Noradrenergic Networks Research Articles

Mice with an autism-associated R451C mutation in neuroligin-3 show intact attention orienting but atypical responses to methylphenidate and atomoxetine in the mouse-Posner task.

Atypical attention orienting has been associated with some autistic symptoms, but the neural mechanisms remain unclear. The human Posner task, a classic attention orienting paradigm, was recently adapted for use with mice, supporting the investigation of the neurobiological underpinnings of atypical attention orienting in preclinical mouse models. The current study tested mice expressing the autism-associated R451C gene mutation in neuroligin-3 (NL3) on the mouse-Posner (mPosner) task. NL3R451C and wild-type (WT) mice were trained to respond to a validly or invalidly cued target on a touchscreen. The cue was a peripheral non-predictive flash in the exogenous task and a central spatially predictive image in the endogenous task. The effects of dopaminergic- and noradrenergic-modulating drugs, methylphenidate and atomoxetine, on task performance were assessed. In both tasks, mice were quicker and more accurate in the validly versus invalidly cued trials, consistent with results in the human Posner task. NL3R451C and WT mice showed similar response times and accuracy but responded differently when treated with methylphenidate and atomoxetine. Methylphenidate impaired exogenous attention disengagement in NL3R451C mice but did not significantly affect WT mice. Atomoxetine impaired endogenous orienting in WT mice but did not significantly affect NL3R451C mice. NL3R451C mice demonstrated intact attention orienting but altered responses to the pharmacological manipulation of the dopaminergic and noradrenergic networks. These findings expand our understanding of the NL3R451C mutation by suggesting that this mutation may lead to selective alterations in attentional processes.

Paired vagus nerve stimulation for treatment of upper extremity impairment after stroke.

The use of a paired vagus nerve stimulation (VNS) system for the treatment of moderate-to-severe upper extremity motor deficits associated with chronic ischemic stroke has recently been approved by the US Food and Drug Administration. This treatment aims to increase the task-specific neuroplasticity through the activation of cholinergic and noradrenergic networks during rehabilitation therapy. A recent pivotal Phase III trial showed that VNS paired with rehabilitation led to improvements in upper extremity impairment and function in people with moderate-to-severe arm weakness for an average of 3 years after ischemic stroke. The between-group difference following 6 weeks of in-clinic therapy and 90 days of home exercise therapy was three points on the upper extremity Fugl-Meyer score. A clinically meaningful response defined as a greater than or equal to six-point improvement was seen in approximately half of the people treated with VNS compared to approximately a quarter of people treated with rehabilitation alone. Further post-marketing research should aim to establish whether the treatment is also of use for people with intracerebral hemorrhage, in people with more severe arm weakness, and for other post-stroke impairments. In addition, high-quality randomized studies of non-invasive VNS are required.

Cognitive impairment in advanced Parkinson's disease

AbstractCognitive impairment is known to be a non‐motor symptom of Parkinson's disease (PD). Multiple cognitive domains, such as executive, attention, visuoperceptual, and memory functions, are impaired in PD. Various cognitive neural networks should, therefore, be involved in PD. Neural degeneration due to the pathology of Lewy bodies spread to many neural networks, leading to cognitive impairment. Executive dysfunction is mostly related to dopaminergic network disruption, projecting from the nigrostriatal and mesocorticolimbic systems to the prefrontal lobes. This idea was strengthened by the convincing evidence that administrating levodopa can provide beneficial effects for executive functions with improvements in motor symptoms. Frontoparietal cholinergic and noradrenergic network dysfunctions induce attention deficits, including cognitive fluctuation. Abnormality in the cholinergic network is related to visuoperceptual processing dysfunction, which induces visual hallucinations and memory impairments. Pharmacological treatments using cholinesterase inhibitors are effective in improving cognitive function in PD with dementia, which strongly supports the above concept. The pathology of Lewy bodies in the cortical and limbic systems relates to cognitive impairment, and the pathology of cortical amyloids facilitates the progression of cognitive decline in PD. Biomarker studies of cerebrospinal fluid measurements, neuroimaging, and neurophysiology have provided much evidence of cognitive impairment in PD. This review discusses the current knowledge on cognitive impairment in advanced PD, focusing on the distinct neural networks affected by neural degeneration.

Impaired metabolic brain networks associated with neurotransmission systems in the α-synuclein spectrum

IntroductionWhile the involvement of multiple neurotransmitter systems in α-synucleinopathies is reported, a comprehensive study on their metabolic connectivity reconfiguration in the preclinical and clinical disease-spectrum is lacking. We aimed to investigate shared and disease-specific neural vulnerabilities of the nigro-striato-cortical dopaminergic, noradrenergic and cholinergic networks within the α-synuclein-spectrum, by means of metabolic connectivity approach. MethodsWe collected 34 polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD) subjects, 29 idiopathic Parkinson's disease (PD) patients without dementia, 30 patients with probable dementia with Lewy bodies (DLB), and 50 healthy controls for comparisons. Neurotransmission networks' analyses were performed through multivariate partial correlations based on FDG-PET brain metabolic data. ResultsWe found: a) the nigro-striato-cortical dopaminergic network with a limited reconfiguration in individuals with iRBD, but moderate-to-severe alterations in patients with DLB and PD; b) an extended connectivity alteration of the noradrenergic network in all groups; c) changes within the cholinergic networks connectivity in the whole disease-spectrum, with some differences: PD with only moderate connectivity reconfiguration and DLB with the most severe alterations, some of these shared with iRBD. ConclusionsSynucleinopathies can be considered multisystem disorders, with common and disease-specific neurotransmission networks reconfigurations. The present findings indicate dopaminergic connectivity alterations only when associated with parkinsonism, a very early involvement of noradrenergic networks, occurring in both the iRBD and in symptomatic PD/DLB patients and cholinergic alterations with disease-specific vulnerabilities shared by iRBD and DLB. The latter finding may represent an early biomarker of disease progression to dementia.

Role of Prefrontal Cortex on Recognition Memory Deficits in Rats following 6-OHDA-Induced Locus Coeruleus Lesion.

Degeneration of the locus coeruleus (LC), the main source of cerebral noradrenaline (NA), has been reported in diverse neurodegenerative diseases, including Parkinson's diseases (PD). There is increasing evidence indicating the role of NA deficiency in the prefrontal cortex (PFC) and the development of early cognitive impairments in PD. Here, we evaluated whether a selective noradrenergic lesion of LC caused by 6-hydroxydopamine (6-OHDA) may induce memory deficits and neurochemical alterations in the PFC. Adult male Wistar rats received stereotaxic bilateral injections of 6-OHDA (5 μg/2 μl) into the LC, and two stainless-steel guide cannulas were implanted in the PFC. The SHAM group received just vehicle. To induce a selective noradrenergic lesion, animals received nomifensine (10 mg/kg), a dopamine transporter blocker, one hour before surgery. 6-OHDA-lesioned rats displayed impairments of the short- and long-term object recognition memory associated to reduced content of tyrosine hydroxylase in the LC. Neurochemical analysis revealed an altered mitochondrial membrane potential in LC. Regarding the PFC, an increased ROS production, cell membrane damage, and mitochondrial membrane potential disruption were observed. Remarkably, bilateral NA (1 μg/0.2 μl) infusion into the PFC restored the recognition memory deficits in LC-lesioned rats. These findings indicate that a selective noradrenergic LC lesion induced by 6-OHDA deregulates a noradrenergic network in the PFC, which could be involved in the early memory impairments observed in nondemented PD patients.

Cognitive and Behavioral Changes in Patients Treated With Droxidopa for Neurogenic Orthostatic Hypotension: A Retrospective Review

Droxidopa is a norepinephrine precursor that improves symptoms of neurogenic orthostatic hypotension in conditions such as Parkinson disease, multiple system atrophy, and pure autonomic failure by inducing a pressor effect. Unlike other pressor agents, droxidopa crosses the blood-brain barrier; however, its central effects are, as of yet, uncharacterized. We present the results of a retrospective cohort study examining cognitive and behavioral side effects linked to droxidopa therapy. We performed a review of 101 patients who had been treated with droxidopa at an academic tertiary care center and identified cases of cognitive and behavioral changes associated with the therapy. We identified six patients who had developed cognitive and behavioral symptoms, including memory difficulties, confusion, mania, and irritability, shortly after droxidopa initiation. All six patients displayed symptoms of synucleinopathy, manifesting with autonomic failure, rapid eye movement sleep behavior disorder, and parkinsonism. Patients had no significant cognitive or behavioral symptoms before droxidopa initiation. Behavioral disturbances were observed early in the droxidopa titration period and at relatively low doses. Symptoms resolved with dose reduction in four patients, and droxidopa was discontinued in two patients due to persistent irritability. No other medical comorbidities or alternative etiologies were identified to explain the symptoms. Droxidopa is designed to act peripherally as a pressor agent but may also exert important central effects. We hypothesize that the cognitive and behavioral manifestations observed in the patients with orthostatic hypotension resulted from an "overdose" of key noradrenergic networks linking orbitofrontal and mesolimbic regions.

Freezing of Gait in Parkinson's Disease Is Associated with Reduced 6-[(18)F]Fluoro-l-m-tyrosine Uptake in the Locus Coeruleus.

Freezing of gait (FOG) is a common disorder in Parkinson's disease (PD) and could be attributed to a reduction in brain noradrenaline. The aim of this study was to determine the relationship between aromatic l-amino acid decarboxylase (AADC) activity in the locus coeruleus (LC) and FOG in PD using high-resolution positron emission tomography with an AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT). We assessed 40 patients with PD and 11 age-matched healthy individuals. PD was diagnosed based on the UK Brain Bank criteria by two movement disorder experts. FOG was directly observed by the clinician and assessed using a patient questionnaire. FMT uptake in the LC, caudate, and putamen was analyzed using PMOD software on coregistered magnetic resonance images. FOG was present in 30 patients. The severity of FOG correlated with the decrease of FMT uptake in the LC regardless of disease duration and the severity of other motor impairments, indicating dysfunction of the noradrenergic network in FOG.

Responses of dopaminergic, serotonergic and noradrenergic networks to acute levo-tetrahydropalmatine administration in naïve rats detected at 9.4 T

Aim The aim of this study was to understand the neuropharmacological characteristics of levo-tetrahydropalmatine ( l-THP), a recently found potential treatment for drug addiction, and discover its neural correlates and sites of action. Methods High-field pharmacological magnetic resonance imaging (phMRI) was used to detect activation induced by acute l-THP administration in the naïve rat brain at dose levels of 5, 10, 20 and 40 mg/kg. Results Interestingly, the pharmacological profile of l-THP selectively binds to the receptors of the dopaminergic, serotonergic and noradrenergic systems. Using the phMRI method, it was demonstrated that l-THP selectively activated the key brain regions of the dopaminergic, serotonergic and noradrenergic systems in a dose-dependent manner. Conclusion Numerous studies suggest a critical role of monoamines in the behavioral, pharmacological and addictive properties of psychostimulants. It is suggested that l-THP holds great potential to be a therapeutic medication for drug addiction.

Adrenergic drugs modify the level of noradrenaline in the insular cortex and alter extinction of conditioned taste aversion in rats

We compared the effect of conditioned taste aversion in rats by measuring the amount of sucrose that they drunk after conditioning, which differed according to whether rats had drunk the sucrose freely (SD: self drinking) during the conditioning session, or had been forced to drink it (IO: intra-oral administration through a chronically implanted cannula). The SD procedure delayed the extinction of conditioned taste aversion. Enhanced arousal, alertness, awareness or attention in the SD condition may have strengthened the memory of the taste. Brain noradrenergic networks are involved in such processes. We administered two noradrenergic drugs that produce opposite effects on noradrenaline release in the brain, methoxy-idazoxan, RX821002 (1 mg/kg, i.p.), and guanfacine (0.12 mg/kg, i.p.). We evaluated their effect (i) on the level of noradrenaline in the gustatory cortex using microdialysis, (ii) on glycaemia that is an essential factor of taste learning and (iii) on the comparative SD versus IO conditioned taste aversion protocol mentioned above. Injecting RX821001 increased the level of noradrenaline in the gustatory cortex up to two-fold of the baseline. This effect lasted 1 h. The same dose of RX821002 did not elicit any alteration of glycaemia. It enhanced extinction of conditioned taste aversion in the SD group of rats. Injecting 0.12 mg/kg of guanfacine produced the opposite effect. The noradrenaline level of the gustatory cortex decreased, but only down to 20% of the baseline. This decrease lasted 2 h. Guanfacine increased glycaemia. Extinction of conditioned taste aversion was only marginally decreased by guanfacine in the SD group of rats. These results fit with Aston-Jones’ point of view that the role of the noradrenergic coeruleo-cortical system may be to enhance arousal, alertness, awareness or attention to an event by a transient increase of cortical noradrenaline.

Association of ADHD and conduct disorder--brain electrical evidence for the existence of a distinct subtype.

To evaluate the impact of psychopathological comorbidity with oppositional defiant/conduct disorder (ODD/CD) on brain electrical correlates in children with attention deficit hyperactivity disorder (ADHD) and to study the pathophysiological background of comorbidity of ADHD+ODD/CD. Event-related potentials (ERPs) were recorded during a cued continuous performance test (CPT-A-X) in children (aged 8 to 14 years) with ICD-10 diagnoses of either hyperkinetic disorder (HD; n = 15), hyperkinetic conduct disorder (HCD; n = 16), or ODD/CD (n = 15) and normal children (n = 18). HD/HCD diagnoses in all children were fully concordant with the DSM-IV diagnosis of ADHD-combined type. ERP-microstates, i.e., time segments with stable brain electrical map topography were identified by adaptive segmentation. Their characteristic parameters and behavioral measures were further analyzed. Children with HD but not comorbid children showed slower and more variable reaction times compared to control children. Children with HD and ODD/CD-only but not comorbid children displayed reduced P3a amplitudes to cues and certain distractors (distractor-X) linked to attentional orienting. Correspondingly, global field power of the cue-CNV microstate related to anticipation and preparation was reduced in HD but not in HCD. Topographical alterations of the HD occurred already in the cue-P2/N2 microstate. In sum, the comorbid group was less deviant than both the HD-group and the ODD/CD-group. The findings suggest that HD children (ADHD-combined type without ODD/CD) suffer from a more general deficit (e.g., suboptimal energetical state regulation) including deficits of attentional orienting and response preparation than just a responseinhibitory deficit, backing the hypothesis of an involvement of a dysregulation of the central noradrenergic networks. The results contradict the hypothesis that ADHD+ODD/CD represents an additive co-occurrence of ADHD and ODD/CD and strongly suggest that it represents a separate pathological entity as considered in the ICD-10 classification system, which differs from both HD and ODD/CD-only.

Editorial

Editorial

Genetics of Childhood Disorders: XIX. ADHD, Part 3: Is ADHD a Noradrenergic Disorder?

Dysregulation of the central noradrenergic network has long been hypothesized to underlie the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) (Arnsten et al., 1996). This hypothesis is derived largely from pharmacological data documenting that drugs which selectively modulate noradrenergic function show efficacy in treating ADHD. However, a noradrenergic hypothesis of ADHD is compelling in its own right because the noradrenergic system has been intimately associated with the modulation of higher cortical functions including attention, alertness, and vigilance.

Noradrenergic and acetylcholinesterase-positive nerve fibres of the uterus in sexually immature and cycling rats.

The distribution and density of the noradrenergic and acetylcholinesterase-positive nerve fibres were histochemically studied in different uterine regions of prepubertal and cycling rats in dioestrus and oestrus. Besides the rich and double innervation of blood vessels, both types of nerve fibre were found in the myometrium and cervical musculature. The non-vascular noradrenergic network looked denser at the tubal end of the horns and at the cervix, whereas the acetylcholinesterase-positive innervation was poor at the tubal end, increasing toward the cervix. Contrasting with the middle third of the uterine horn, at the tubal end, the myometrial longitudinal layer was much more innervated than the circular one, especially by the noradrenergic nerve fibres. The prepubertal rats presented an adult pattern of uterine autonomic innervation. In the cycling animals, this innervation was nearly the same during oestrus and dioestrus regarding both the density of nerve fibres and intensity of the histochemical reactions.

Peripheral, autonomic regulation of locus coeruleus noradrenergic neurons in brain: putative implications for psychiatry and psychopharmacology.

In 1946 von Euler identified the major transmitter of sympathetic nerve fibers, norepinephrine (NE), and about a decade later Vogt (1954) provided the first evidence that NE may also serve as a neurotransmitter in the central nervous system (CNS). Since that time, a literal explosion in CNS neurotransmitter research has taken place involving histological, biochemical, physiological, pharmacological and clinical investigations. Yet, it is only now that we are beginning to understand the biological function of NE in brain, in particular because of recent advances regarding the physiology and regulation of NE neurons in locus coeruleus (LC), a bilateral pontine structure with a uniquely wide-spread terminal network reaching throughout the neuroaxis and in primates accounting for about 70% of all brain NE. Recently, the neurobiology of the LC noradrenergic network was extensively reviewed by Foote et al. (1983), and its implication in vigilance as well as global orientation of behavior towards imperative, environmental sensory stimuli was outlined. Yet, more recent information regarding the peripheral, autonomic regulation of LC neurons in brain provides fundamentally new biological aspects on behavior and mental function which seem to allow a more integrated view of the rôle of brain NE in the overall function of the individual than previously understood. The purpose of this review is to summarize these findings and, furthermore, to outline some putative implications for psychiatry and neuropsychopharmacology.(ABSTRACT TRUNCATED AT 250 WORDS)

The vegetative network in the guinea pig and rat sacral spinal cords.

The intermediate zones in the sacral segments of guinea pig and rat spinal cords are histochemically investigated for the presence of catecholaminergic and cholinergic structures. The presence of a well-developed noradrenergic network is demonstrated. This network connects the preganglionic vegetative nuclei in horizontal and vertical directions. In addition, only some fibers from the bundles composing this network show acetylcholinesterase activity.