The flight response impairs cytoprotective mechanisms by activating the insulin pathway.

An animal's stress response requires different adaptive strategies depending on the nature and duration of the stressor. Whereas acute stressors, such as predation, induce a rapid and energy-demanding fight-or-flight response, long-term environmental stressors induce the gradual and long-lasting activation of highly conserved cytoprotective processes1-3. In animals across the evolutionary spectrum, continued activation of the fight-or-flight response weakens the animal's resistance to environmental challenges4,5. However, the molecular and cellular mechanisms that regulate the trade-off between the flight response and long-term stressors are poorly understood. Here we show that repeated induction of the flight response in Caenorhabditis elegans shortens lifespan and inhibits conserved cytoprotective mechanisms. The flight response activates neurons that release tyramine, an invertebrate analogue of adrenaline and noradrenaline. Tyramine stimulates the insulin-IGF-1 signalling (IIS) pathway and precludes the induction of stress response genes by activating an adrenergic-like receptor in the intestine. By contrast, long-term environmental stressors, such as heat or oxidative stress, reduce tyramine release and thereby allow the induction of cytoprotective genes. These findings demonstrate that a neural stress hormone supplies a state-dependent neural switch between acute flight and long-term environmental stress responses and provides mechanistic insights into how the flight response impairs cellular defence systems and accelerates ageing.

Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems.

Atomoxetine is a selective noradrenaline reuptake inhibitor drug. Based on the knowledge that agents increasing monoamine levels in the central nervous system have therapeutic potential for neuropathic pain, it is planned to investigate the possible efficacy of atomoxetine on diabetes-induced hyperalgesia, in this study. Randall-Selitto (mechanical noxious stimuli) and Hargreaves (thermal noxious stimuli) tests were used to evaluate nociceptive perception of rats. Obtained data indicated that streptozotocin-induced diabetes causes significant decreases in the paw withdrawal threshold and paw withdrawal latency values of the animals, respectively. However, atomoxetine administered at 3 mg/kg/day for 7 and 14 days improved these diabetes-induced hyperalgesia responses. Furthermore, antihyperalgesic activity was antagonized with α-methyl-para-tyrosine methyl ester, phentolamine, propranolol, and sulpiride pre-treatments. The same effect was not reversed, however, by SCH 23390. These findings demonstrated, for the first time, that atomoxetine possesses significant antihyperalgesic activity on diabetes-induced neuropathic pain and this effect seems to be mediated by α- and ß-adrenergic and D2/D3 dopaminergic receptors. Results of this present study seem to offer a new indication for an old drug; atomoxetine, but these preclinical data should first be confirmed with further well-designed clinical trials.

Exercise prior to, but not concomitant with, stress reverses stress-induced delayed skin wound healing.

Stress-induced prolonged inflammation impairs cutaneous wound healing. Exercise may inhibit this effect via an anti-inflammatory mechanism. Our aim was to investigate the effect of moderate exercise on skin wound healing in chronically stressed mice. Mice were trained five times per week on a treadmill or received no training. Mice underwent daily rotational stress from the 6th week until euthanasia. During the 8th week, two wounds were created in the dorsum and collected 10 days later. A control group only received wounds. Exercise was performed prior to and simultaneous with stress for 2 weeks or only prior to stress. Stress increased normetanephrine levels 10 days after wounding, resulting in an increased amount of inflammatory cells and reduced expression of inflammatory cytokines as well as angiogenesis, myofibroblast differentiation and matrix deposition. Concomitant exercise and stress potentiated these effects, intensifying the delayed wound contraction. When exercise was performed only prior to stress, however, the mice showed reduced inflammatory cells in granulation tissue 10 days after wounding and improved wound healing compared with animals with exercise and concomitant stress. Moderate exercise in association with stress potentiates the stress effect; however, when exercise was performed prior to stress, wound healing was improved.

Catecholamine receptor polymorphisms affect decision-making in C. elegans.

Innate behaviours are flexible: they change rapidly in response to transient environmental conditions, and are modified slowly by changes in the genome. A classical flexible behaviour is the exploration-exploitation decision, which describes the time at which foraging animals choose to abandon a depleting food supply. We have used quantitative genetic analysis to examine the decision to leave a food patch in Caenorhabditis elegans. Here we show that patch-leaving is a multigenic trait regulated in part by naturally occurring non-coding polymorphisms in tyra-3 (tyramine receptor 3), which encodes a G-protein-coupled catecholamine receptor related to vertebrate adrenergic receptors. tyra-3 acts in sensory neurons that detect environmental cues, suggesting that the internal catecholamines detected by tyra-3 regulate responses to external conditions. These results indicate that genetic variation and environmental cues converge on common circuits to regulate behaviour, and suggest that catecholamines have an ancient role in regulating behavioural decisions.

Early redox imbalance is associated with liver dysfunction at weaning in overfed rats.

Neonatal overfeeding induced by litter size reduction leads to further obesity and other metabolic disorders, such as liver oxidative stress and microsteatosis at adulthood. We hypothesized that overfeeding causes an early redox imbalance at weaning, which could programme the animals to future liver dysfunction. Thus, we studied lipogenesis, adipogenesis, catecholamine status and oxidative balance in weaned overfed pups. To induce early overfeeding, litters were adjusted to three pups at the 3rd day of lactation (SL group). The control group contained 10 pups per litter until weaning (NL group). Peripheral autonomic nerve function was determined in vivo at 21 days old. Thereafter, pups were killed for further analysis. Differences were considered significant when P < 0.05. The SL pups presented with a higher visceral adipocyte area, higher content of lipogenic enzymes (ACC, FAS) and with a lower content of adipogenic factors (CEBP, PPARγ) in visceral adipose tissue (VAT). Although autonomic nerve activity and adrenal catecholamine production were not significantly altered, catecholamine receptor (ß3ADR) content was lower in VAT. The SL pups also presented with higher triglyceride, PPARγ, PPARα and PGC1α contents in liver. In plasma and liver, the SL pups showed an oxidative imbalance, with higher lipid peroxidation and protein oxidation. The SL group presented with a higher serum alanine aminotransferase (ALT). The early increase in lipogenesis in adipose tissue and liver in weaned overfed rats suggests that the higher oxidative stress and lower catecholamine content in VAT are associated with the early development of liver dysfunction and adipocyte hypertrophy.

Neuropeptides amplify and focus the monoaminergic inhibition of nociception in Caenorhabditis elegans.

Monoamines and neuropeptides interact to modulate most behaviors. To better understand these interactions, we have defined the roles of tyramine (TA), octopamine, and neuropeptides in the inhibition of aversive behavior in Caenorhabditis elegans. TA abolishes the serotonergic sensitization of aversive behavior mediated by the two nociceptive ASH sensory neurons and requires the expression of the adrenergic-like, Gαq-coupled, TA receptor TYRA-3 on inhibitory monoaminergic and peptidergic neurons. For example, TA inhibition requires Gαq and Gαs signaling in the peptidergic ASI sensory neurons, with an array of ASI neuropeptides activating neuropeptide receptors on additional neurons involved in locomotory decision-making. The ASI neuropeptides required for tyraminergic inhibition are distinct from those required for octopaminergic inhibition, suggesting that individual monoamines stimulate the release of different subsets of ASI neuropeptides. Together, these results demonstrate that a complex humoral mix of monoamines is focused by more local, synaptic, neuropeptide release to modulate nociception and highlight the similarities between the tyraminergic/octopaminergic inhibition of nociception in C. elegans and the noradrenergic inhibition of nociception in mammals that also involves inhibitory peptidergic signaling.

Involvement of multiple distinct Bordetella receptor proteins in the utilization of iron liberated from transferrin by host catecholamine stress hormones.

Bordetella bronchiseptica is a pathogen that can acquire iron using its native alcaligin siderophore system, but can also use the catechol xenosiderophore enterobactin via the BfeA outer membrane receptor. Transcription of bfeA is positively controlled by a regulator that requires induction by enterobactin. Catecholamine hormones also induce bfeA transcription and B. bronchiseptica can use the catecholamine noradrenaline for growth on transferrin. In this study, B. bronchiseptica was shown to use catecholamines to obtain iron from both transferrin and lactoferrin in the absence of siderophore. In the presence of siderophore, noradrenaline augmented transferrin utilization by B. bronchiseptica, as well as siderophore function in vitro. Genetic analysis identified BfrA, BfrD and BfrE as TonB-dependent outer membrane catecholamine receptors. The BfeA enterobactin receptor was found to not be involved directly in catecholamine utilization; however, the BfrA, BfrD and BfrE catecholamine receptors could serve as receptors for enterobactin and its degradation product 2,3-dihydroxybenzoic acid. Thus, there is a functional link between enterobactin-dependent and catecholamine-dependent transferrin utilization. This investigation characterizes a new B. bronchiseptica mechanism for iron uptake from transferrin that uses host stress hormones that not only deliver iron directly to catecholamine receptors, but also potentiate siderophore activity by acting as iron shuttles.

Effects of acute stress-induced immunomodulation on TH1/TH2 cytokine and catecholamine receptor expression in human peripheral blood cells.

AIMS: There is evidence that psychological stress can modulate immune functions. It has been hypothesized that acute stressors can affect both immune balance (including Th1 and Th2 cytokines) and expression of stress hormone receptors. This study investigated the impact of an acute stressor on gene expressions of glucocorticoid receptor (GR), and ß2-adrenergic receptor (ß2AR) in leukocytes. The effect on T regulatory cells (Treg), regulatory cytokines IL-10 and TGF-ß, Th1 and Th2 cytokines and their receptors IFN-γR and IL-4R was also studied. METHOD: Fourteen normal volunteers completed an acute laboratory stressor, and blood samples were collected before, immediately after, and 1, 2, 6 and 24 h after completion of the tasks. Cytokine production and Treg were determined by flow cytometry. Gene expressions of receptors were analyzed by real-time PCR. RESULTS: IFN-γ was increased immediately and 1 h after stressor (p<0.05, respectively) and upregulation of IFN-γR mRNA was noted at 2, 6 and 24 h (p<0.01, respectively). IL-10 was decreased at 2 h (p<0.01). There were no significant changes in post-task IL-4R, Treg, or TGF-ß. ß2AR mRNA was increased at 2, 6 and 24 h (p<0.01, respectively). On the other hand, no significant alterations were observed in GR expression. CONCLUSION: An acute stressor increased Th1 cytokine production and its receptor expression. ß2AR but not GR was significantly increased after an acute stressor, which supports the hypothesis that catecholamine-mediated signal pathways in communication with the central nervous and immune systems play a fundamental role in acute stress-mediated immune alterations.

Cardiovascular catecholamine receptors in children: their significance in cardiac disease.

Adrenoceptors and dopamine receptors are grouped together under the name 'catecholamine receptors.' Catecholamines and catecholaminergic drugs act on catecholamine receptors located on or near the cardiovascular system. The physiological effects of catecholamine receptor stimulation are only partly understood. The catecholaminergic drugs used in critical care medicine today are not selective, or are, at best, in part selective for the various catecholamine receptor subtypes. Many patients, however, depend on them. A variety of animal models has been developed to unravel catecholamine distribution and function. However, the identification of species heterogeneity makes it imperative to determine catecholamine receptor distribution and function in humans. In addition, age-related alterations in catecholamine receptor distribution and function have been identified in human adults. This might have implications for our understanding of the effect of catecholamines in pediatric patients. This article will focus on the pediatric population and will review currently available in vitro data on the distribution and the function of catecholamine receptors in the cardiovascular system of fetuses and children. Also discussed are relevant young animal models and in vivo hemodynamic effects of cardiotonic drugs acting on the catecholamine receptor in children requiring major cardiac surgery. A better understanding of these topics might provide clues for new, receptor subtype-selective, therapeutic approaches in newborns and children with cardiac disease.

Trimethylamine modulates dauer formation, neurodegeneration, and lifespan through tyra-3/daf-11 signaling in Caenorhabditis elegans.

In the nematode Caenorhabditis elegans, signals derived from bacteria in the diet, the animal's major nutrient source, can modulate both behavior and healthspan. Here we describe a dual role for trimethylamine (TMA), a human gut flora metabolite, which acts as a nutrient signal and a neurotoxin. TMA and its associated metabolites are produced by the human gut microbiome and have been suggested to serve as risk biomarkers for diabetes and cardiovascular diseases. We demonstrate that the tyramine receptor TYRA-3, a conserved G protein-coupled receptor (GPCR), is required to sense TMA and mediate its responses. TMA activates guanylyl cyclase DAF-11 signaling through TYRA-3 in amphid neurons (ASK) and ciliated neurons (BAG) to mediate food-sensing behavior. Bacterial mutants deficient in TMA production enhance dauer formation, extend lifespan, and are less preferred as a food source. Increased levels of TMA lead to neural damage in models of Parkinson's disease and shorten lifespan. Our results reveal conserved signaling pathways modulated by TMA in C. elegans that are likely to be relevant for its effects in mammalian systems.

Catecholamine levels and gene expression of their receptors in tissues of adults with osteosarcoma.

AIM: The purpose of this work was to identify and measure catecholamines, their metabolites, and the gene expression of catecholamine receptors in osteosarcoma tissue. MATERIALS AND METHODS: The levels of 3,4-dihydroxyphenylacetic acid, norepinephrine, serotonin, and 5-hydroxyindoleacetic acid in cancer tissue and in adjacent and non-oncological bone tissue were analysed by high-performance liquid chromatography, and the gene expression of catecholamine receptors and of dopamine ß-hydroxylase, monoaminoxidase, ki67, and Runx2 in the osteosarcoma tissue, tissue adjacent to the tumour, non-oncological bone, and human brain tissue was analysed by RT-PCR. RESULTS: We found significantly higher levels of 3,4-dihydroxyphenylacetic acid and norepinephrine in the cancer sample than in adjacent and non-oncological bone. We found that ß-adrenergic receptors and dopaminergic receptors, dopamine ß-hydroxylase, ki67, Runx2, and serotonergic receptor gene expression were significantly higher in tumour tissue than in adjacent and non-oncological bone. CONCLUSION: Catecholamines and their receptors could be potential molecular markers for osteosarcoma progression.

Time-course of changes in key catecholaminergic receptors and trophic systems in rat brain after antidepressant administration.

Several biochemical parameters within the brain are altered by antidepressants. However, it is still uncertain which parameters are important for the evaluation of the effectiveness of these drugs. What seems certain is that the response of the nervous system is dynamic. The dynamic nature of the nervous system is still poorly understood, although it has implications in clinical management. Criteria for evaluating treatment resistant depression are based on this temporal variability. The present study was designed to evaluate dynamic alterations in catecholaminergic receptors and calcyon (associated with monoaminergic theory of depression) in the rat brain as well as brain-derived neurotrophic factor (BDNF) and tyrosine kinase beta (TRKB; related to neurotrophin theory) induced by three antidepressant drugs (ADs) with various pharmacological profiles (imipramine, desipramine, and citalopram) administered for 21 days or acutely, followed by various drug-free periods. Receptor autoradiography and in situ hybridization studies allowed us to identify changes in various brain regions simultaneously in each rat. Repeated treatment with ADs induced biochemical alterations, which were in agreement with the results of previous studies. These alterations include the downregulation of ß1, ß2, and α1 adrenergic receptors, upregulation of α2-adrenergic receptors and dopamine D2 receptors, and increased expression of BDNF in the hippocampus. Additionally, we observed dynamic alterations in the measured parameters after acute drug administration, particularly at the level of dopamine receptors, which were extremely sensitive to a single dose of ADs followed by various drug-free periods. All three ADs induced the upregulation of dopamine D2 receptor mRNA levels in the nucleus accumbens. The same effect was induced by single doses of ADs followed by various drug-free periods. The obtained results indicate that alterations in the availability of neurotransmitters at synapses induced by ADs are strong enough to induce immediate and long-lasting adaptive changes in the neuronal network.

Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.

Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.

Brain neurotransmitter receptor-binding characteristics in rats after oral administration of haloperidol, risperidone and olanzapine.

The present study was conducted to characterize the binding of neurotransmitter receptors (dopamine D(2), serotonin 5-HT(2), histamine H(1), adrenaline alpha(1) and muscarine M(l) receptors) in the rat's brain after the oral administration of haloperidol, risperidone, and olanzapine. Haloperidol at 1 and 3 mg/kg displayed significant activity to bind the D(2) receptor (increase in the Kd value for [(3)H]raclopride binding) in the corpus striatum with little change in the activity toward the 5-HT(2) receptor (binding parameters for [(3)H]ketanserin). In contrast, risperidone (0.1-3 mg/kg) showed roughly 30 times more affinity for the 5-HT(2) receptor than D(2) receptor. Also, olanzapine (1-10 mg/kg) was most active toward the H(1) receptor in the cerebral cortex, corpus striatum, and hippocampus, was less active in binding 5-HT(2) and D(2) receptors, and showed the least affinity for alpha(1) and M(1) receptors. In conclusion, haloperidol and risperidone administered orally selectively bind D(2) and 5-HT(2) receptors, respectively, in the rat brain, while olanzapine binds H(1), 5-HT(2), and D(2) receptors more than alpha(1) and M(1) receptors.

An oxytocin-dependent social interaction between larvae and adult C. elegans.

Oxytocin has a conserved role in regulating animal social behaviour including parental-offspring interactions. Recently an oxytocin-like neuropeptide, nematocin, and its cognate receptors have been identified in the nematode Caenorhabditis elegans. We provide evidence for a pheromone signal produced by C. elegans larvae that modifies the behaviour of adult animals in an oxytocin-dependent manner increasing their probability of leaving a food patch which the larvae are populating. This increase is positively correlated to the size of the larval population but cannot be explained by food depletion nor is it modulated by biogenic amines, which suggest it is not an aversive behaviour. Moreover, the food-leaving behaviour is conspecific and pheromone dependent: C. elegans adults respond more strongly to C. elegans larvae compared to other nematode species and this effect is absent in C. elegans daf-22 larvae which are pheromone deficient. Neurotransmitter receptors previously implicated in C. elegans foraging decisions NPR-1 and TYRA-3, for NPY-like neuropeptides and tyramine respectively, do not appear to be involved in oxytocin-dependent adult food-leaving. We conclude oxytocin signals within a novel neural circuit that regulates parental-offspring social behaviour in C. elegans and that this provides evidence for evolutionary conservation of molecular components of a parental decision making behaviour.

Catecholaminergic A1/C1 neurons contribute to the maintenance of upper airway muscle tone but may not participate in NREM sleep-related depression of these muscles.

Neural mechanisms of obstructive sleep apnea, a common sleep-related breathing disorder, are incompletely understood. Hypoglossal motoneurons, which provide tonic and inspiratory activation of genioglossus (GG) muscle (a major upper airway dilator), receive catecholaminergic input from medullary A1/C1 neurons. We aimed to determine the contribution of A1/C1 neurons in control of GG muscle during sleep and wakefulness. To do so, we placed injections of a viral vector into DBH-cre mice to selectively express the hMD4i inhibitory chemoreceptors in A1/C1 neurons. Administration of the hM4Di ligand, clozapine-N-oxide (CNO), in these mice decreased GG muscle activity during NREM sleep (F1,1,3=17.1, p<0.05); a similar non-significant decrease was observed during wakefulness. CNO administration had no effect on neck muscle activity, respiratory parameters or state durations. In addition, CNO-induced inhibition of A1/C1 neurons did not alter the magnitude of the naturally occurring depression of GG activity during transitions from wakefulness to NREM sleep. These findings suggest that A1/C1 neurons have a net excitatory effect on GG activity that is most likely mediated by hypoglossal motoneurons. However, the activity of A1/C1 neurons does not appear to contribute to NREM sleep-related inhibition of GG muscle activity, suggesting that A1/C1 neurons regulate upper airway patency in a state-independent manner.

Elevated central monoamine receptor mRNA in rats bred for high endurance capacity: implications for central fatigue.

Although alteration to peripheral systems at the skeletal muscle level can contribute to one's ability to sustain endurance capacity, neural circuits regulating fatigue may also play a critical role. Previous studies demonstrated that increasing brain serotonin (5-HT) release is sufficient to hasten the onset of exercise-induced fatigue, while manipulations that increase brain dopamine (DA) release can delay the onset of fatigue. These results suggest that individual differences in endurance capacity could be due to factors capable of influencing the activity of 5-HT and DA systems. We evaluated possible differences in central fatigue pathways between two contrasting rat groups selectively bred for high (HCR) or low (LCR) capacity running. Using quantitative in situ hybridization, we measured messenger RNA (mRNA) levels of tryptophan hydroxylase (TPH), 5-HT transporter (5-HTT), 5-HT1A and 5-HT1B autoreceptors, dopamine receptor-D2 (DR-D2) autoreceptors and postsynaptic receptors, and dopamine receptor-D1 (DR-D1) postsynaptic receptors, in discrete brain regions of HCR and LCR. HCR expressed higher levels of 5-HT1B autoreceptor mRNA in the raphe nuclei relative to LCR, but similar levels of TPH, 5-HTT, and 5-HT1A mRNA in these areas. Surprisingly, HCR expressed higher levels of DR-D2 autoreceptor mRNA in the midbrain, while simultaneously expressing greater DR-D2 postsynaptic mRNA in the striatum compared to LCR. There were no differences in DR-D1 mRNA levels in the striatum or cortex between groups. These data suggest that central serotonergic and dopaminergic systems may be involved in the mechanisms by which HCR have delayed onset of exercise-induced fatigue compared to LCR.

Takotsubo cardiomyopathy.

Recently, many reports have been published about apical ballooning or takotsubo cardiomyopathy. This disease is a new entity of acute reversible heart failure. Abnormal catecholamine dynamics due to stress may be the primary cause of this condition.

Catecholaminergic based therapies for functional recovery after TBI.

Among the many pathophysiologic consequences of traumatic brain injury are changes in catecholamines, including dopamine, epinephrine, and norepinephrine. In the context of TBI, dopamine is the one most extensively studied, though some research exploring epinephrine and norepinephrine have also been published. The purpose of this review is to summarize the evidence surrounding use of drugs that target the catecholaminergic system on pathophysiological and functional outcomes of TBI using published evidence from pre-clinical and clinical brain injury studies. Evidence of the effects of specific drugs that target catecholamines as agonists or antagonists will be discussed. Taken together, available evidence suggests that therapies targeting the catecholaminergic system may attenuate functional deficits after TBI. Notably, it is fairly common for TBI patients to be treated with catecholamine agonists for either physiological symptoms of TBI (e.g. altered cerebral perfusion pressures) or a co-occuring condition (e.g. shock), or cognitive symptoms (e.g. attentional and arousal deficits). Previous clinical trials are limited by methodological limitations, failure to replicate findings, challenges translating therapies to clinical practice, the complexity or lack of specificity of catecholamine receptors, as well as potentially counfounding effects of personal and genetic factors. Overall, there is a need for additional research evidence, along with a need for systematic dissemination of important study details and results as outlined in the common data elements published by the National Institute of Neurological Diseases and Stroke. Ultimately, a better understanding of catecholamines in the context of TBI may lead to therapeutic advancements. This article is part of a Special Issue entitled SI:Brain injury and recovery.