Search

Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a successful treatment option in Parkinson's disease (PD) for different motor and non-motor symptoms, but has been linked to postoperative cognitive impairment., Aim: Since both dopaminergic and norepinephrinergic neurotransmissions play important roles in symptom development, we analysed STN-DBS effects on dopamine and norepinephrine availability in different brain regions and morphological alterations of catecholaminergic neurons in the 6-hydroxydopamine PD rat model., Methods: We applied one week of continuous unilateral STN-DBS or sham stimulation, respectively, in groups of healthy and 6-hydroxydopamine-lesioned rats to quantify dopamine and norepinephrine contents in the striatum, olfactory bulb and dentate gyrus. In addition, we analysed dopaminergic cell counts in the substantia nigra pars compacta and area tegmentalis ventralis and norepinephrinergic neurons in the locus coeruleus after one and six weeks of STN-DBS., Results: In 6-hydroxydopamine-lesioned animals, one week of STN-DBS did not alter dopamine levels, while striatal norepinephrine levels were decreased. However, neither one nor six weeks of STN-DBS altered dopaminergic neuron numbers in the midbrain or norepinephrinergic neuron counts in the locus coeruleus. Dopaminergic fibre density in the dorsal and ventral striatum also remained unchanged after six weeks of STN-DBS. In healthy animals, one week of STN-DBS resulted in increased dopamine levels in the olfactory bulb and decreased contents in the dentate gyrus, but had no effects on norepinephrine availability., Conclusions: STN-DBS modulates striatal norepinephrinergic neurotransmission in a PD rat model. Additional behavioural studies are required to investigate the functional impact of this finding., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus coeruleus-norepinephrine (LC-NE) system is a critical regulator of arousal levels and higher executive processes affected by TBI including attention, working memory, and decision making. LC-NE axon injury and impaired signaling within the prefrontal cortex (PFC) is a potential contributor to the neuropsychiatric symptoms after single, moderate to severe TBI. The majority of TBIs are mild, yet long-term cognitive deficits and increased susceptibility for further injury can accumulate after each repetitive mild TBI. As a potential treatment for restoring cognitive function and daytime sleepiness after injury psychostimulants, including methylphenidate (MPH) that increase levels of NE within the PFC, are being prescribed "off-label". The impact of mild and repetitive mild TBI on the LC-NE system remains limited. Therefore, we determined the extent of LC-NE and arousal dysfunction and response to therapeutic doses of MPH in rats following experimentally induced single and repetitive mild TBI. Microdialysis measures of basal NE efflux from the medial PFC and arousal measures were significantly lower after repetitive mild TBI. Females showed higher baseline PFC-NE efflux than males following single and repetitive mild TBI. In response to MPH challenge, males exhibited a blunted PFC-NE response and persistent arousal levels following repetitive mild TBI. These results provide critical insight into the role of catecholamine system dysfunction associated with cognitive deficits following repeated injury, outcome differences between sex/gender, and lack of success of MPH as an adjunctive therapy to improve cognitive function following injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Prolonged confinement in cramped spaces can lead to derangements in brain function/structure, yet the underlying mechanisms remain unclear. To investigate, we subjected mice to restraint stress to simulate long-term narrow and enclosed space confinement, assessing their mental state through behavioral tests. Stressed mice showed reduced center travel and dwell time in the Open Field Test and increased immobility in the Tail Suspension Test. We measured lower hippocampal brain-derived neurotrophic factor levels and cortical monoamine neurotransmitters (5-HT and NE) in the stressed group. Further examination of the body's immune levels and serum metabolism revealed immune dysregulation and metabolic imbalance in the stressed group. The results of the metabolic network regulation analysis indicate that the targets affected by these differential metabolites are involved in several metabolic pathways that the metabolites themselves participate in, such as the "long-term depression" and "purine metabolism" pathways. Additionally, these targets are also associated with numerous immune-related pathways, such as the TNF, NF-κB, and IL-17 signaling pathways, and these findings were validated using GEO dataset analysis. Molecular docking results suggest that differential metabolites may regulate specific immune factors such as TNF-α, IL-1β, and IL-6, and these results were confirmed in experiments. Our research findings suggest that long-term exposure to confined and narrow spaces can lead to the development of psychopathologies, possibly mediated by immune system dysregulation and metabolic disruption., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D 2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α 2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective β receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D 1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α 1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D 2 , α 2 , and β 1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We investigated the effects of catecholamines, adrenaline and noradrenaline, as well as β-adrenoceptor (AR) modulators on a resting membrane potential at the junctional and extrajunctional regions of mouse fast-twitch Levator auris longus muscle. The aim of the study was to find which AR subtypes, signaling molecules and Na,K-ATPase isoforms are involved in the hyperpolarizing action of catecholamines and whether this action could be accompanied by changes in the pump abundance on the sarcolemma. Adrenaline, noradrenaline and specific β2-AR agonist induced hyperpolarization of both junctional and extrajunctional membrane, but the underlying mechanisms were different. In the junctional membrane the hyperpolarization depended on α2 isoform of the Na,K-ATPase and Gi-protein, whereas in the extrajunctional regions the hyperpolarization mainly relied on α1 isoform of Na,K-ATPase and adenylyl cyclase activities. In both junctional and extrajunctional regions, AR activation caused an increase in Na,K-ATPase abundance in the plasmalemma in a protein kinase A-dependent manner. Thus, the compartment-specific mechanisms are responsible for catecholamine-mediated hyperpolarization in the skeletal muscle., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Working memory impairment is a common symptom occurred in Parkinson's disease (PD). The medial septum-diagonal band (MS-DB) complex and 5-HT 6 receptor are involved in modulation of cognition. However, their roles in working memory in PD are still unknown. Here, we used behavioral, neurochemical and immunohistochemical approaches to assess the role of MS-DB 5-HT 6 receptor in working memory in unilateral 6-hydroxydopamie (6-OHDA)-induced PD rats. Intra-MS-DB injection of 5-HT 6 receptor agonist WAY208466 (3, 6 and 12 μg/rat) enhanced working memory and increased dopamine (DA) and noradrenaline (NA) levels in the medial prefrontal cortex (mPFC) and hippocampus in sham and 6-OHDA-lesioned rats. The dose that produced significant effect on working memory in 6-OHDA-lesioned rats was lower than that in sham rats, indicating hypersensitivity of 5-HT 6 receptor after lesioning. Intra-MS-DB injection of 5-HT 6 receptor antagonist SB258585 (2, 4 and 8 μg/rat) alleviated working memory deficits and increased DA level in the mPFC and hippocampus and NA level in the mPFC in 6-OHDA-lesioned rats while having no effect in sham rats, suggesting that SB258585 did not change normal cognitive status. These results suggest that activation and blockade of MS-DB 5-HT 6 receptor recovered working memory in 6-OHDA-lesioned rats, which is probably related to changes in monoamine levels in the mPFC and hippocampus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Spasticity and balance disability are major complications following traumatic brain injury (TBI). Although monoaminergic inputs provide critical adaptive neuromodulations to the motor system, data are not available regarding the levels of monoamines in the brain regions related to motor functions following repetitive blast TBI (bTBI). The objective of this study was to determine if mild, repetitive bTBI results in spasticity/balance deficits and if these are correlated with altered levels of norepinephrine, dopamine, and serotonin in the brain regions related to the motor system. Repetitive bTBI was induced by a blast overpressure wave in male rats on days 1, 4, and 7. Following bTBI, physiological/behavioral tests were conducted and tissues in the central motor system (i.e., motor cortex, locus coeruleus, vestibular nuclei, and lumbar spinal cord) were collected for electrochemical detection of norepinephrine, dopamine, and serotonin by high-performance liquid chromatography. The results showed that norepinephrine was significantly increased in the locus coeruleus and decreased in the vestibular nuclei, while dopamine was significantly decreased in the vestibular nuclei. On the other hand, serotonin was significantly increased in the motor cortex and the lumbar spinal cord. Because these monoamines play important roles in regulating the excitability of neurons, these results suggest that mild, repetitive bTBI-induced dysregulation of monoaminergic inputs in the central motor system could contribute to spasticity and balance disability. This is the first study to report altered levels of multiple monoamines in the central motor system following acute mild, repetitive bTBI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

The ventromedial hypothalamic nucleus (VMN) is a vital component of the neural circuitry that regulates glucostasis. Norepinephrine (NE) controls VMN gluco-inhibitory γ-aminobutyric acid (GABA) and gluco-stimulatory nitric oxide (NO) transmission. Sex-specific insulin-induced hypoglycemic (IIH) patterns of VMN GABA signaling are estrogen receptor-alpha (ERα)- and -beta (ERβ)-dependent. Current research utilized combinatory immunocytochemistry, laser-microdissection, and Western blot techniques in a pharmacological approach to address the hypothesis that ERα and/or -β mediate sex-dimorphic VMN GABAergic and/or nitrergic nerve cell receptivity to NE and estradiol during IIH. The impact of these ER on expression of the pyruvate recycling pathway marker proteins glutaminase (GLS) and malic enzyme-1 (ME-1) was also examined. Both VMN neuron populations express ERα, ERβ, and G protein-coupled estrogen receptor-1 (GPER), along with alpha 1 , alpha 2 , and beta 1 adrenergic receptor (AR) proteins. NO neurons exhibited ERα/β-dependent (beta 1 AR, GPER) and -independent (alpha 1 AR) sex differences in receptor protein responses to hypoglycemia. Similarly, sex-dimorphic effects of IIH on alpha 1 AR, alpha 2 AR, and ERα profiles in GABA neurons involve ERα/β. These ERs also underlie divergent adjustments in gluco-regulatory nerve cell GLS and ME-1 protein expression in hypoglycemic males and females. Sex-specific nitrergic and GABAergic nerve cell sensitivity to NE and E, respectively, during IIH may contribute to sex-contingent patterns of neurotransmitter signaling., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The ability to cope with acute stressors is impaired in people with chronic neuropathic injuries. The regulation of stress coping responses depends critically on several parallel interconnected neural circuits, one of which originates in the Locus Coeruleus. In rats, chronic constriction injury (CCI) and acute stress each modulate noradrenergic activity of the Locus Coeruleus (LC) although with different temporal patterns. This study investigated the effects of CCI on the neuronal activity of the LC to acute restraint stress using the immunohistochemical detection of Fos-family protein expression. Male Sprague-Dawley rats underwent CCI surgery and 11 days later were restrained for 15 min. The number and location of single-labelled neurons (c-Fos, FosB/ΔFosB and tyrosine hydroxylase (TH) immunoreactive) neurons and double labelled neurons (c-Fos, or FosB/ΔFosB with TH) were quantified for the LC and surrounding regions. Comparisons were made with rats that underwent sham surgery or anaesthesia (20 min). Restraint triggered a struggling response in all rats. CCI attenuated restraint-induced Fos expression in LC neurons. A significant proportion (30-50%) of these LC Fos positive neurons did not contain TH. These data suggest that nerve injury might impair the ordinary cellular response of the LC to an acute stress. The association of stress-related disorders in people with neuropathic injuries suggests that the observations made in this study may reflect a part of the mechanism underlying these clinical comorbidities., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

The ventromedial hypothalamic energy sensor AMP-activated protein kinase (AMPK) maintains glucostasis via neurotransmitter signals that diminish [γ-aminobutyric acid] or enhance [nitric oxide] counter-regulation. Ventromedial hypothalamic nucleus (VMN) 'fuel-inhibited' neurons are sensitive to astrocyte-generated metabolic substrate stream. Norepinephrine (NE) regulates astrocyte glycogen metabolism in vitro, and hypoglycemia intensifies VMN NE activity in vivo. Current research investigated the premise that NE elicits AMPK-dependent adjustments in VMN astrocyte glycogen metabolic enzyme [glycogen synthase (GS); glycogen phosphorylase (GP)] and gluco-regulatory neuron biomarker [glutamate decarboxylase 65/67 (GAD); neuronal nitric oxide synthase (nNOS); SF-1] protein expression in male rats. We also examined whether VMN astrocytes are directly receptive to NE and if noradrenergic input regulates cellular sensitivity to the neuro-protective steroid estradiol. Intra-VMN NE correspondingly augmented or reduced VMN tissue GAD and nNOS protein despite no change in circulating glucose, data that imply that short-term exposure to NE promotes persistent improvement in VMN nerve cell energy stability. The AMPK inhibitor Compound C (Cc) normalized VMN nNOS, GS, and GP expression in NE-treated animals. NE caused AMPK-independent down-regulation of alpha 2 -, alongside Cc-reversible augmentation of beta 1 -adrenergic receptor protein profiles in laser-microdissected astrocytes. NE elicited divergent adjustments in astrocyte estrogen receptor-beta (AMPK-unrelated reduction) and GPR-30 (Cc-revocable increase) proteins. Outcomes implicate AMPK in noradrenergic diminution of VMN nitrergic metabolic-deficit signaling and astrocyte glycogen shunt activity. Differentiating NE effects on VMN astrocyte adrenergic and estrogen receptor variant expression suggest that noradrenergic regulation of glycogen metabolism may be mediated, in part, by one or more receptors characterized here by sensitivity to this catecholamine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Abnormal glucocorticoid levels can cause psychiatric symptoms ranging from depression to euphoria that have been implicated in mood disorders. My overarching hypothesis is that these opposing effects are mediated by glucocorticoid receptors (GR) in different brain regions. My laboratory has shown that GR in the serotonergic dorsal raphé nucleus (DRN) promote depression-like social and behavioral withdrawal in mice. We have also shown that GR in the DRN and noradrenergic locus coeruleus (LC) exhibit divergent regulation by antidepressants that have differential efficacy for depression subtypes with opposing abnormalities in glucocorticoids. The current study tested the hypothesis that LC GR would have effects opposite to those in the DRN by preventing rather than promoting social withdrawal. GR was deleted from LC NE neurons in female and male floxed GR mice by bilateral injections of lentivirus transducing Cre recombinase under control of a multimerized Phox 2a/2b response sequence (PRS) from the dopamine β-hydroxylase promoter (PRS-Cre). Female but not male PRS-Cre mice exhibited lower social interaction compared to controls injected with lentivirus transducing green fluorescent protein (PRS-GFP). Differences in social interaction between PRS-GFP and PRS-Cre females were not associated with differences in exploratory behavior, plasma corticosterone, male-female differences in LC GR expression, or changes in LC mineralocorticoid receptor or tyrosine hydroxylase gene expression. These results indicate that LC NE GR have sex-dependent effects to prevent social withdrawal, supporting the concept that glucocorticoids exert opposing effects on depression symptoms via different brain targets, and potentially revealing novel drug targets to treat depression, particularly in women., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Flexible and adaptive behaviors have evolved with increasing complexity and numbers of neuromodulator systems. The neuromodulatory locus coeruleus-norepinephrine (LC-NE) system is central to regulating cognitive function in a behaviorally-relevant and arousal-dependent manner. Through its nearly ubiquitous efferent projections, the LC-NE system acts to modulate neuron function on a cell-by-cell basis and exert a spectrum of actions across different brain regions to optimize target circuit function. As LC neuron activity, NE signaling, and arousal level increases, cognitive performance improves over an inverted-U shaped curve. Additionally, LC neurons burst phasically in relation to novel or salient sensory stimuli and top-down decision- or response-related processes. Together, the variety of LC activity patterns and complex actions of the LC-NE system indicate that the LC-NE system may dynamically regulate the function of target neural circuits. The manner in which neural networks encode, represent, and perform neurocomputations continue to be revealed. This has improved our ability to understand the optimization of neural circuits by NE and generation of flexible and adaptive goal-directed behaviors. In this review, the rat vibrissa somatosensory system is explored as a model neural circuit to bridge known modulatory actions of NE and changes in cognitive function. It is argued that fluid transitions between neural computational states reflect the ability of this sensory system to shift between two principal functions: detection of novel or salient sensory information and detailed descriptions of sensory information. Such flexibility in circuit function is likely critical for producing context-appropriate sensory signal processing. Nonetheless, many challenges remain including providing a causal link between NE mediated changes in sensory neural coding and perceptual changes, as well as extending these principles to higher cognitive functions including behavioral flexibility and decision making., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We here review modulation of olfactory guided behavioral tasks by noradrenaline. In this review we focus on modulation of the main olfactory system in adult rodents. We detail behavioral paradigms commonly used and discuss how sensory perception and learning can be measured using these paradigms. We then describe neuromodulatory effects on several aspects of olfactory processing, including detection and encoding. We describe how memory duration, specificity and duration are affected by noradrenergic modulation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Prescription stimulants are used to treat attention deficit hyperactivity disorder (ADHD). Psychostimulants are also used off-label by non-ADHD patients as performance-enhancing agents across academic, occupational, athletic, and social settings. Extensive work has focused on the reinforcing effects and abuse liability of psychostimulants, but understanding the mechanisms through which these agents regulate neural circuit functions that govern cognitive and sensorimotor processes to result in their performance-enhancing effects has received less attention. Optimal detection of sensory information within complex, dynamic environments is critical for appropriate decision making and executive actions. As such, overall performance enhancement may significantly rely on improvements in the processing of incoming sensory stimuli. Psychostimulants enhance catecholamine neurotransmission through the blockade of dopamine and norepinephrine (NE) reuptake transporters. The ascending locus coeruleus (LC)-NE system regulates behavioral state and modulates state dependent transmission of sensory signals. LC stimulation and local administration of NE to sensory processing areas of the brain can change the dynamics of both cellular and circuit activity in response to incoming sensory information. Here we explore the LC-NE system's neuromodulatory role in altering sensory signal processing as a plausible mechanism through which psychostimulant agents amplify physiological responses to important sensory stimuli as a component of their performance-enhancing effects in both ADHD patients and otherwise healthy individuals. We further consider sensory enhancement as a desirable outcome that has not previously been explored as an element of therapeutic efficacy, as well as added motivation for otherwise healthy individuals to engage in off-label self-administration of psychostimulant drugs., (Copyright © 2018. Published by Elsevier B.V.)

In this commentary we utilize recent observations regarding the organization and actions of the locus coeruleus-noradrenergic system to identify major issues in need of further study to more fully understand the behavioral actions of this major neurotransmitter system., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Many studies in intact animals have shown that locally applied or synaptically released norepinephrine (NE) can enhance individual neuron and neural network responses to sensory inputs. However, a major unanswered question is how and when noradrenergically-mediated changes in sensory signal processing can influence downstream decision making, motor responding, and ultimately behavioral outcomes. Recent work using a variety of approaches in different sensory networks has started to consider this question. Evidence collected to date as reported in this Special Edition of Brain Research suggests that output from the brainstem locus coeruleus (LC)-NE system can modify task-related sensory signal processing and by so doing influence goal-directed behavioral responding. This report reviews the work leading to this most recent line of inquiry and at the same time identifies areas for future investigation., (Copyright © 2018. Published by Elsevier B.V.)

Norepinephrine (NE), a central neuromodulator, influences sensory processing at the behavioral and physiological levels, potentially by regulating signal-to-noise ratio in sensory neural networks. To understand neuromodulatory function at the perceptual level, one must understand the neural mechanisms underlying these effects. In this review, we illustrate this process using the olfactory system as a model system. We discuss basic computations in the olfactory system and their modulation by NE. We review known cellular effects of NE in the olfactory bulb and cortex and how these effects modulate olfactory computation. We then illustrate how computational modeling can relate cellular and perceptual data using the example of NE modulation of odor detection thresholds., (Copyright © 2018. Published by Elsevier B.V.)

Type I Diabetes (T1D) is associated with reduced leptin levels and increased stress axis activity marked by elevations in norepinephrine (NE) levels in the paraventricular nucleus (PVN) of the hypothalamus. We hypothesized that leptin suppresses stress axis activity in T1D through central and peripheral mechanisms. In the first experiment, adult male Sprague Dawley rats were implanted with a cannula in the PVN and randomly divided into a non-diabetic group treated with vehicle (n = 6) and a diabetic group treated with streptozotocin (n = 13). Food intake and water intake was measured for 14 days. On the last day, a subset of diabetic rats were treated with 500 µg of leptin i.p. Rats were subjected to push-pull perfusion of the PVN and hourly blood sampling for 5 h. In the next experiment, diabetic rats were treated either with an alpha-2 adrenergic agonist, clonidine (CLON), or a beta adrenergic agonist isoproterenol (ISO), to reverse the effects of leptin. Rats were subjected to push pull perfusion and hourly blood sampling. In experiment 1, T1D increased food intake, water intake, NE release in the PVN and circulating CS levels. Leptin treatment decreased NE release modestly but produced a robust reduction in corticosterone (CS) levels. In experiment 2, CLON but not ISO was able to reverse the effect of leptin on NE levels in the PVN, however, both agonists were capable of blocking leptin's effects on circulating CS. These results suggest that in diabetic rats, the sensitivity of the hypothalamus to beta adrenergic agonists is altered, while the adrenals remain sensitive to both alpha and beta adrenergic agonists., (Copyright © 2018. Published by Elsevier B.V.)

The locus coeruleus (LC)-norepinephrine (NE) system is a key nucleus in which endogenous opioid and stress systems intersect to regulate the stress response. LC neurons of male rats become sensitized to stress following chronic morphine administration. Whether sex dictates this pattern of opioid-induced plasticity has not been demonstrated. Delineating the neurobiological adaptations produced by chronic opioids will enhance our understanding of stress vulnerability in opioid-dependent individuals, and may reveal how stress negatively impacts addiction recovery. In the present study, the effect of chronic morphine on the subcellular distribution of mu-opioid (MOR) and CRF receptors (CRFR) was investigated in the LC of male and female rats using immunoelectron microscopy. Results showed that placebo-treated females exhibited higher MOR and CRFR cytoplasmic distribution ratio when compared to placebo-treated males. Chronic morphine exposure induced a shift in the distribution of MOR immunogold-silver particles from the plasma membrane to the cytoplasm selectively in male LC neurons. Interestingly, chronic morphine exposure induced CRFR recruitment to the plasma membrane of both male and female LC neurons. These findings provide a potential mechanism by which chronic opioid administration increases stress vulnerability in males and females via an increase in surface availability of CRFR in LC neurons. However, our results also support the notion that cellular adaptations to chronic opioids differ across the sexes as redistribution of MOR following morphine exposure was only observed in male LC neurons., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Damage to noradrenergic neurons in the Locus coeruleus (LC) occurs contributes to neuropathology and behavioral deficits in Alzheimer's disease (AD); methods to reduce LC damage may therefore be of benefit. We previously showed that vindeburnol, a derivative of the plant alkaloid vincamine, reduced neuroinflammation, amyloid burden, and LC damage in a mouse model of AD; however, effects on behavior were not tested. We now tested the effects of vindeburnol on anxiety-like behavior in 5xFAD mice which develop robust amyloid burden at early ages. During novel object recognition testing, we observed that 5xFAD mice spent more time exploring than wildtype littermates, and that time was reduced by vindeburnol. Vindeburnol also reduced hyperlocomotion in the 5xFAD mice which may have contributed to their increased exploration times. In an open field test, vindeburnol normalized the increase of time spent in the center, and the decrease of time spent near the walls in 5xFAD mice. Vindeburnol reduced amyloid burden in the hippocampus and cortex, areas that contribute to regulation of anxiety-like behavior. In vitro, vindeburnol increased neuronal BDNF expression in a cAMP-dependent manner; and inhibited phosphodiesterase activity with an EC 50 near 50 μM. These findings suggest that cAMP-mediated increases in neurotrophic factors contribute to beneficial effects of vindeburnol within the context of LC damage, which may be of value for treatment of some neuropsychiatric symptoms of AD., (Published by Elsevier B.V.)

The evolution of peptidergic signaling systems in the central nervous system serves a distinct and crucial role in brain processes and function. The diversity of physiological peptides and the complexity of their regulation and secretion from the dense core vesicles (DCV) throughout the brain is a topic greatly in need of investigation, though recent years have shed light on cellular and molecular mechanisms that are summarized in this review. Here, we focus on the convergence of peptidergic systems onto the Locus Coeruleus (LC), the sole provider of norepinephrine (NE) to the cortex and hippocampus, via large DCV. As the LC-NE system is one of the first regions of the brain to undergo degeneration in Alzheimer's Disease (AD), and markers of DCV have consistently been demonstrated to have biomarker potential for AD progression, here we summarize the current literature linking the LC-NE system with DCV dysregulation and Aβ peptides. We also include neuroanatomical data suggesting that the building blocks of senile plaques, Aβ monomers, may be localized to DCV of the LC and noradrenergic axon terminals of the prefrontal cortex. Finally, we explore the putative consequences of chronic stress on Aβ production and the role that DCV may play in LC degeneration. Clinical data of immunological markers of DCV in AD patients are discussed., (Copyright © 2018. Published by Elsevier B.V.)

Building upon the knowledge that a number of important brain circuits undergo significant degeneration in Alzheimer's disease, numerous recent studies suggest that the norepinephrine-ergic system in the brainstem undergoes significant alterations early in the course of both Alzheimer's disease and Down syndrome. Massive projections from locus coeruleus neurons to almost the entire brain, extensive innervation of brain capillaries, and widespread distribution of noradrenergic receptors enable the norepinephrine-ergic system to play a crucial role in neural processes, including cognitive function. These anatomical and functional characteristics support the role of the norepinephrine-ergic system as an important target for developing new therapies for cognitive dysfunction. Careful neuropathological examinations using postmortem samples from individuals with Alzheimer's disease have implicated the role of the norepinephrine-ergic system in the etiopathogenesis of Alzheimer's disease. Furthermore, numerous studies have supported the existence of a strong interaction between norepinephrine-ergic and neuroimmune systems. We explore the interaction between the two systems that could play a role in the disease-modifying effects of norepinephrine in Alzheimer's disease and Down syndrome., (Copyright © 2017. Published by Elsevier B.V.)

The locus coeruleus-noradrenergic (LC-NA) system supplies the cerebral cortex with norepinephrine, a key modulator of cognition. Neurodegeneration of the LC is an early hallmark of Alzheimer's disease (AD). In this article, we analyze current literature to understand whether NA degeneration in AD simply leads to a loss of norepinephrine input to the cortex. With reported adaptive changes in the LC-NA system at the anatomical, cellular, and molecular levels in AD, existing evidence support a seemingly sustained level of extracellular NE in the cortex, at least at early stages of the long course of AD. We postulate that loss of the integrity of the NA system, rather than mere loss of NE input, is a key contributor to AD pathogenesis. A thorough understanding of NA dysfunction in AD has a large impact on both our comprehension and treatment of this devastating disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The locus coeruleus (LC) is the noradrenaline (norepinephrine, NE)-containing nucleus in the brainstem and innervates into widespread brain regions. This LC-NE system plays a critical role in a variety of brain functions, including attention, arousal, emotion, cognition, and the sleep-wake cycle. The LC is one of the brain regions vulnerable to the occurrence of neurofibrillary tangles (NFTs), which is associated with "primary age-related tauopathy (PART)" that describes the pathology commonly observed in the brains of aged individuals. In Alzheimer's disease (AD), the LC is one of the first places to develop NFTs, which may act as a seed for subsequent spreading of the pathology throughout the brain upon amyloid-β (Aβ) accumulation. As AD progresses, significant neuron loss occurs in the LC. Moreover, LC neurodegeneration is not only a consequence of AD, but also drives clinical and pathological manifestations of AD, such as microglial dysregulation, sleep disturbance, cognitive decline, and neurovascular dysfunction. Therefore, prevention of NFT pathology and neuron loss in the LC-NE system is critical for suppressing the progression of AD. We propose that targeting aging itself may be a proactive intervention against age-associated changes in the LC. Such an approach could open the way for novel interventions against age-associated neurodegenerative disorders, in particular, AD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

TREK-2-like channels were identified on the basis of electrophysiological and pharmacological tests performed on freshly isolated and enzymatically/mechanically dispersed pyramidal neurons of the rat medial prefrontal cortex (mPFC). Single-channel currents were recorded in cell-attached configuration and the impact of adrenergic receptors (α 1 , α 2 , β) stimulation on spontaneously appearing TREK-2-like channel activity was tested. The obtained results indicate that noradrenaline decreases the mean open probability of TREK-2-like channel currents by activation of β 1 but not of α 1 - and α 2 -adrenergic receptors. Mean open time and channel conductance were not affected. The system of intracellular signaling pathways depends on the activation of protein kinase A. We also show that adrenergic control of TREK-2-like channel currents by adrenergic receptors was similar in pyramidal neurons isolated from young, adolescent, and adult rats. Immunofluorescent confocal scans of mPFC slices confirmed the presence of the TREK-2 protein, which was abundant in layer V pyramidal neurons. The role of TREK-2-like channel control by adrenergic receptors is discussed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

With the decline of ovarian steroids levels at menopause, many women experience an increase in anxiety and stress sensitivity. The locus coeruleus (LC), a central source of noradrenaline (NE), is activated by stress and is inhibited by β-endorphin. Moreover, increased NE has been implicated in pathological anxiety syndromes. Hormone replacement therapy (HRT) in menopause appears to decrease anxiety and vulnerability to stress. Therefore, we questioned the effect of HRT on the inhibitory β-endorphin innervation of the LC. In addition, we found that progesterone protects serotoninergic neurons in monkeys, leading us to question whether ovarian steroids are also neuroprotective in LC neurons in monkeys. Adult Rhesus monkeys (Macaca mulatta) were ovariectomized, and either treated with Silastic capsules that contained estradiol, estradiol+progesterone, progesterone alone or that were empty (ovariectomized; control). After 1month, the LC was obtained and processed for immunohistochemistry for β-endorphin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL). The density of β-endorphin axons was determined with image analysis using ImageJ. The TUNEL-positive neurons were counted in the entire LC. Progesterone-alone significantly increased the density of the β-endorphin axons in the LC (p<0.01). No significant differences between groups in the number of TUNEL-positive cells in the LC were found. In conclusion, we found that HRT increases the inhibitory influence of β-endorphin in the LC, which could, in turn, contribute to reduce anxiety and increase stress resilience. In addition, we did not find compelling evidence of neurodegeneration or neuroprotection by HRT in the LC of Rhesus monkeys., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rapid monoamine release in the dorsal hippocampus is not well characterized, despite its postulated role in modulating fast hippocampal circuit dynamics. We measured monoamine release in the dorsal hippocampus upon stimulation of the ventral tegmental area (VTA) with fast-scan cyclic voltammetry in anesthetized norepinephrine-depleted and non-depleted mice. Within the hippocampus, norepinephrine depletion altered the ability of α 2 adrenergic compounds and transporter blockers to modulate the small, evoked monoamine signal. These manipulations also affected the pH shifts observed after stimulation in a drug-dependent manner. The evoked signal was potentiated by α 2C adrenoceptor subtype antagonism, but was not affected by or α 2A adrenoceptor antagonism. The same subtype-specific pattern was observed on evoked dopamine release in the ventral striatum. The pharmacological and anatomical evidence supports a contribution by dopamine to the VTA-evoked hippocampal monoamine signal, and confirms the interaction between the mesohippocampal and coeruleohippocampal systems. These results also reinforce the notion that α 2C, but not α 2A adrenoceptors regulate endogenous dopaminergic activity. We believe our findings hold implications for understanding the efficacy of α 2 adrenergic agonists and antagonists that are used widely for therapeutic purposes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Preclinical studies indicate that serotonin7 (5-HT7) receptors may regulate depressive-like behaviors. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT7 receptors in the lateral habenular nucleus (LHb) involve in the regulation of PD-related depression. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-LHb injection of 5-HT7 receptor agonist AS19 (1, 2 and 4μg/rat) induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-LHb injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6μg/rat) produced antidepressant effects in the two groups of rats. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-LHb injection of AS19 (4μg/rat) decreased dopamine and 5-HT levels in the medial prefrontal cortex, habenula and hippocampus in sham-operated and the lesioned rats; whereas SB269970 (6μg/rat) increased dopamine and 5-HT levels in these structures. In addition, noradrenaline levels in these structures were not changed after intra-LHb injection of AS19 or SB269970 in the two groups of rats. These findings suggest that activation or blockade of 5-HT7 receptors in the LHb may change the activity of LHb glutamate neurons, and then decreases or increases dopamine and 5-HT levels in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The present study investigated the antidepressant potential of curcumin in olfactory bulbectomy and forced swimming test models of depression in male albino rats under chronic treatment. The experimental animals were divided into four groups, and curcumin was administered for 45 days. Our results showed that the curcumin significantly reduced olfactory bulbectomy-induced behavioral abnormalities including deficits in step-down passive avoidance, increased activity in the open area and immobility time. Chronic administration of curcumin significantly reversed levels of 3, 4-dihydroxyphenylacetic acid, noradrenaline, serotonin and 5-hydroxyindoleacetic acid in the hippocampus region of male albino rats. Also, curcumin normalizes the levels of dopamine, noradrenaline, and 5-hydroxyindoleacetic acid in the frontal cortex of rats. Taking all these results together, it may suggest that curcumin is potent compound acting against the depression in the male albino rats., (Copyright © 2016. Published by Elsevier B.V.)

Introduction: Prenatal stress (PNS) and stress in adulthood are risk factors for development of major depressive disorder. The present study aimed to 1) confirm previous neuroendocrine and behavioral changes induced by PNS, and 2) to characterize the effect of early- and late life stress on the in vivo activity of monoamine systems., Methods: Gestational dams were restrained thrice daily under bright illumination from gestational day (GD)11-20. Behavior and neuroendocrine responses to the forced swim test (FST) were determined in adult (50-80 days) offspring, and electrophysiological single unit recordings of dorsal raphe nucleus serotonin (5-HT), ventral tegmental area dopamine (DA) and locus coeruleus norepinephrine (NE) neurons were obtained at baseline and 24h after the FST., Results: Gestational dams did not habituate to chronic restraint stress, and PNS reduced the birth weight of offspring. In adulthood, swim stress elevated CORT levels longer in PNS animals, while it had no effect on swim behaviors. Baseline firing activity of 5-HT neurons was decreased in PNS animals, while the firing activity of NE and DA neurons was increased. Swim stress had no effect on the firing on 5-HT neurons, but normalized the firing activity of catecholamine neurons in PNS animals., Conclusion: The present data confirm previously established effects on neuroendocrine and physiological measures, and demonstrate an altering effect of PNS and stress on monoamine system activities in adulthood. Since PNS did not result in a depressive-like phenotype, these central changes following PNS might play reflect adaptive changes contributing to stress resilience in adulthood., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal-enhancing actions that involve signaling at α1- and β-noradrenergic receptors within a distributed network of subcortical regions. The majority of research into noradrenergic modulation of arousal has focused on the nucleus locus coeruleus. Nevertheless, anatomical studies demonstrate that multiple noradrenergic nuclei innervate subcortical arousal-related regions, providing a substrate for differential regulation of arousal across these distinct noradrenergic nuclei. The arousal-promoting actions of psychostimulants and other drugs of abuse contribute to their widespread abuse. Moreover, relapse can be triggered by a variety of arousal-promoting events, including stress and re-exposure to drugs of abuse. Evidence has long-indicated that norepinephrine plays an important role in relapse. Recent observations suggest that noradrenergic signaling elicits affectively-neutral arousal that is sufficient to reinstate drug seeking. Collectively, these observations indicate that norepinephrine plays a key role in the interaction between arousal, motivation, and relapse. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The brainstem nucleus locus coeruleus (LC) innervates the entire central nervous system and is the primary source of norepinephrine (NE) to the neocortex. While classically considered a homogenous modulator of forebrain activity by virtue of highly widespread and divergent axons, recent behavioral and pharmacological evidence suggest this nucleus may execute distinct operations within functionally distinct terminal fields. Summarized in this review are the anatomical and physiological properties of the nucleus within a historical context that led to the interpretation of the nucleus as a homogeneous entity with uniform and simultaneous actions throughout its terminal fields. Also included are findings from several laboratories which point to a more nuanced model of LC/NE function that parallels that seen in other forebrain-projecting monoaminergic nuclei. Such compartmentalized models of the nucleus promote the idea that specific LC circuits are involved in discrete behavioral operations, and therefore, by identifying the networks that are engaged by LC, the substrates for these behaviors can be identified and manipulated. Perturbations in the functional anatomy and physiology of this system may be related to neuropsychiatric conditions associated with dysregulation of the LC-noradrenergic system such as attention deficit hyperactivity disorder. Recent findings regarding the organization and operation of the LC/NE system collectively challenge the classical view of the nucleus as a relatively homogenous modulator of forebrain activity and provide the basis for a renewed scientific interest in this region of the brain. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson's disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The cerebral cortex is a critical target of the central noradrenergic system. The importance of norepinephrine (NE) in the regulation of cortical activity is underscored by clinical findings that involve this catecholamine and its receptor subtypes in the regulation of a large number of emotional and cognitive functions and illnesses. In this review, we highlight diverse effects of the LC/NE system in the mammalian cortex. Indeed, electrophysiological, pharmacological, and behavioral studies in the last few decades reveal that NE elicits a mixed repertoire of excitatory, inhibitory, and biphasic effects on the firing activity and transmitter release of cortical neurons. At the intrinsic cellular level, NE can produce a series of effects similar to those elicited by other monoamines or acetylcholine, associated with systemic arousal. At the synaptic level, NE induces numerous acute changes in synaptic function, and ׳gates' the induction of long-term plasticity of glutamatergic synapses, consisting in an enhancement of engaged and relevant cortical synapses and/or depression of unengaged synapses. Equally important in shaping cortical function, in many cortical areas NE promotes a characteristic, most often reversible, increase in the gain of local inhibitory synapses, whose extent and temporal properties vary between different areas and sometimes even between cortical layers of the same area. While we are still a long way from a comprehensive theory of the function of the LC/NE system, its cellular, synaptic, and plastic effects are consistent with the hypothesis that noradrenergic modulation is critical in coordinating the activity of cortical and subcortical circuits for the integration of sensory activity and working memory. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2016 Elsevier B.V. All rights reserved.)

While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Noradrenergic neurons of the brainstem extend projections throughout the neuraxis to modulate a wide range of processes including attention, arousal, autonomic control and sensory processing. A spinal projection from the locus coeruleus (LC) is thought to regulate nociceptive processing. To characterize and selectively manipulate the pontospinal noradrenergic neurons in rats, we implemented a retrograde targeting strategy using a canine adenoviral vector to express channelrhodopsin2 (CAV2-PRS-ChR2-mCherry). LC microinjection of CAV2-PRS-ChR2-mCherry produced selective, stable, transduction of noradrenergic neurons allowing reliable opto-activation in vitro. The ChR2-transduced LC neurons were opto-identifiable in vivo and functional control was demonstrated for >6 months by evoked sleep-wake transitions. Spinal injection of CAV2-PRS-ChR2-mCherry retrogradely transduced pontine noradrenergic neurons, predominantly in the LC but also in A5 and A7. A pontospinal LC (ps:LC) module was identifiable, with somata located more ventrally within the nucleus and with a discrete subset of projection targets. These ps:LC neurons had distinct electrophysiological properties with shorter action potentials and smaller afterhyperpolarizations compared to neurons located in the core of the LC. In vivo recordings of ps:LC neurons showed a lower spontaneous firing frequency than those in the core and they were all excited by noxious stimuli. Using this CAV2-based approach we have demonstrated the ability to retrogradely target, characterise and optogenetically manipulate a central noradrenergic circuit and show that the ps:LC module forms a discrete unit. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

The anti-Parkinsonian drug rasagiline is a selective, irreversible inhibitor of monoamine oxidase and is used in the treatment of Parkinson׳s disease (PD). Its postulated neuroprotective effects may be attributed to MAO inhibition, or to its propargylamine moiety. The major metabolite of rasagiline, aminoindan, has shown promising neuroprotective properties in vitro but there is a paucity of studies investigating in vivo effects of this compound. Therefore, we examined neuroprotective effects of rasagiline and its metabolite aminoindan in a double lesion model of PD. Male Fisher 344 rats received i.p. injections of the noradrenergic neurotoxin DSP-4 and intra-striatal stereotaxic microinjections of the dopamine neurotoxin 6-OHDA. Saline, rasagiline or aminoindan (3mg/kg/day s.c.) were delivered via Alzet minipumps for 4 weeks. Rats were then tested for spontaneous locomotion and a novel object recognition task. Following behavioral testing, brain tissue was processed for ELISA measurements of growth factors and immunohistochemistry. Double-lesioned rats treated with rasagiline or aminoindan had reduced behavioral deficits, both in motor and cognitive tasks compared to saline-treated double-lesioned rats. BDNF levels were significantly increased in the hippocampus and striatum of the rasagiline- and aminoindan-lesioned groups compared to the saline-treated lesioned group. Double-lesioned rats treated with rasagiline or aminoindan exhibited a sparing in the mitochondrial marker Hsp60, suggesting mitochondrial involvement in neuroprotection. Tyrosine hydroxylase (TH) immunohistochemistry revealed a sparing of TH-immunoreactive terminals in double-lesioned rats treated with rasagiline or aminoindan in the striatum, hippocampus, and substantia nigra. These data provide evidence of neuroprotection by aminoindan and rasagiline via their ability to enhance BDNF levels., (Published by Elsevier B.V.)

The degeneration of noradrenergic neurons in the locus coeruleus (LC) commonly occurs in patients with Parkinson's disease (PD), which is characterized by a selective injury of dopaminergic neurons in the substantia nigra (SN). The pathological impact of the LC on the SN in the disease is unknown. In the present study, we used a noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), to deplete noradrenaline (NA) derived from the LC to explore its influence on degeneration or injury of dopaminergic neurons in the SN in mouse model produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide (LPS). Our results demonstrated that lesion of the LC could change microglial function in the brain, which led to enhanced or prolonged expression of pro-inflammatory cytokines, diminished neurotrophic factors, and weakened ability of anti-oxidation in the SN. The in vitro experiments further confirmed that NA could reduce the inflammatory reaction of microglia. The selective injury of dopaminergic neurons by inflammation, however, was due to the inflammation in different brain regions rather than the depletion of NA. Our results indicate that the lesion in the LC is an important factor in promoting dopaminergic neuron degeneration by impacting the function of microglia in the midbrain., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Increasing evidence indicates that dexmedetomidine (DEX), a selective α2-adrenergic receptor agonist, has a neuroprotective effect against cerebral injury. However, it remains unknown whether and how DEX functionally prevents the pathological form of synaptic plasticity caused by ischemia in the hippocampal CA1 neurons. To address this issue, we analyzed the role of DEX using a model of brain ischemia (oxygen and glucose deprivation, OGD) referred to as post-ischemic LTP (i-LTP). We found that DEX could reduce i-LTP by selectively activating α2 receptors. To clarify its detailed mechanisms, the presynaptic and postsynaptic roles of DEX were investigated. The activation of the α2 receptors of DEX decreased the frequency spontaneous mEPSCs, which exerted its presynaptic mechanisms. In addition, DEX also decreased the amplitude of mEPSCs and prevented the depolarization of postsynaptic membranes during OGD treatment, which exerted its postsynaptic mechanisms. More importantly, our results indicate that postsynaptic β receptors, not α1 receptors, participated in i-LTP. Therefore, these results demonstrated that decreasing β receptors activation by DEX-medicated pre- and post-synaptic α2 receptors activation is responsible for i-LTP. Because of the NMDARs required for i-LTP, we further examined the critical roles of postsynaptic β receptors downstream PKA regulation of NMDA receptor-mediated EPSCs (NMDA EPSC). We clarified that it is attributable to the direct effect of DEX on NMDA EPSC as mediated by PKA inactivation. These findings suggest that DEX can protect neurons from functional damage caused by a relatively mild degree of transient cerebral ischemia, and this effect is mediated by both presynaptic reduction of NE and glutamate release and postsynaptic suppression of NMDAR activation by β receptors and downstream PKA regulation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The dorsal periaqueductal gray area (dPAG) is involved in cardiovascular modulation. In a previous study, we showed that noradrenaline (NA) microinjected into the dPAG caused a vasopressin-mediated pressor response, involving a relay in the hypothalamic paraventricular nucleus (PVN). In the present study, we evaluated the involvement of ionotropic glutamate receptors within the PVN in the cardiovascular response to NA microinjection into the dPAG of unanesthetized rats. Microinjection of the selective NMDA glutamate receptor antagonist LY235959 (2nmol/100nL) unilaterally into the PVN did not affect the cardiovascular response evoked by microinjection of NA (15nmol/50nL) into the dPAG. On the other hand, unilateral PVN pretreatment with the non-NMDA glutamate receptor antagonist NBQX (2nmol/100nL) significantly reduced the pressor and cardiac response caused by microinjection of NA into the dPAG. In addition, bilateral PVN pretreatment with NBQX (2nmol/100nL) blocked the cardiovascular response to NA injected into the dPAG. In conclusion, the present results suggest that bilateral PVN activation of non-NMDA glutamate receptors mediates the vasopressin-related cardiovascular response to the microinjection of NA into the dPAG., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The naturally occurring β-carboline, harmane, has been implicated in various physiological and psychological conditions. Some of these effects are attributed to its interaction with monoaminergic systems. Previous literature indicates that certain β-carbolines including harmane modulate central monoamine levels partly through monoamine oxidase (MAO) inhibition. However, this is not always the case and thus additional mechanisms may be involved. This study set to assess the potential modulatory role of harmane on the basal or K(+) stimulated release of preloaded radiolabelled noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in rat brain cortex in vitro in the presence of the MAO inhibitor pargyline. Harmane displayed an overt elevation in K(+) -evoked [(3)H]5-HT release; whilst little and no effect was reported with [(3)H]DA and [(3)H]NA respectively. The effect of harmane on [(3)H]5-HT efflux was partially compensated in K(+)-free medium. Further analyses demonstrated that removal of Ca(2+) ions and addition of 1.2mM EGTA did not alter the action of harmane on [(3)H]5-HT release from rat brain cortex. The precise mechanism of action however remains unclear but is unlikely to reflect an involvement of MAO inhibition. The current finding aids our understanding on the modulatory action of harmane on monoamine levels and could potentially be of therapeutic use in psychiatric conditions such as depression and anxiety., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hypoxia-induced chemosensory activity in the carotid body (CB) may be enhanced by the sympathetic regulation of vascular tone in the CB. In the present study, we recorded cervical sympathetic nerve activity in rats exposed to hypoxia, and examined noradrenaline (NA)- and serotonin (5-HT)-induced intracellular Ca(2+) ([Ca(2+)]i) responses in smooth muscle cells and pericytes in isolated blood vessels from the CB. Multifiber electrical activity recorded from the cervical sympathetic trunk was increased during the inhalation of hypoxic gas. NA induced [Ca(2+)]i increases in smooth muscle cells in arteriole specimens, whereas 5-HT did not cause any [Ca(2+)]i responses. However, NA did not induce [Ca(2+)]i increases in pericytes in capillaries, whereas 5-HT did and this response was inhibited by the 5-HT2 receptor antagonist, ketanserin. In conclusion, cervical sympathetic nerves enhanced by hypoxia may reduce blood flow in the CB in order to increase chemosensitivity. Thus, hypoxic chemosensitivity in the CB may involve a positive feedback mechanism via sympathetic nerves., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Parkinson׳s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Systemic and intranigral exposure to rotenone in rodents reproduces many of the pathological and behavioral features of PD in humans and thus has been used as an animal model of the disease. Melatonin is a neurohormone secreted by the pineal gland, which has several important physiological functions. It has been reported to be neuroprotective in some animal models of PD. The present study investigated the effects of prolonged melatonin treatment in rats previously exposed to rotenone. The animals were intraperitoneally treated for 10 days with rotenone (2.5mg/kg) or its vehicle. 24h later, they were intraperitoneally treated with melatonin (10mg/kg) or its vehicle for 28 days. One day after the last rotenone exposure, the animals exhibited hypolocomotion in the open field test, which spontaneously reversed at the last motor evaluation. We verified that prolonged melatonin treatment after dopaminergic lesion did not alter motor function but produced antidepressant-like effects in the forced swim test, prevented the rotenone-induced reduction of striatal dopamine, and partially prevented tyrosine hydroxylase immunoreactivity loss in the SNpc. Our results indicate that melatonin exerts neuroprotective and antidepressant-like effects in the rotenone model of PD., (Copyright © 2014. Published by Elsevier B.V.)

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous, developmental disorder, and is one of the most common child-psychiatric disorders. It is also a risk factor for early smoking and adult nicotine dependence. Nicotine has been shown to improve symptoms associated with ADHD, including problems with attention, working memory and response inhibition. Norepinephrine, a neurotransmitter involved in attention, is highly implicated in ADHD, and often targeted in the treatment thereof. In the present study we investigated nicotine׳s effect on release of norepinephrine in the hippocampus of a validated rat model of ADHD, the spontaneously hypertensive rat (SHR), as well as in two control strains: Wistar-Kyoto rats (WKY) and Sprague-Dawley rats (SD). Hippocampal slices obtained from male SHR, WKY and SD (postnatal day 31-33) were pre-incubated with radioactively labelled norepinephrine ([3H]NE) and perfused with buffer. The slices were stimulated by exposure to different concentrations of nicotine (1, 10, 100 or 1000 µM) for 1 min at 2 intervals (S1 and S2, separated by 20 min). Following a 10 min wash, slices were stimulated with 25 mM potassium. Since glutamate and GABA receptor function differ in SHR and WKY, we investigated the possible involvement of AMPA and GABA(A) receptors in nicotine (100 µM)-stimulated release of hippocampal [3H]NE in each of the strains by blocking these receptors with CNQX (AMPA receptor antagonist, 10 µM) or bicuculline (GABAA receptor antagonist, 30 µM) respectively. Nicotine-stimulated release (S1) of [3H]NE from SHR hippocampal slices was less than that of WKY and SD, at 100 µM and 1000 µM nicotine, suggesting reduced density and/or function of nicotinic receptors in SHR hippocampus. Nicotine-stimulated release of [3H]NE in response to S2 was reduced compared to S1 in all strains, indicating desensitization of receptors involved in stimulation of [3H]NE by nicotine. Potassium-stimulated release of [3H]NE following the nicotine stimulations (S1 and S2) was elevated in SHR hippocampal slices compared to that of WKY and SD, agreeing with the hypothesis that SHR have reduced negative feedback inhibition by α2-adrenoceptors on varicosities of locus coeruleus-norepinephrine neurons. Blocking AMPA receptors with CNQX had no effect on nicotine-stimulated release of [3H]NE in any of the strains. In WKY, nicotine-stimulated release of [3H]NE was reduced by the GABAA receptor antagonist, bicuculline. We conclude that reduced nicotinic receptor activity, and reduced involvement of GABA(A) receptors in nicotine receptor activity, may be part of ADHD neuropathology., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Melatonin is involved in various neuronal functions such as circadian rhythmicity and thermoregulation. Melatonin has a wide range of pharmacologically effective concentration levels from the nanomolar to millimolar levels. Recently, the antiepileptic effect of high dose melatonin has been the focus of clinical studies; however, its detailed mechanism especially in relation to neurotransmitter release and synaptic transmission remains unclear. We studied the effect of melatonin at high concentrations on the neurotransmitter release by monitoring norepinephrine release in PC12 cells, and excitatory postsynaptic potential in rat hippocampal slices. Melatonin inhibits the 70mM K(+)-induced Ca(2+) increase at millimolar levels without effect on bradykinin-triggered Ca(2+) increase in PC12 cells. Melatonin (1mM) did not affect A2A adenosine receptor-evoked cAMP production, and classical melatonin receptor antagonists did not reverse the melatonin-induced inhibitory effect, suggesting G-protein coupled receptor independency. Melatonin inhibits the 70mM K(+)-induced norepinephrine release at a similar effective concentration range in PC12 cells. We confirmed that melatonin (100µM) inhibits excitatory synaptic transmission of the hippocampal Schaffer collateral pathway with the decrease in basal synaptic transmission and the increase in paired pulse ratio. These results show that melatonin inhibits neurotransmitter release through the blocking of voltage-sensitive Ca(2+) channels and suggest a possible mechanism for the antiepileptic effect of melatonin., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Cocaine-induced psychomotor stimulation may be mediated by metabolic hypofrontality and modification of brain functional connectivity. Functional connectivity refers to the pattern of relationships among brain regions, and one way to evaluate this pattern is using interactivity correlations of the metabolic marker cytochrome oxidase among different regions. This is the first study of how repeated cocaine modifies: (1) mean cytochrome oxidase activity in neural areas using quantitative enzyme histochemistry, and (2) functional connectivity among brain regions using inter-correlations of cytochrome oxidase activity. Rats were injected with 15 mg/kg i.p. cocaine or saline for 5 days, which lead to cocaine-enhanced total locomotion. Mean cytochrome oxidase activity was significantly decreased in cocaine-treated animals in the superficial dorsal and lateral frontal cortical association areas Fr2 and Fr3 when compared to saline-treated animals. Functional connectivity showed that the cytochrome oxidase activity of the noradrenergic locus coeruleus and the infralimbic cortex were positively inter-correlated in cocaine but not in control rats. Positive cytochrome oxidase activity inter-correlations were also observed between the dopaminergic substantia nigra compacta and Fr2 and Fr3 areas and the lateral orbital cortex in cocaine-treated animals. In contrast, cytochrome oxidase activity in the interpeduncular nucleus was negatively correlated with that of Fr2, anterior insular cortex, and lateral orbital cortex in saline but not in cocaine groups. After repeated cocaine specific prefrontal areas became hypometabolic and their functional connectivity changed in networks involving noradrenergic and dopaminergic brainstem nuclei. We suggest that this pattern of hypofrontality and altered functional connectivity may contribute to cocaine-induced psychomotor stimulation.

Recent studies have investigated the role of γ-aminobutyric acid (GABA) in the behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD), specifically in behavioural disinhibition. Spontaneously hypertensive rats (SHR) are widely accepted as an animal model of ADHD, displaying core symptoms of the disorder. Using an in vitro superfusion technique, we have shown that glutamate-stimulated release of radio-actively labelled norepinephrine ([(3)H]NE) from prefrontal cortex and hippocampal slices is greater in SHR than in their normotensive control strain, Wistar-Kyoto rats (WKY), and/or a standard control strain, Sprague-Dawley rats (SD). In the present study, we investigated how the level of extracellular (tonic) GABA affects release of [(3)H]NE in hippocampal slices of male and female SHR, WKY and SD rats, in response to 3 glutamate stimulations (S1, S2, and S3). The hippocampal slices were prelabelled with [(3)H]NE and superfused with buffer containing 0μM, 1μM, 10μM, or 100μM GABA. Three consecutive glutamate stimulations were achieved by exposing slices to 3 pulses of glutamate (1mM), each separated by 10min. Increasing tonic levels of GABA increased basal and stimulated release of [(3)H]NE in all strains. When GABA was omitted from the superfusion buffer used to perfuse SHR hippocampal slices, but present at 100µM in the buffer used to perfuse WKY and SD hippocampal slices, glutamate-stimulated release of [(3)H]NE was similar in all three strains. In these conditions, the decrease in [(3)H]NE release from S1 to S2 and S3 was also similar in all three strains. These findings suggest that extracellular concentrations of GABA may be reduced in SHR hippocampus, in vivo, compared to WKY and SD. An underlying defect in GABA function may be at the root of the dysfunction in catecholamine transmission noted in SHR, and may underlie their ADHD-like behaviours., (© 2013 Elsevier B.V. All rights reserved.)

Scope: Ascorbic acid (ascorbate) is required to recycle tetrahydrobiopterin, which is necessary for neurotransmitter synthesis by the rate-limiting enzymes tyrosine and tryptophan hydroxylases. We sought to determine whether ascorbate might regulate embryonic brain cortex monoamine synthesis utilizing transgenic mouse models with varying intracellular ascorbate levels., Methods and Results: In embryos lacking the sodium-dependent vitamin C transporter 2 (SVCT2), very low levels of brain ascorbate decreased cortex levels of norepinephrine and dopamine by approximately 33%, but had no effect on cortex serotonin or its metabolite, 5-hydroxyindole acetic acid. This decrease in ascorbate also led to a decrease in protein levels of tyrosine hydroxylase, but not of tryptophan hydroxylase. Increased cortex ascorbate in embryos carrying extra copies of the SVCT2 resulted in increased levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), as well as serotonin and 5-hydroxyindole acetic acid., Conclusion: The dependence of embryonic brain cortex neurotransmitter synthesis and tyrosine hydroxylase expression on intracellular ascorbate emphasizes the importance of receiving adequate ascorbate during development., (© 2013 Elsevier B.V. All rights reserved.)