Locus Coeruleus-Norepinephrine System: Spheres of Influence and Contribution to the Development of Neurodegenerative Diseases.

Locus coeruleus is a small bilateral nucleus in the brainstem. It is the main source of norepinephrine (noradrenaline) throughout the central nervous system (about 70% of all norepinephrine in the central nervous system), and, as shown in numerous studies, it is involved in regulating a significant number of functions. The detailed study of the functions of the Locus Coeruleus (LC) and its significance in human life became possible only after the development of histofluorescence methods for monoamines in the 1960s. The widespread locus coeruleus-norepinephrine (LC-NE) projection system regulates the entire central nervous system and modulates sensory processing, motor behavior, arousal, and cognitive processes. Damage to the LC and the associated decrease in norepinephrine levels are involved in a wide range of clinical conditions and pathological processes. Although much about the anatomy and physiology of the LC is currently known, its ultimate role in the regulation of behavior, control of the sleep-wake cycle, stress response, and the development of pathological conditions (such as Alzheimer's disease, dementia, depression, suicidal behavior, chronic traumatic encephalopathy, and Parkinson's disease) is not fully understood. Non-invasive visualization of the LC can be used for differential diagnosis, determining the stage of the disease, and predicting its course. Studying the dysfunction of the LC-norepinephrine system, involved in the pathogenesis of various neurological diseases, may ultimately form the basis for the development of new treatment methods based on the pharmacological elevation of norepinephrine levels. In this review, we will attempt to highlight the key points regarding the structure and function of the Locus Coeruleus, as well as outline the main directions and prospects for its study.

Long-term olfactory enrichment promotes non-olfactory cognition, noradrenergic plasticity and remodeling of brain functional connectivity in older mice.

Brain functional and structural changes lead to cognitive decline during aging, but a high level of cognitive stimulation during life can improve cognitive performances in the older adults, forming the cognitive reserve. Noradrenaline has been proposed as a molecular link between environmental stimulation and constitution of the cognitive reserve. Taking advantage of the ability of olfactory stimulation to activate noradrenergic neurons of the locus coeruleus, we used repeated olfactory enrichment sessions over the mouse lifespan to enable the cognitive reserve buildup. Mice submitted to olfactory enrichment, whether started in early or late adulthood, displayed improved olfactory discrimination at late ages and interestingly, improved spatial memory and cognitive flexibility. Moreover, olfactory and non-olfactory cognitive performances correlated with increased noradrenergic innervation in the olfactory bulb and dorsal hippocampus. Finally, c-Fos mapping and connectivity analysis revealed task-specific remodeling of functional neural networks in enriched older mice. Long-term olfactory enrichment thus triggers structural noradrenergic plasticity and network remodeling associated with better cognitive aging and thereby forms a promising mouse model of the cognitive reserve buildup.

Temperament and probabilistic predictive coding in visual-spatial attention.

Cholinergic (Ach), Noradrenergic (NE), and Dopaminergic (DA) pathways play an important role in the regulation of spatial attention. The same neurotransmitters are also responsible for inter-individual differences in temperamental traits. Here we explored whether biologically defined temperamental traits determine differences in the ability to orient spatial attention as a function of the probabilistic association between cues and targets. To this aim, we administered the Structure of Temperament Questionnaire (STQ-77) to a sample of 151 participants who also performed a Posner task with central endogenous predictive (80 % valid/20 % invalid) or non-predictive cues (50 % valid/50 % invalid). We found that only participants with high scores in Plasticity and Intellectual Endurance showed a selective abatement of attentional costs with non-predictive cues. In addition, stepwise regression showed that costs in the non-predictive condition were negatively predicted by scores in Plasticity and positively predicted by scores in Probabilistic Thinking. These results show that stable temperamental characteristics play an important role in defining the inter-individual differences in attentional behaviour, especially in the presence of different probabilistic organisations of the sensory environment. These findings emphasize the importance of considering temperamental and personality traits in social and professional environments where the ability to control one's attention is a crucial functional skill.

Declining locus coeruleus-dopaminergic and noradrenergic modulation of long-term memory in aging and Alzheimer's disease.

Memory is essential in defining our identity by guiding behavior based on past experiences. However, aging leads to declining memory, disrupting older adult's lives. Memories are encoded through experience-dependent modifications of synaptic strength, which are regulated by the catecholamines dopamine and noradrenaline. While cognitive aging research demonstrates how dopaminergic neuromodulation from the substantia nigra-ventral tegmental area regulates hippocampal synaptic plasticity and memory, recent findings indicate that the noradrenergic locus coeruleus sends denser inputs to the hippocampus. The locus coeruleus produces dopamine as biosynthetic precursor of noradrenaline, and releases both to modulate hippocampal plasticity and memory. Crucially, the locus coeruleus is also the first site to accumulate Alzheimer's-related abnormal tau and severely degenerates with disease development. New in-vivo assessments of locus coeruleus integrity reveal associations with Alzheimer's markers and late-life memory impairments, which likely stem from impaired dopaminergic and noradrenergic neurotransmission. Bridging research across species, the reviewed findings suggest that degeneration of the locus coeruleus results in deficient dopaminergic and noradrenergic modulation of hippocampal plasticity and thus memory decline.

The monoaminergic system is a bilaterian innovation.

Monoamines like serotonin, dopamine, and adrenaline/noradrenaline (epinephrine/norepinephrine) act as neuromodulators in the nervous system. They play a role in complex behaviours, cognitive functions such as learning and memory formation, as well as fundamental homeostatic processes such as sleep and feeding. However, the evolutionary origin of the genes required for monoaminergic modulation is uncertain. Using a phylogenomic approach, in this study, we show that most of the genes involved in monoamine production, modulation, and reception originated in the bilaterian stem group. This suggests that the monoaminergic system is a bilaterian novelty and that its evolution may have contributed to the Cambrian diversification.

The role of beta- and alpha-adrenergic receptors on alcohol drinking.

Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), where intake despite negative consequences can be a major clinical obstacle. With few treatment options available for AUD, there is a significant need for novel therapies. The noradrenergic system is an important hub for regulating stress responses and maladaptive drives for alcohol. Studies have shown that drugs targeting α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of ß ARs for treating human drinking has received scant investigation, and thus we sought to provide pre-clinical validation for possible AR utility for CLAD by analyzing whether ß AR antagonists propranolol (ß1/2), betaxolol (ß1), and ICI, 118,551 (ß2) impacted CLAD and alcohol-only drinking (AOD) in male Wistar rats. We found that the highest dose of propranolol tested systemically (10 mg/kg) reduced alcohol drinking, while 5 mg/kg propranolol reduced drinking with a trend to impact CLAD more than AOD, and with no effects of 2.5 mg/kg. Betaxolol (2.5 mg/kg) also decreased drinking, while ICI 118.551 had no effects. Also, while AR compounds might have utility for AUD, they can also lead to undesirable side effects. Here, a combination of ineffective doses of propranolol and prazosin reduced both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol in two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10 µg) in aINS or mPFC did not affect CLAD or AOD. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.

Testing locus coeruleus-norepinephrine accounts of working memory, attention control, and fluid intelligence.

The current set of studies examined the relationship among working memory capacity, attention control, fluid intelligence, and pupillary correlates of tonic arousal regulation and phasic responsiveness in a combined sample of more than 1,000 participants in two different age ranges (young adults and adolescents). Each study was designed to test predictions made by two recent theories regarding the role of the locus coeruleus-norepinephrine (LC-NE) system in determining individual differences in cognitive ability. The first theory, proposed by Unsworth and Robison (2017a), posits two important individual differences: the moment-to-moment regulation of tonic arousal, and the phasic responsiveness of the system to goal-relevant stimuli. The second theory, proposed by Tsukahara and Engle (2021a), argues that people with higher cognitive abilities have greater functional connectivity between the LC-NE system and cortical networks at rest. These two theories are not mutually exclusive, but they make different predictions. Overall, we found no evidence consistent with a resting-state theory. However, phasic responsiveness was consistently correlated with working memory capacity, attention control, and fluid intelligence, supporting a prediction made by Unsworth and Robison (2017a). Tonic arousal regulation was not correlated with working memory or fluid intelligence and was inconsistently correlated with attention control, which offers only partial support for Unsworth and Robison's (2017a) second prediction.

Effects of chronic exposure to cold stress on ovarian functions in prepubertal rats.

Ovarian functions are modulated by the hypothalamus-pituitary-ovary axis and neural signals. Stress modifies the activity of the sympathetic nervous system. In adult female rats, cold stress results in higher noradrenergic and steroidogenic activity of the ovary, anovulation and the presence of ovarian cysts; however, it is unknown whether this response occurs in prepubertal rats. The purpose of this study was to analyse the effects of cold stress initiated in the prepubertal stage of female rats on ovarian function. Female rats 24 days old were exposed to three, five or eight weeks of cold stress. Autopsies were performed at the end of each stress period. The parameters analysed were the number of ova shed by ovulating animals; the number of ovulating animals; the serum concentrations of progesterone, testosterone, and oestradiol; and the ovarian concentrations of norepinephrine and 3-methoxy-4-hydroxyphenyl-glycol. Our results show that chronic cold stress applied to prepubertal rats did not modify the number of ovulating animals, the total number of ova shed, or progesterone and testosterone concentrations in any of the periods analysed. Oestradiol concentration was lower in the animals exposed to five or eight weeks of stress. The ovarian norepinephrine concentration was higher in the animals exposed to three weeks of stress and was lower at eight weeks of stress. No changes in ovarian morphology were observed. Our data suggest that the changes in noradrenergic activity resulting from chronic cold stress experienced in the prepubertal stage do not modify ovarian architecture or affect the ovulatory response in adulthood.

Disentangling the roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human decision-making.

Balancing the exploration of new options and the exploitation of known options is a fundamental challenge in decision-making, yet the mechanisms involved in this balance are not fully understood. Here, we aimed to elucidate the distinct roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human choice. To this end, we used a double-blind, placebo-controlled design in which participants received either a placebo, 400 mg of the D2/D3 receptor antagonist amisulpride, or 40 mg of the ß-adrenergic receptor antagonist propranolol before they completed a virtual patch-foraging task probing exploration and exploitation. We systematically varied the rewards associated with choice options, the rate by which rewards decreased over time, and the opportunity costs it took to switch to the next option to disentangle the contributions of dopamine and noradrenaline to specific choice aspects. Our data show that amisulpride increased the sensitivity to all of these three critical choice features, whereas propranolol was associated with a reduced tendency to use value information. Our findings provide novel insights into the specific roles of dopamine and noradrenaline in the regulation of human choice behavior, suggesting a critical involvement of dopamine in directed exploration and a role of noradrenaline in more random exploration.

Monoaminergic mediation of hyperalgesic and analgesic descending control of nociception in mice.

ABSTRACT: Descending control of nociception (DCN; also known as conditioned pain modulation [CPM], the behavioral correlate of diffuse noxious inhibitory controls) is the phenomenon whereby pain inhibits pain in another part of the body and is the subject of increasing study because it may represent a biomarker of chronic pain. We recently discovered that pain modulation on the application of a DCN paradigm involving low-intensity test stimuli occurs in the direction of hyperalgesia in healthy mice and rats, whereas the use of high-intensity stimuli produces analgesia. To elucidate the physiological mechanisms underlying hyperalgesic DCN, we administered agonists and antagonists of norepinephrine (NE) and serotonin (5-HT) receptors, key neurochemical players in the production of analgesic DCN. We find that 3 different monoamine reuptake inhibitors-the NE-selective reboxetine, the 5-HT-selective fluoxetine, and the dual NE/5-HT agonist duloxetine-all abolish hyperalgesic DCN when administered into the spinal cord (but not systemically), with no effect on heat or mechanical pain sensitivity. The reversal by reboxetine of hyperalgesic DCN is mediated by α 2 -adrenergic receptors (ie, blocked by atipamezole), and the fluoxetine reversal is mediated by 5-HT 7 receptors (ie, blocked by SB269970). By contrast, analgesic DCN was found to be reversed by atipamezole and SB269970 themselves, with no effect of reboxetine or fluoxetine. Thus, hyperalgesic DCN seems to be the neurochemical opposite to analgesic DCN. These data further validate and help elucidate a preclinical paradigm that mimics dysfunctional CPM and thus may form the basis of translational experiments that aim to reveal preventative pharmacological strategies for individuals predisposed to persistent pain.

Quinazoline alkylthio derivative targets norepinephrine and calcitonin gene-related peptide to improve behavior and radiographic score in the rat model of cervical vertigo.

The present study investigated the effect of quinazoline alkylthio derivative (QAD) on cervical vertigo in the rat model and explored the underlying mechanism. Treatment of the cervical vertigo rats with QAD led to a significant (P<0.05) improvement in balance beam score compared to the model group. Cervical vertigo-mediated reduction in CGRP level in rat plasma samples was effectively inhibited on treatment with QAD. Treatment with QAD led to a significant (P<0.05) reduction in cervical vertigo-induced increase in ET-1 and NE levels in rats. An increase in NO production by cervical vertigo induction showed a significant (P<0.05) decrease in rats by QAD treatment. The QAD treatment of the rats significantly (P<0.05) inhibited cervical vertigo-induced increase in radiographic score on day 56. The radiographic score in cervical vertigo rats was decreased to 0.42 on treatment with QAD compared to 8.2 in the model group. Therefore, QAD treatment of the cervical vertigo rats improves behavioral score and inhibits radiographic score. It upregulates CGRP expression and suppresses ET-1, NE and NO levels in a rat model of cervical vertigo. Thus, QAD can be used for the treatment of cervical vertigo however, further investigations are required to study the mechanism in detail.

Adrenoceptor sub-type involvement in Ca2+ current stimulation by noradrenaline in human and rabbit atrial myocytes.

Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca2+ current (ICaL) by noradrenaline (NA). However, the contribution of the adrenoceptor (AR) sub-types to such ICaL-increase is poorly understood, particularly in human. We therefore investigated effects of various broad-action and sub-type-specific α- and ß-AR antagonists on NA-stimulated atrial ICaL. ICaL was recorded by whole-cell-patch clamp at 37 °C in myocytes isolated enzymatically from atrial tissues from consenting patients undergoing elective cardiac surgery and from rabbits. NA markedly increased human atrial ICaL, maximally by ~ 2.5-fold, with EC75 310 nM. Propranolol (ß1 + ß2-AR antagonist, 0.2 microM) substantially decreased NA (310 nM)-stimulated ICaL, in human and rabbit. Phentolamine (α1 + α2-AR antagonist, 1 microM) also decreased NA-stimulated ICaL. CGP20712A (ß1-AR antagonist, 0.3 microM) and prazosin (α1-AR antagonist, 0.5 microM) each decreased NA-stimulated ICaL in both species. ICI118551 (ß2-AR antagonist, 0.1 microM), in the presence of NA + CGP20712A, had no significant effect on ICaL in human atrial myocytes, but increased it in rabbit. Yohimbine (α2-AR antagonist, 10 microM), with NA + prazosin, had no significant effect on human or rabbit ICaL. Stimulation of atrial ICaL by NA is mediated, based on AR sub-type antagonist responses, mainly by activating ß1- and α1-ARs in both human and rabbit, with a ß2-inhibitory contribution evident in rabbit, and negligible α2 involvement in either species. This improved understanding of AR sub-type contributions to noradrenergic activation of atrial ICaL could help inform future potential optimisation of pharmacological AR-antagonism strategies for inhibiting adrenergic AF.

Norepinephrine, beyond the Synapse: Coordinating Epigenetic Codes for Memory.

The noradrenergic system is implicated in neuropathologies contributing to major disorders of the memory, including post-traumatic stress disorder and Alzheimer's disease. Determining the impact of norepinephrine on cellular function and plasticity is thus essential for making inroads into our understanding of these brain conditions, while expanding our capacity for treating them. Norepinephrine is a neuromodulator within the mammalian central nervous system which plays important roles in cognition and associated synaptic plasticity. Specifically, norepinephrine regulates the formation of memory through the stimulation of ß-ARs, increasing the dynamic range of synaptic modifiability. The mechanisms through which NE influences neural circuit function have been extended to the level of the epigenome. This review focuses on recent insights into how the noradrenergic recruitment of epigenetic modifications, including DNA methylation and post-translational modification of histones, contribute to homo- and heterosynaptic plasticity. These advances will be placed in the context of synaptic changes associated with memory formation and linked to brain disorders and neurotherapeutic applications.

Dopamine and norepinephrine are embracing their immune side and so should we.

While the history of neuroimmunology is long, the explicit study of neuroimmune communication, and particularly the role of catecholamines in neuroimmunity, is still emerging. Recent studies have shown that catecholamines, norepinephrine, epinephrine, and dopamine, are central to multiple complex mechanisms regulating immune function. These studies show that catecholamines can be released from both the nervous system and directly from immune cells, mediating both autocrine and paracrine signaling. This commentary highlights the importance of catecholaminergic immunomodulation and discusses new considerations needed to study the role of catecholamines in immune homeostasis to best leverage their contribution to disease processes for the development of new therapeutic approaches.

Alpha-2 Adrenoreceptor Antagonist Yohimbine Potentiates Consolidation of Conditioned Fear.

BACKGROUND: Hyperconsolidation of aversive associations and poor extinction learning have been hypothesized to be crucial in the acquisition of pathological fear. Previous animal and human research points to the potential role of the catecholaminergic system, particularly noradrenaline and dopamine, in acquiring emotional memories. Here, we investigated in a between-participants design with 3 groups whether the noradrenergic alpha-2 adrenoreceptor antagonist yohimbine and the dopaminergic D2-receptor antagonist sulpiride modulate long-term fear conditioning and extinction in humans. METHODS: Fifty-five healthy male students were recruited. The final sample consisted of n = 51 participants who were explicitly aware of the contingencies between conditioned stimuli (CS) and unconditioned stimuli after fear acquisition. The participants were then randomly assigned to 1 of the 3 groups and received either yohimbine (10 mg, n = 17), sulpiride (200 mg, n = 16), or placebo (n = 18) between fear acquisition and extinction. Recall of conditioned (non-extinguished CS+ vs CS-) and extinguished fear (extinguished CS+ vs CS-) was assessed 1 day later, and a 64-channel electroencephalogram was recorded. RESULTS: The yohimbine group showed increased salivary alpha-amylase activity, confirming a successful manipulation of central noradrenergic release. Elevated fear-conditioned bradycardia and larger differential amplitudes of the N170 and late positive potential components in the event-related brain potential indicated that yohimbine treatment (compared with a placebo and sulpiride) enhanced fear recall during day 2. CONCLUSIONS: These results suggest that yohimbine potentiates cardiac and central electrophysiological signatures of fear memory consolidation. They thereby elucidate the key role of noradrenaline in strengthening the consolidation of conditioned fear associations, which may be a key mechanism in the etiology of fear-related disorders.

Sustained chemogenetic activation of locus coeruleus norepinephrine neurons promotes dopaminergic neuron survival in synucleinopathy.

Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson's disease. However, non-motor symptoms of Parkinson's disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson's disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human α-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate α-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.

Pupillary correlates of individual differences in long-term memory.

The present study is the first to examine individual differences in long-term memory, arousal dysregulation, and intensity of attention within the same experiment. Participants (N = 106) completed 28 lists of an immediate free-recall task while their pupil diameter was recorded via an eye-tracker during the encoding period. Two main pupillary measures were extracted: intraindividual variability in pre-list pupil diameter and evoked pupillary responses during item encoding. Variability in pre-list pupil diameter served as a measure of arousal dysregulation, and evoked pupillary responses served as a measure of intensity of attention. Based on prior work, we hypothesized that there would be a positive association between intensity of attention and recall ability, and that there would be a negative association between arousal dysregulation and recall ability. Collectively these two measures accounted for 19% of interindividual variance in recall, with 5% attributable uniquely to intensity of attention and 12% attributable uniquely to arousal regulation. The findings demonstrate that there are sources of individual differences in long-term memory that can be revealed via pupillometry, notably the amount of effort deployed during item encoding and the degree to which people exhibit dysregulated arousal. Both findings are consistent with recent theorizing regarding the role of the locus coeruleus (LC)-norepinephrine (NE) system's role in goal-directed cognition. Specifically, the LC governs both moment-to-moment arousal and NE release to cortical regions subserving cognitive processing. Among people for whom this system operates most optimally, long-term memory retention is superior.

Prefrontal Cortical Connectivity Mediates Locus Coeruleus Noradrenergic Regulation of Inhibitory Control in Older Adults.

Response inhibition is a core executive function enabling adaptive behavior in dynamic environments. Human and animal models indicate that inhibitory control and control networks are modulated by noradrenaline, arising from the locus coeruleus. The integrity (i.e., cellular density) of the locus coeruleus noradrenergic system can be estimated from magnetization transfer (MT)-sensitive magnetic resonance imaging (MRI), in view of neuromelanin present in noradrenergic neurons of older adults. Noradrenergic psychopharmacological studies indicate noradrenergic modulation of prefrontal and frontostriatal stopping-circuits in association with behavioral change. Here, we test the noradrenergic hypothesis of inhibitory control, in healthy adults. We predicted that locus coeruleus integrity is associated with age-adjusted variance in response inhibition, mediated by changes in connectivity between frontal inhibitory control regions. In a preregistered analysis, we used MT MRI images from N = 63 healthy humans aged above 50 years (of either sex) who performed a Stop-Signal Task (SST), with atlas-based measurement of locus coeruleus contrast. We confirm that better response inhibition is correlated with locus coeruleus integrity and stronger connectivity between presupplementary motor area (preSMA) and right inferior frontal gyrus (rIFG), but not volumes of the prefrontal cortical regions. We confirmed a significant role of prefrontal connectivity in mediating the effect of individual differences in the locus coeruleus on behavior, where this effect was moderated by age, over and above adjustment for the mean effects of age. Our results support the hypothesis that in normal populations, as in clinical settings, the locus coeruleus noradrenergic system regulates inhibitory control.SIGNIFICANCE STATEMENT We show that the integrity of the locus coeruleus, the principal source of cortical noradrenaline, is related to the efficiency of response inhibition in healthy older adults. This effect is in part mediated by its effect on functional connectivity in a prefrontal cortical stopping-network. The behavioral effect, and its mediation by connectivity, are moderated by age. This supports the psychopharmacological and genetic evidence for the noradrenergic regulation of behavioral control, in a population-based normative cohort. Noradrenergic treatment strategies may be effective to improve behavioral control in impulsive clinical populations, but age, and locus coeruleus integrity, are likely to be important stratification factors.

Noradrenergic circuits and signaling in substance use disorders.

The central noradrenergic system innervates almost all regions of the brain and, as such, is well positioned to modulate many neural circuits implicated in behaviors and physiology underlying substance use disorders. Ample pharmacological evidence demonstrates that α1, α2, and ß adrenergic receptors may serve as therapeutic targets to reduce drug -seeking behavior and drug withdrawal symptoms. Further, norepinephrine is a key modulator of the stress response, and stress has been heavily implicated in reinstatement of drug taking. In this review, we discuss recent advances in our understanding of noradrenergic circuitry and noradrenergic receptor signaling in the context of opioid, alcohol, and psychostimulant use disorders.

The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders.

The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. However, the mechanisms involving the LC that underlie these effects have not been fully elucidated, in part owing to the technical difficulties inherent in exploring such a tiny nucleus. However, novel research tools are now available that have helped redefine the LC system, moving away from the traditional view of LC as a homogeneous structure that exerts a uniform influence on neural activity. Indeed, innovative techniques such as DREADDs (designer receptors exclusively activated by designer drugs) and optogenetics have demonstrated the functional heterogeneity of LC, and novel magnetic resonance imaging applications combined with pupillometry have opened the way to evaluate LC activity in vivo. This review aims to bring together the data available on the efferent activity of the LC-noradrenergic system in relation to pain and its comorbidity with anxiodepressive disorders. Acute pain triggers a robust LC stress response, producing spinal cord-mediated endogenous analgesia while promoting aversion, vigilance, and threat detection through its ascending efferents. However, this protective biological system fails in chronic pain, and LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. Thus, the activation/deactivation of specific LC projections contributes to different behavioral outcomes in the shift from acute to chronic pain.