SciCombinator

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Concept: Norepinephrine

216

Musical performance is a skilled activity performed under intense pressure, thus is often a profound source of anxiety. In other contexts, anxiety and its concomitant symptoms of sympathetic nervous system arousal have been successfully ameliorated with HRV biofeedback (HRV BF), a technique involving slow breathing which augments autonomic and emotional regulatory capacity. Objective: This randomised-controlled study explored the impact of a single 30-minute session of HRV BF on anxiety in response to a highly stressful music performance.

Concepts: Psychology, Brain, Autonomic nervous system, Sympathetic nervous system, Norepinephrine, Music, Parasympathetic nervous system

191

We describe a disease encompassing infantile-onset movement disorder (including severe parkinsonism and nonambulation), mood disturbance, autonomic instability, and developmental delay, and we describe evidence supporting its causation by a mutation in SLC18A2 (which encodes vesicular monoamine transporter 2 [VMAT2]). VMAT2 translocates dopamine and serotonin into synaptic vesicles and is essential for motor control, stable mood, and autonomic function. Treatment with levodopa was associated with worsening, whereas treatment with direct dopamine agonists was followed by immediate ambulation, near-complete correction of the movement disorder, and resumption of development.

Concepts: Parkinson's disease, Neurotransmitter, Serotonin, Transport, Dopamine, Norepinephrine, Monoamine transporter, Monoamine neurotransmitter

169

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/-) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/-) and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.

Concepts: Alcoholism, Nicotine, Enzyme inhibitor, Neurotransmitter, Inhibitor, Dopamine, Norepinephrine, Cocaine

165

Modafinil, in its two clinical formulations (Provigil(®) and Nuvigil(®)), is a widely prescribed wake-promoting therapeutic agent. It binds competitively to the cell-membrane dopamine (DA) transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. The clinical spectrum of effects for modafinil is distinct from the effects seen with other catecholaminergic agents. Relative to other commonly used agents that act through catecholaminergic mechanisms, modafinil has a relatively low abuse potential, produces wakefulness with an attenuated compensatory sleep recovery thereafter, and does not ameliorate cataplexy in narcolepsy. These clinically relevant phenomenological differences between modafinil and agents such as amphetamines and cocaine do not eliminate catecholaminergic effects as a possible mediator of its wake-promoting action; they merely reflect its unique pharmacological profile. Modafinil is an exceptionally weak, but apparently very selective, DA transporter inhibitor. The pharmacodynamic response to modafinil, as measured by DA levels in brain microdialyzate, is protracted relative to other agents that act via catecholaminergic mechanisms. The conformational constraints on the interaction of modafinil with the DA transporter - and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell - are unique among catecholaminergic agents. These unique pharmacological properties of modafinil should be considered both in seeking to thoroughly understand its putatively elusive mechanism of action and in the design of novel therapeutic agents.

Concepts: Pharmacology, Attention-deficit hyperactivity disorder, Dopamine, Norepinephrine, Cocaine, Methamphetamine, Narcolepsy, Therapeutic index

133

In a simulation experiment we studied the effects of cognitive, emotional, sensorimotor, and mixed stressors on driver arousal and performance with respect to (wrt) baseline. In a sample of n = 59 drivers, balanced in terms of age and gender, we found that all stressors incurred significant increases in mean sympathetic arousal accompanied by significant increases in mean absolute steering. The latter, translated to significantly larger range of lane departures only in the case of sensorimotor and mixed stressors, indicating more dangerous driving wrt baseline. In the case of cognitive or emotional stressors, often a smaller range of lane departures was observed, indicating safer driving wrt baseline. This paradox suggests an effective coping mechanism at work, which compensates erroneous reactions precipitated by cognitive or emotional conflict. This mechanisms' grip slips, however, when the feedback loop is intermittently severed by sensorimotor distractions. Interestingly, mixed stressors did not affect crash rates in startling events, suggesting that the coping mechanism’s compensation time scale is above the range of neurophysiological latency.

Concepts: Psychology, Effect, Neuroscience, Feedback, Sympathetic nervous system, Emotion, Norepinephrine, Driver's license

124

Brown adipose tissue (BAT) plays a central role in regulating energy homeostasis, and may provide novel strategies for the treatment of human obesity. BAT-mediated thermogenesis is regulated by mitochondrial uncoupling protein 1 (UCP1) in classical brown and ectopic beige adipocytes, and is controlled by sympathetic nervous system (SNS). Previous work indicated that fish oil intake reduces fat accumulation and induces UCP1 expression in BAT; however, the detailed mechanism of this effect remains unclear. In this study, we investigated the effect of fish oil on energy expenditure and the SNS. Fish oil intake increased oxygen consumption and rectal temperature, with concomitant upregulation of UCP1 and the β3 adrenergic receptor (β3AR), two markers of beige adipocytes, in the interscapular BAT and inguinal white adipose tissue (WAT). Additionally, fish oil intake increased the elimination of urinary catecholamines and the noradrenaline (NA) turnover rate in interscapular BAT and inguinal WAT. Furthermore, the effects of fish oil on SNS-mediated energy expenditure were abolished in transient receptor potential vanilloid 1 (TRPV1) knockout mice. In conclusion, fish oil intake can induce UCP1 expression in classical brown and beige adipocytes via the SNS, thereby attenuating fat accumulation and ameliorating lipid metabolism.

Concepts: Metabolism, Fat, Adipose tissue, Epinephrine, Norepinephrine, Brown adipose tissue, Thermogenesis, Uncoupling protein

57

Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.

Concepts: Selective serotonin reuptake inhibitor, Bipolar disorder, Norepinephrine, Bupropion, Sertraline

56

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses.

Concepts: Scientific method, Environment, Natural environment, Neurotransmitter, Dopamine, Norepinephrine, Amphetamine, Bayesian probability

45

Impairments in metacognition, the ability to accurately report one’s performance, are common in patients with psychiatric disorders, where a putative neuromodulatory dysregulation provides the rationale for pharmacological interventions. Previously, we have shown how unexpected arousal modulates metacognition (Allen et al., 2016). Here, we report a double-blind, placebo-controlled, study that examined specific effects of noradrenaline and dopamine on both metacognition and perceptual decision making. Signal theoretic analysis of a global motion discrimination task with adaptive performance staircasing revealed that noradrenergic blockade (40 mg propranolol) significantly increased metacognitive performance (type-II area under the curve, AUROC2), but had no impact on perceptual decision making performance. Blockade of dopamine D2/3 receptors (400 mg amisulpride) had no effect on either metacognition or perceptual decision making. Our study is the first to show a pharmacological enhancement of metacognitive performance, in the absence of any effect on perceptual decision making. This enhancement points to a regulatory role for noradrenergic neurotransmission in perceptual metacognition.

Concepts: Cognition, Neurotransmitter, Attention-deficit hyperactivity disorder, Epinephrine, Dopamine, Norepinephrine, Adrenergic receptor, Neuropsychological assessment

43

Slow, controlled breathing has been used for centuries to promote mental calming, and it is used clinically to suppress excessive arousal such as panic attacks. However, the physiological and neural basis of the relationship between breathing and higher-order brain activity is unknown. We found a neuronal subpopulation in the mouse preBötzinger complex (preBötC), the primary breathing rhythm generator, which regulates the balance between calm and arousal behaviors. Conditional, bilateral genetic ablation of the ~175 Cdh9/Dbx1 double-positive preBötC neurons in adult mice left breathing intact but increased calm behaviors and decreased time in aroused states. These neurons project to, synapse on, and positively regulate noradrenergic neurons in the locus coeruleus, a brain center implicated in attention, arousal, and panic that projects throughout the brain.

Concepts: Nervous system, Neuron, Brain, Human brain, Axon, Neurotransmitter, Dopamine, Norepinephrine