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β 3 -Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of β 3 -adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a β-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical β-adrenoceptor agonist isoprenaline, the β 2 -selective fenoterol and the β 3 -selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the β 2 component of rat bladder relaxation but much weaker or even absent for the β 3 component. Moreover, β-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of β 3 -adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder.

RationaleIn rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated.ObjectiveWe sought to define the role of central NE transmission in neophilic and neophobic behaviors.MethodsWe assessed dopamine β-hydroxylase knockout (Dbh −/−) mice lacking NE and their NE-competent (Dbh +/−) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions.ResultsDbh −/− mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh −/− mice by acute pharmacological restoration of central NE with the synthetic precursor l-3,4-dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory α2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh −/− mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala.ConclusionThese findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.

Nitric oxide (NO) is one of the most important immune molecules in innate immunity of invertebrates and it can be regulated by norepinephrine in ascidian haemocytes. In the present study, the mutual modulation and underlying mechanism between norepinephrine and NO were explored in haemocytes of the scallop Chlamys farreri . After lipopolysaccharide stimulation, NO production increased to a significant level at 24 h and norepinephrine concentration rose to remarkable levels at 3 h and 12~48 h. A significant decrease of NO production was observed in the haemocytes concomitantly stimulated with lipopolysaccharide and α-adrenoceptor agonist, while a dramatic increase of NO production was observed in the haemocytes incubated with lipopolysaccharide and β-adrenoceptor agonist. Meanwhile, the concentration of cyclic adenosine monophosphate (cAMP) decreased significantly in the haemocytes treated by lipopolysaccharide and α/β-adrenoceptor agonist, while the content of Ca 2+ was elevated in those triggered by lipopolysaccharide and β-adrenoceptor agonist. When the haemocytes was incubated with NO donor, norepinephrine concentration was significantly enhanced during 1~24 h. Collectively, these results suggested that norepinephrine exerted varied effects on NO production at different immune stages via a novel α/β-adrenoceptor-cAMP/Ca 2+ regulatory pattern and NO might have a feedback effect on the synthesis of norepinephrine in the scallop haemocytes.

Brown and beige adipose tissues contain thermogenic fat cells that can be activated by β3-adrenergic receptor agonists. In rodents, such drugs both diminish obesity and improve glucose homeostasis. In this issue of the JCI, O'Mara et al. and Finlin and Memetimin et al. report that chronic administration of the approved β3 agonist mirabegron to human subjects was without effect on body weight or fat mass, but improved several measures of glucose homeostasis. Though the mechanisms mediating these metabolic effects are uncertain, the data suggest that β3 agonists could have therapeutic utility in disorders of glucose homeostasis.

Rationale Pupillometry can be used to characterize autonomic drug effects. Objective This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function. Methods Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo–MDMA (125 mg), placebo–placebo, pretreatment–placebo, or pretreatment–MDMA using a crossover design. Results MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6 h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function. Conclusions The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration–time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute tolerance.

The autonomic nervous system, consisting of sympathetic and parasympathetic branches, plays an important role in regulating metabolic homeostasis. The sympathetic nervous system (SNS) regulates hepatic lipid metabolism by regulating adrenergic receptor activation, resulting in the stimulation of hepatic very-low-density lipoprotein-triglyceride (TG) production in vivo. However, only a few studies on the relationship between SNS and hepatic steatosis have been reported. Here, we investigate the effect of adrenergic receptor agonists on hepatic steatosis in mice fed a high-fat diet (HFD). The α-adrenergic receptor agonist phenylephrine (10 mg/kg/d) or the β-adrenergic receptor agonist isoproterenol (30 mg/kg/d) was coadministered with HFD to male mice. After five weeks, hepatic steatosis, TG levels, and hepatic fat metabolism-related biomarkers were examined. HFD treatment induced hepatic steatosis, and cotreatment with phenylephrine, but not isoproterenol, attenuated this effect. Phenylephrine administration upregulated the mRNA levels of hepatic peroxisome proliferator-activated receptor alpha and its target genes (such as carnitine palmitoyltransferase 1) and increased hepatic β-hydroxybutyrate levels. Additionally, phenylephrine treatment increased the expression of the autophagosomal marker LC3-II but decreased that of p62, which is selectively degraded during autophagy. These results indicate that phenylephrine inhibits hepatic steatosis through stimulation of β-oxidation and autophagy in the liver.

Glaucoma affects millions of people around the world. With the baby boom generation aging, the number of people affected by primary open-angle glaucoma in the US is expected to reach 3.3 million by 2020, and about half may not know they have the disease. The treatment of most forms of glaucoma includes the use of topical agents that enhance aqueous humour outflow, reduce aqueous production, or both. Topical intraocular pressure-lowering drugs must penetrate across the tissues of the eye to reach their therapeutic targets. Often, these tissues show the first signs and symptoms of drug toxicity and adverse effects. These include eyelid dermatitis, malpositions, lacrimal system scarring, ocular discomfort upon instillation, tear film instability, conjunctival inflammation, subconjunctival fibrosis, conjunctival epithelium changes, and corneal surface and endothelial impairment. For these reasons, ophthalmologists should evaluate the risks and benefits of ophthalmic medications before initiating therapy, identify the minimum dosages necessary to achieve a therapeutic benefit, and monitor patients for local and systemic adverse effects. Adverse events may be reduced by changing to a different class of topical medication, using corticosteroids, lubricating the eyes frequently, and reducing exposure to preservatives. This in turn can lead to higher levels of adherence to antiglaucoma therapy, improved outcomes and a reduction in the costs associated with long-term glaucoma complications. This article reviews the ocular adverse effects associated with the various classes of topical antiglaucoma drugs, with a particular focus on the ocular surface, eyelids and periorbital tissue.

Hypoglycemia can alter arousal and negatively impact mood. This study tests the hypothesis that acute drops in glucose metabolism cause an aversive state mediated by monoamine activity. In experiment 1, male Sprague-Dawley rats were either food deprived (FD) or pre-fed (PF) and tested on conditioned place avoidance (CPA; biased place conditioning design; 3 pairings drug/vehicle, each 30 min-long) induced by the glucose antimetabolite 2-deoxy- d -glucose (2-DG; 0, 300 or 500 mg/kg, SC). Locomotion and blood glucose were also assessed. Experiment 2 examined whether clonidine (noradrenergic α2 agonist, 0, 10 or 40 μg/kg, SC) or bupropion (monoamine reuptake blocker, 0, 10 or 30 mg/kg, SC) could alter CPA induced by 500 mg/kg 2-DG. In experiment 3, blood corticosterone (CORT) was measured in response to 500 mg/kg 2-DG, alone or in combination with 40 μg/kg clonidine or 30 mg/kg bupropion. Finally, experiment 4 controlled for possible place conditioning induced by 10 or 40 μg/kg clonidine, or 10 or 30 mg/kg bupropion injected without 2-DG. It was found that 2-DG increased blood glucose and produced a robust CPA. The feeding status of the animals modulated these effects, including CORT levels. Both clonidine and bupropion attenuated the effects of 2-DG on CPA and CORT, but only bupropion reversed suppression of locomotion. Taken together, these results in rats suggest that impaired glucose metabolism can negatively impact arousal and mood via effects on HPA and monoamine systems.

Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis.

The alpha-1A-adrenergic receptor (AR) subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR) on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse.