Harmine is an effective therapeutic small molecule for the treatment of cardiac hypertrophy.

Harmine is a ß-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.

Participation of the descending noradrenergic inhibitory system in the anti-hyperalgesic effect of acetaminophen in a rat model of inflammation.

AIMS: This study investigated the relationship between the analgesic efficacy of acetaminophen and the descending noradrenergic systems using rodent models of inflammatory pain. MAIN METHODS: Inflammatory pain models were established by carrageenan injection into rats' paws. The models were defined as acute (4 h after carrageenan injection), subacute (24 h after carrageenan injection), and late (1 week after carrageenan injection) phase. To evaluate intravenous acetaminophen treatment, the withdrawal threshold to mechanical stimuli was assessed simultaneously with in vivo microdialysis assay of noradrenaline levels in the locus coeruleus (LC). Further analyses were performed to observe the effect of yohimbine on the treatment and the impact of AM404 treatment, a metabolite of acetaminophen, on noradrenaline levels in the LC. KEY FINDINGS: In all phases, intravenous acetaminophen had a significant anti-hyperalgesic effect (p < 0.05). There was a significant time-dependent increase in the noradrenaline concentration within the LC (acetaminophen versus saline treatment; at 30 min, p < 0.001; 60 min, p < 0.01) in the subacute pain model, but not in the acute and late phase pain models. Intrathecal pre-injection of yohimbine attenuated the anti-hyperalgesic effect after acetaminophen injection only in the subacute model (p < 0.05). In the subacute pain model, intracerebroventricular administration of AM404 showed the same trend in noradrenaline levels as acetaminophen administration (AM404 versus vehicle group at 30 min, p < 0.001). SIGNIFICANCE: We found the descending noradrenergic inhibitory system is involved in the antinociceptive action of acetaminophen in the subacute phase of inflammatory pain.

Discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and structurally related synthetic cathinones.

The 3,4-methylenedioxypyrovalerone (MDPV), and other structurally related synthetic cathinones, are popular alternatives to prototypical illicit psychostimulants, such as cocaine and methamphetamine. These drugs are often referred to as 'bath salts' and function either as cocaine-like inhibitors of monoamine uptake, or amphetamine-like substrates for dopamine, norepinephrine and serotonin transporters. These studies used male Sprague-Dawley rats trained to discriminate MDPV from saline to evaluate the substitution profiles of structurally related synthetic cathinones, cocaine, and other direct-acting dopamine and noradrenergic receptor agonists in order to characterize the relative contributions of dopamine, norepinephrine and serotonin to the discriminative stimulus effects of MDPV. As expected, each of the cathinones and cocaine dose-dependently increased MDPV-appropriate responding, with a rank-order potency that was positively correlated with their potency to inhibit dopamine and norepinephrine, but not serotonin, a relationship that is consistent with the rank order to maintain self-administration. The dopamine D2/3 receptor-preferring agonist quinpirole produced a modest increase in MDPV-appropriate responding, whereas the dopamine D1/5 receptor agonist, SKF 82958, nonselective dopamine receptor agonist, apomorphine, as well as the α-1, and α-2 adrenergic receptor agonists, phenylephrine and clonidine, respectively, failed to increase MDPV-appropriate responding at doses smaller than those that suppressed responding altogether. Although these studies do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV, convergent evidence is provided to suggest that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit dopamine uptake, and the subsequent activation of dopamine D2 or D3 receptors.

Neuropharmacological and antidepressant-like effects of ZY-1408: A novel serotonin/norepinephrine reuptake inhibitor and serotonin receptor 2C antagonist.

Depression is a common mental illness and leading cause of disability. Most current antidepressants are associated with significant limitations, and in particular, a delayed onset and low rate of efficacy. Consequently, there remains an ongoing need for antidepressants that are either more effective or better tolerated than existing standards. We previously identified ZY-1408 as a drug with a novel chemical structure and potential anti-depressant-like activity. Specifically, ZY-1408 is a novel serotonin 2C (5-HT2C) receptor antagonist and serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. In this study, we further investigated the antidepressant-like efficacy of ZY-1408 using in vitro and in vivo behavioral tests. ZY-1408 showed 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor properties in vitro. Meanwhile, ZY-1408 decreased immobility in vivo in a dose-dependent manner in rats (via the forced-swim test) and mice (via the tail-suspension test). The behavioral test results do not appear to result from stimulation of locomotor activity. In chronically stressed rats, repeated ZY-1408 treatment significantly reversed depressive-like behavior, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis showed that administration of ZY-1408 significantly increased extracellular concentrations of 5-HT and NE in the hippocampus of freely moving rats. Thus, ZY-1408 is a potent and orally active 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor with antidepressant-like activity in rodents.

Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release.

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca2+ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca2+ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca2+ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca2+ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication.

Corticotropin releasing factor, but not alcohol, modulates norepinephrine release in the rat central nucleus of the amygdala.

Alcohol misuse and dependence is a widespread health problem. The central nucleus of the amygdala (CeA) plays important roles in both the anxiety associated with alcohol (ethanol) dependence and the increased alcohol intake that is observed during withdrawal in dependent animals. We and others have shown the essential involvement of the corticotropin releasing factor (CRF) system in alcohol's synaptic effects on the CeA and in the development of ethanol dependence. Another system that has been shown to be critically involved in the molecular underpinnings of alcohol dependence is the norepinephrine (NE) system originating in the locus coeruleus. Both the CRF and NE systems act in concert to facilitate a stress response: central amygdalar afferents release CRF in the locus coeruleus promoting widespread release of NE. In this study, we are the first to use fast-scan cyclic voltammetry to classify local electrically-evoked NE release in the CeA and to determine if acute alcohol and CRF modulate it. Evoked NE release is action potential dependent, is abolished after depletion of monoaminergic vesicles, differs pharmacologically from dopamine release, is insensitive to acute alcohol, and decreases in response to locally applied CRF. Taken together, these results indicate that NE release in the CeA is released canonically in a vesicular-dependent manner, and that while acute alcohol does not directly alter NE release, CRF decreases it. Our results suggest that CRF acts locally on NE terminals as negative feedback and potentially prevents hyperactivation of the CRF-norepinephrine stress pathway.

Pharmacological depletion of serotonin and norepinephrine with para-chlorophenylalanine and alpha-methyl-p-tyrosine reverses the antidepressant-like effects of adolescent caffeine exposure in the male rat.

Adolescent exposure to caffeine has been shown to decrease immobility in the forced swim test, suggesting and antidepressant-like effect of caffeine; however, studies have produced different results with regard to caffeine-induced active behaviors. The present study attempted to clarify the possible neurochemical mechanisms of caffeine's action by selectively depleting norepinephrine with alpha-methyl-p-tyrosine or serotonin with para-chlorophenylalanine in two separate experiments and assessing the ability for caffeine to alter anxiety-like and depressive-like behavior. Caffeine-treated adolescent male rats were exposed to caffeine (0.25 g/L) in their drinking water beginning on P28. A-methyl-p-tyrosine, para-chlorophenylalanine, or saline were administered prior to light-dark, open field, and forced swim testing beginning on P45. Caffeine-induced reductions in immobility and increases in swimming in the forced swim test were reversed by both a-methyl-p-tyrosine and para-chlorophenylalanine. Caffeine-induced increases in crosses and rears were reversed by para-chlorophenylalanine but not alpha-methyl-p-tyrosine, whereas caffeine-induced increases in transitions in the LD test were reversed by alpha-methyl-p-tyrosine but not para-chlorophenylalanine. Taken together, these results suggest that caffeine-induced decreases in immobility in male rats requires both norepinephrine and serotonin as depletion of either prevents the induction of immobility by chronic caffeine.

Noradrenergic tone mediates marble burying behavior after chronic stress and ethanol.

RATIONALE: Stress plays a major role in the development of alcohol use disorder (AUD)-a history of chronic stress contributes to alcohol misuse, and withdrawal from alcohol elevates stress, perpetuating cycles of problematic drinking. Recent studies have shown that, in male mice, repeated chronic intermittent ethanol (CIE) and stress elevates alcohol use above either manipulation alone and impacts cognitive functions such as behavioral flexibility. OBJECTIVE: Here, we investigated the impact of CIE and stress on anxiety in both sexes, and whether the norepinephrine (NE) system via locus coeruleus, which is implicated in both stress and alcohol motivation, is involved. RESULTS: Male and female mice received multiple cycles of CIE and/or repeated forced swim stress (FSS), producing elevated drinking in both sexes. CIE/FSS treatment increased anxiety, which was blocked by treatment with the α1-AR inverse agonist prazosin. In contrast, administration of the corticotropin releasing factor receptor antagonist CP376395 into locus coeruleus did not reduce CIE/FSS-elevated anxiety. We also observed sex differences in behavioral responses to a history of CIE or FSS alone as well as differential behavioral consequences of prazosin treatment. CONCLUSIONS: These data indicate that NE contributes to the development of anxiety following a history of alcohol and/or stress, and that the influence of both treatment history and NE signaling is sex dependent. These results argue for further investigation of the NE system in relation to disrupted behavior following chronic alcohol and stress, and support the assertion that treatments may differ across sex based on differential neural system engagement.

Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma.

Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An in vitro assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-ß-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2.

A systematic review on the genotoxic effect of serotonin and norepinephrine reuptake inhibitors (SNRIs) antidepressants.

RATIONALE: Depression is a major mental disorder affecting millions of people worldwide. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are one of the antidepressant drugs prescribed for depression treatment. OBJECTIVE AND METHOD: There are many contradiction studies about the adverse effect and genotoxicity of SNRIs. So here, based on the guidelines proposed at the PRISMA statement, we performed a quantitative systematic review by searching international electronic databases (PubMed, Scopus, Embase, and Web of Science) for published documents on SSNRIs and their genotoxicity effects. RESULTS: The database searches retrieved 336 records, 18 of which met the inclusion criteria. Evaluation of the selected articles showed that a total of 9 articles were appropriate for final review. Most of these studies (78%) reported positive results for the genotoxicity of SNRIs CONCLUSION: Finally, we can conclude that these drugs have the potential to damage DNA.

Noradrenergic projections from the locus coeruleus to the amygdala constrain fear memory reconsolidation.

Memory reconsolidation is a fundamental plasticity process in the brain that allows established memories to be changed or erased. However, certain boundary conditions limit the parameters under which memories can be made plastic. Strong memories do not destabilize, for instance, although why they are resilient is mostly unknown. Here, we investigated the hypothesis that specific modulatory signals shape memory formation into a state that is reconsolidation-resistant. We find that the activation of the noradrenaline-locus coeruleus system (NOR-LC) during strong fear memory encoding increases molecular mechanisms of stability at the expense of lability in the amygdala of rats. Preventing the NOR-LC from modulating strong fear encoding results in the formation of memories that can undergo reconsolidation within the amygdala and thus are vulnerable to post-reactivation interference. Thus, the memory strength boundary condition on reconsolidation is set at the time of encoding by the action of the NOR-LC.

New memories must go through a period of consolidation to become stable and long-lasting in the brain. Recalling memories can make them unstable again, so that they need reconsolidating. Treatments in which the reconsolidation process is interrupted have been used to help weaken traumatic fear memories. However, memories of severe trauma, such as in post-traumatic stress disorder, are particularly resistant to reconsolidation treatments. Haubrich et al. used rats to study how trauma shapes memory formation and what biological mechanisms are involved in preventing the destabilization/reconsolidation cycle. The rats were exposed to a sound at the same time as receiving a mild electric shock. Half of the rats experienced the shock once, creating a 'weak' memory. The other half experienced it ten times, creating a 'strong' memory. The rats' memory of the electric shock was measured by seeing how they responded when they heard the sound again without the shock. Some of the rats were given the drug anisomycin, an antibiotic that stops cells from making new proteins and is known for producing amnesia, to block reconsolidation of the memory after hearing the sound again. Treatment with the drug reduced future responses in the rats that had experienced the shock once, but had no effect on the rats that had experienced it ten times, demonstrating that the stronger memories were resistant to reconsolidation therapy. The rats with the strong memories also had lower levels of proteins in the brain that are involved in plasticity ­ the ability of the brain to change and adapt. Haubrich et al. hypothesized that the stability of the strong memories could be caused by signaling from the locus coeruleus, a region of the brainstem involved in the response to stress. When the signaling from the locus coeruleus was blocked in the strong-memory rats, they became responsive to reconsolidation therapy with anisomycin. These results help to better understand how traumatic memories become engrained, potentially leading to new treatment options for people with post-traumatic stress disorder.

Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder.

RATIONALE: Obsessive-compulsive disorder (OCD) is characterized by repetitive behaviors exacerbated by stress. Many OCD patients do not respond to available pharmacotherapies, but neurosurgical ablation of the anterior cingulate cortex (ACC) can provide symptomatic relief. Although the ACC receives noradrenergic innervation and expresses adrenergic receptors (ARs), the involvement of norepinephrine (NE) in OCD has not been investigated. OBJECTIVE: To determine the effects of genetic or pharmacological disruption of NE neurotransmission on marble burying (MB) and nestlet shredding (NS), two animal models of OCD. METHODS: We assessed NE-deficient (Dbh -/-) mice and NE-competent (Dbh +/-) controls in MB and NS tasks. We also measured the effects of anti-adrenergic drugs on NS and MB in control mice and the effects of pharmacological restoration of central NE in Dbh -/- mice. Finally, we compared c-fos induction in the locus coeruleus (LC) and ACC of Dbh -/- and control mice following both tasks. RESULTS: Dbh -/- mice virtually lacked MB and NS behaviors seen in control mice but did not differ in the elevated zero maze (EZM) model of general anxiety-like behavior. Pharmacological restoration of central NE synthesis in Dbh -/- mice completely rescued NS behavior, while NS and MB were suppressed in control mice by anti-adrenergic drugs. Expression of c-fos in the ACC was attenuated in Dbh -/- mice after MB and NS. CONCLUSION: These findings support a role for NE transmission to the ACC in the expression of stress-induced compulsive behaviors and suggest further evaluation of anti-adrenergic drugs for OCD is warranted.

[Discontinuation of SSRIs and SNRIs]. / Het afbouwen van SSRI's en SNRI's.

Interruption or abrupt discontinuation of the use of antidepressants may lead to withdrawal symptoms. These are most common with selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs).There is insufficient scientific evidence about the prevalence of antidepressant withdrawal symptoms and how to optimally discontinue antidepressants. The multidisciplinary document 'Discontinuation of SSRIs & SNRIs' offers a rationale and suggestions for the gradual tapering of these antidepressants. The following factors are consistently named as risk factors for the occurrence of withdrawal symptoms: (a) the patient experiences withdrawal symptoms in case of non-compliance or skipped doses; (b) a previous attempt to stop was unsuccessful; and (c) the patient is being treated with higher doses than the smallest effective dose of SSRIs or SNRIs. In patients with one or more risk factors, a tapering schedule with non-linear dose-reduction steps should be considered. The speed at which these steps are taken, should be adjusted depending on occurrence of withdrawal symptoms. Shared decision-making by patient and physician is the best way to select a tapering schedule.

Effects of 5-HT2C receptor modulation and the NA reuptake inhibitor atomoxetine in tests of compulsive and impulsive behaviour.

Drug repositioning has gained strategic value as a reaction to high attrition rates of new drugs as they pass through the clinical development process. The 5-HT2C receptor agonist lorcaserin (Belviq®), and the selective NA reuptake inhibitor atomoxetine (Strattera®) represent two drugs FDA approved for obesity and ADHD respectively. Although both drugs are of differing pharmacological class, each share a property of regulating impulsive behaviours in preclinical studies, and thus represent candidates for consideration in clinical conditions labelled as 'impulsive-compulsive disorders'. The present studies investigated both drugs, as well as the highly selective 5-HT2C agonist CP-809101 in two tests of compulsive action: schedule-induced polydipsia (SIP) and increased perseverative [PSV] (and premature [PREM]) responses emitted during an extended ITI 5-choice task. While lorcaserin (0.06-0.6 mg/kg), CP-809101 (0.1-1 mg/kg) and atomoxetine (0.1-1 mg/kg) each reduced both PREM and PSV measures in the 5-choice task, at equivalent doses only lorcaserin and CP-809101 affected excessive water intake in the SIP task, atomoxetine (0.1-2 mg/kg) was essentially ineffective. Further evidence supporting a role of the 5-HT2C receptor as an important regulator of impulsive-compulsive behaviours, the selective antagonist SB-242084 produced the opposing effects to lorcaserin, i.e promoting both impulsive and compulsive behaviours. The profile of atomoxetine may suggest differences in the nature of compulsive action measured either as non-regulatory drinking in the SIP task, and PSV responses made in a 5-choice task. These studies support the consideration of 5-HT2C receptor agonists, typified by lorcaserin, and atomoxetine as potential treatments for clinical conditions categorised as 'impulsive-compulsive disorders'. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Amitifadine, a triple reuptake inhibitor, reduces self-administration of the opiate remifentanil in rats.

RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.

Kava and its Kavalactones Inhibit Norepinephrine-induced Intracellular Calcium Influx in Lung Cancer Cells.

Kava, the extract of the roots of Piper methysticum, has been traditionally consumed in the South Pacific islands for its natural relaxing property. Epidemiological data suggests that kava consumption may reduce human cancer risk, and in vitro and in vivo models suggest chemopreventive potential against carcinogen-induced tumorigenesis. Therefore, knowledge about its molecular mechanisms and responsible ingredient(s) for these beneficial properties will better guide kava's use for the management of these disorders. Psychological stress typically results in increased production of stress hormones, such as norepinephrine (NE), which activate adrenergic receptors (ARs). Psychological stress has also been associated with increased cancer incidence and poor clinical outcomes in cancer patients. Mechanistically, binding of NE to ARs induces intracellular calcium influx, which activates downstream signaling pathways involved in both stress and cancer development. In this study, we characterized the effect of kava and its components, 3 fractions and 6 major kavalactones, on NE-induced intracellular calcium influx in H1299, a human non-small cell lung carcinoma cell line. Results show that kava extract effectively inhibits NE-mediated intracellular calcium influx in H1299 cells, potentially through antagonizing ß-AR signaling. This inhibitory activity is recapitulated by the major kavalactones in kava. Among the 6 major kavalactones, DHK demonstrated the best potency. Taken together, our study suggests a novel mechanism through which kava and its ingredients potentially offer the anxiolytic and cancer-preventive activity.

Diverse Effects of Noradrenaline and Adrenaline on the Quantal Secretion of Acetylcholine at the Mouse Neuromuscular Junction.

Despite the long history of investigations of adrenergic compounds and their biological effects, specific mechanisms of their action in distinct compartments of the motor unit remain obscure. Recent results have suggested that not only skeletal muscles but also the neuromuscular junctions represent important targets for the action of catecholamines. In this paper, we describe the effects of adrenaline and noradrenaline on the frequency of miniature endplate potentials, the quantal content of the evoked endplate potentials and the kinetics of acetylcholine quantal release in the motor nerve endings of the mouse diaphragm. Noradrenaline and adrenaline decreased the frequency of the spontaneous release of acetylcholine quanta. The effect of noradrenaline was prevented by the ß adrenoreceptor blocker propranolol, whereas the action of adrenaline was abolished by the α adrenoreceptor antagonist phentolamine. Noradrenaline did not alter the quantal content of endplate potentials, while adrenaline suppressed the evoked release of acetylcholine. Blocking the α adrenoreceptors prevented the decrease in quantal secretion caused by adrenaline. Quantal release became more asynchronous under noradrenaline, as evidenced by a greater dispersion of real synaptic delays; in contrast, adrenaline synchronized the release process. Our data suggest an involvement of α and ß adrenoreceptors in the diverse modulation of the frequency of miniature endplate potentials, the quantal content of the evoked endplate potentials and the kinetics of acetylcholine quantal secretion in the mouse neuromuscular junction. Moreover, the adrenoblockers affected both the evoked and spontaneous quantal release of acetylcholine, suggesting the presence of endogenous catecholamines in the vicinity of cholinergic synapses.

Norepinephrine upregulates the expression of tyrosine hydroxylase and protects dopaminegic neurons against 6-hydrodopamine toxicity.

As a classic neurotransmitter in the brain, norepinephrine (NE) also is an important modulator to other neuronal systems. Using primary cultures from rat ventral mesencephalon (VM) and dopaminergic cell line MN9D, the present study examined the neuroprotective effects of NE and its effects on the expression of tyrosine hydroxylase (TH). The results showed that NE protected both VM cultures and MN9D cells against 6-hydroxydopamine-caused apoptosis, with possible involvement of adrenal receptors. In addition, treatment with NE upregulated TH protein levels in dose- and time-dependent manner. Further experiments to investigate the potential mechanisms underlying this NE-induced upregulation of TH demonstrated a marked increase in protein levels of the brain-derived neurotrophic factor (BDNF) and the phosphorylated extracellular signal-regulated protein kinase 1 and 2 (pERK1/2) in VM cultures treated with NE. In MN9D cells, a significantly increase of TH and pERK1/2 protein levels were observed after their transfection with BDNF cDNA or exposure to BDNF peptides. Treatment of VM cultures with K252a, an antagonist of the tropomyosin-related kinase B, blocked the upregulatory effects of NE on TH, BDNF and pERK1/2. Administration of MEK1 & MEK2 inhibitors also reversed NE-induced upregulation of TH and pERK1/2. Moreover, ChIP assay showed that treatment with NE or BDNF increased H4 acetylation in the TH promoter. These results suggest that the neuroprotection and modulation of NE on dopaminergic neurons are mediated via BDNF and MAPK/ERK pathways, as well as through epigenetic histone modification, which may have implications for the improvement of therapeutic strategies for Parkinson's disease.

Activation of alpha-1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus.

Norepinephrine (NE) activates adrenergic receptors (ARs) in the hypothalamic paraventricular nucleus (PVN) to increase excitatory currents, depolarise neurones and, ultimately, augment neuro-sympathetic and endocrine output. Such cellular events are known to potentiate intracellular calcium ([Ca2+ ]i ); however, the role of NE with respect to modulating [Ca2+ ]i in PVN neurones and the mechanisms by which this may occur remain unclear. We evaluated the effects of NE on [Ca2+ ]i of acutely isolated PVN neurones using Fura-2 imaging. NE induced a slow increase in [Ca2+ ]i compared to artificial cerebrospinal fluid vehicle. NE-induced Ca2+ elevations were mimicked by the α1 -AR agonist phenylephrine (PE) but not by α2 -AR agonist clonidine (CLON). NE and PE but not CLON also increased the overall number of neurones that increase [Ca2+ ]i (ie, responders). Elimination of extracellular Ca2+ or intracellular endoplasmic reticulum Ca2+ stores abolished the increase in [Ca2+ ]i and reduced responders. Blockade of voltage-dependent Ca2+ channels abolished the α1 -AR induced increase in [Ca2+ ]i and number of responders, as did inhibition of phospholipase C inhibitor, protein kinase C and inositol triphosphate receptors. Spontaneous phasic Ca2+ events, however, were not altered by NE, PE or CLON. Repeated K+ -induced membrane depolarisation produced repetitive [Ca2+ ]i elevations. NE and PE increased baseline Ca2+ , whereas NE decreased the peak amplitude. CLON also decreased peak amplitude but did not affect baseline [Ca2+ ]i . Taken together, these data suggest receptor-specific influence of α1 and α2 receptors on the various modes of calcium entry in PVN neurones. They further suggest Ca2+ increase via α1 -ARs is co-dependent on extracellular Ca2+ influx and intracellular Ca2+ release, possibly via a phospholipase C inhibitor-mediated signalling cascade.

Atomoxetine modulates the relationship between perceptual abilities and response bias.

Elucidation of how neuromodulators influence motivated behaviors is a major challenge of neuroscience research. It has been proposed that the locus-cœruleus-norepinephrine system promotes behavioral flexibility and provides resources required to face challenges in a wide range of cognitive processes. Both theoretical models and computational models suggest that the locus-cœruleus-norepinephrine system tunes neural gain in brain circuits to optimize behavior. However, to the best of our knowledge, empirical proof demonstrating the role of norepinephrine in performance optimization is scarce. Here, we modulated norepinephrine transmission in monkeys performing a Go/No-Go discrimination task using atomoxetine, a norepinephrine-reuptake inhibitor. We tested the optimization hypothesis by assessing perceptual sensitivity, response bias, and their functional relationship within the framework of the signal detection theory. We also manipulated the contingencies of the task (level of stimulus discriminability, target stimulus frequency, and decision outcome values) to modulate the relationship between sensitivity and response bias. We found that atomoxetine increased the subject's perceptual sensitivity to discriminate target stimuli regardless of the task contingency. Atomoxetine also improved the functional relationship between sensitivity and response bias, leading to a closer fit with the optimal strategy in different contexts. In addition, atomoxetine tended to reduce reaction time variability. Taken together, these findings support a role of norepinephrine transmission in optimizing response strategy.