway, but this seems to constitute only part of the whole pathological process of the disease. Accumulating data have documented the concomitant degeneration of other dopaminergic pathways and of the serotonergic, cholinergic and noradrenergic neurotransmitter systems. In addition, pathologic process is not only restricted in the brain, since the spinal cord and the peripheral autonomic nervous system are also affected. The pathogenesis of PD remains unclear. The use of positron emission tomography and single photon emission tomography may contribute to the understanding of these aspects of the disease. This review will discuss the role of PET and SPET in imaging the extrastriatal dopaminergic system and other neurotransmitter systems as well as the imaging of microglial activation and cardiac sympathetic denervation in PD. In conclusion, several PET and SPET ligands can detect changes in extrastriatal dopaminergic system as well as in the serotonergic, cholinergic and noradrenergic systems in PD and also explore its possible correlation with motor and non motor symptoms. The use of PET scintigraphy allows the detection of microglial activation in PD, while (123)I-MIBG scintigraphy depicts cardiac sympathetic denervation in PD and is a useful imaging tool for differentiating PD from other types of parkinsonism.

Association study between the dopamine-related candidate gene polymorphisms and ADHD among Saudi Arabia population via PCR technique

Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders characterized by inattention, hyperactivity and impulsivity. In Saudi Arabia the prevalence of combined ADHD is 16.4 %. ADHD etiology is not clear and not completely understood. There are several evidences for involvement of dopaminergic, serotonergic and noradrenergic neurotransmitter systems in the pathogenesis of ADHD. Monoamine Oxidase A (MAOA) is involved in the degradation of all three of these neurotransmitters. Dopamine Transporter 1 (DAT1) plays an important role in controlling blood levels of dopamine. The aim of the present study is to investigate the association between ADHD and polymorphisms of MAOA 30 bp-promoter VNTR and DAT1 40 bp 3' UTRVNTR in Saudi population. PCR technique was employed to detect polymorphisms of MAOA and DAT1 genes in a sample of 120 ADHD subjects and 160 controls. Alleles and genotypes frequencies for both of MAOA and DAT1 polymorphisms were compared among ADHD subjects against controls. Association between ADHD and alleles as well as genotypes for each studied polymorphisms was tested by odds ratio (OR) test and the magnitude of this association was estimated by 95 % confidence interval (95 % CI). A significant association was found between two MAOA genotypes 3/4 and 3/2 with ADHD (P < 0.01, OR = 3, 4.9) as a risk effect. No significant association was found with MAOA alleles. Among DAT1 polymorphisms two alleles (7 and 11 repeats) (P < 0.01, OR = 2.5 and 3.3) as well as two genotypes (11/11 and 11/7) (P < 0.01, OR = 4, 3) showed significant association with ADHD as a risk effect. On the contrary, 9 and 10 repeats revealed significant association as a protective effect as well as 10/10 and 10/9 genotypes. These findings support the hypothesis that some of the MAOA and DAT1 polymorphisms have a causative role in the development of ADHD in the Saudi population. Another polymorphism did not give rise to support this hypothesis. This is the first report investigated the association between MAOA and DAT1 polymorphism at molecular level in Saudi Arabia population as well as Arab world. Therefore further studies are needed to generalize obtained results at Saudi Arabia.