Role Of Β-adrenergic Receptors Research Articles

Sex differences in hippocampal β-adrenergic receptor subtypes drive retrieval, retention, and learning of cocaine-associated memories.

Drug seeking behavior occurs in response to environmental contexts and drug-associated cues. The presence of these pervasive stimuli impedes abstinence success. β-adrenergic receptors (β-ARs) have a long-standing historical implication in driving processes associated with contextual memories, including drug-associated memories in substance use disorders. However, sex differences in the role of β-adrenergic receptors in drug memories remain unknown. Prior reports indicate a selective role for β2-ARs in retrieval and retention of contextual drug memories in males, and substantial sex differences exist in the expression of β-ARs of male and female rats. Therefore, we hypothesized that there are sex differences in selective recruitment of β-ARs during different stages of memory encoding and retrieval. The role of β-ARs in driving retrieval and learning of contextual cocaine memories was investigated using cocaine conditioned place preference (CPP) in adult male and female Sprague-Dawley rats. Rats were infused directly to the dorsal hippocampus with Propranolol (β1 and β2) or ICI-118,551 (β1) and/or Betaxolol (β2), immediately prior to testing (retrieval), or paired to each cocaine (10 mg/kp, IP) conditioning session (learning). In males, administration of either β1, β2, or combined β1 and β2-ARs before the initial CPP testing reduced the expression of a CPP compared to vehicle administration. In females, β2-ARs transiently decreased CPP memories, whereas β1 had long lasting but not immediate effects to decrease CPP memories. Additionally, β1 and combined β1 and β2-ARs had immediate and persistent effects to decrease CPP memory expression. DG Fos + neurons predicted cocaine CPP expression in males, whereas CA1 and CA3 Fos + neurons predicted cocaine CPP expression in females. There are significant sex differences in the role of dorsal hippocampus β-ARs in the encoding and expression of cocaine conditioned place preference. Furthermore, sub regions of the dorsal hippocampus appear to activate differently between male and female rats during CPP. Therefore DG, CA3, and CA1 may have separate region- and sex-specific impacts on driving drug- associated, or context-associated cues.

The role of β-adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do β-adrenergic receptor agonists and antagonists protect the heart?

Catecholamines and β-adrenergic receptors (β-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This systematic review analyzed the molecular mechanisms of the cardioprotective activity of β-AR ligands. We performed an electronic search of topical articles using PubMed databases from 1966 to 2023. We cited original in vitro and in vivo studies and review articles that documented the cardioprotective properties of β-AR agonists and antagonists. The infarct-reducing effect of β-AR antagonists did not depend on a decrease in the heart rate. The target for β-blockers is not only cardiomyocytes but also neutrophils. β1-blockers (metoprolol, propranolol, timolol) and the selective β2-AR agonist arformoterol have an infarct-reducing effect in coronary artery occlusion (CAO) in animals. Antagonists of β1- and β2-АR (metoprolol, propranolol, nadolol, carvedilol, bisoprolol, esmolol) are able to prevent reperfusion cardiac injury. All β-AR ligands that reduced infarct size are the selective or nonselective β1-blockers. It was hypothesized that β1-AR blocking promotes an increase in cardiac tolerance to I/R. The activation of β1-AR, β2-AR, and β3-AR can increase cardiac tolerance to I/R. The cardioprotective effect of β-AR agonists is mediated via the activation of kinases and reactive oxygen species production. It is unclear why β-blockers with the similar receptor selectivity have the infarct-sparing effect while other β-blockers with the same selectivity do not affect infarct size. What is the molecular mechanism of the infarct-reducing effect of β-blockers in reperfusion? Why did in early studies β-blockers decrease the mortality rate in patients with acute myocardial infarction (AMI) and without reperfusion and in more recent studies β-blockers had no effect on the mortality rate in patients with AMI and reperfusion? The creation of more effective β-AR ligands depends on the answers to these questions.

The Role of β-Adrenergic Receptors in the Regulation of the Functions of Innate Immune Cells during Cold Stress In Vivo.

It was found that 10-min cold stress enhanced stimulated production of ROS, while 60-min cold stress increased both spontaneous and stimulated ROS production by peritoneal macrophages. β-Adrenergic receptor blockade leveled the effect of 10-min stress in stimulated cultures and the effect of 60-min stress in spontaneous cultures. None variants of cold stress affected spontaneous and stimulated production of IL-1β. We observed an increase in the production of IL-1β in stimulated cultures from animals subjected to 10- and 60-min stress against the background of propranolol. At the same time, both variants of cold exposure, irrespective of β-adrenergic receptor blockade, stimulated IL-10 synthesis in spontaneous and activated samples. None of the used models of cold exposure affected the phagocytic activity of peritoneal macrophages. Thus, β-adrenergic receptors are directly involved in the regulation of cytokine production and microbicidal potential of macrophages in acute cold stress.

β-Adrenergic Receptors and Adipose Tissue Metabolism: Evolution of an Old Story.

The role of β-adrenergic receptors (βARs) in adipose tissue to promote lipolysis and the release of fatty acids and nonshivering thermogenesis in brown fat has been studied for so many decades that one would think there is nothing left to discover. With the rediscovery of brown fat in humans and renewed interest in UCP1 and uncoupled mitochondrial respiration, it seems that a review of adipose tissue as an organ, pivotal observations, and the investigators who made them would be instructive to understanding where the field stands now. The discovery of the β3-adrenergic receptor was important for accurately defining the pharmacology of the adipocyte, while the clinical targeting of this receptor for obesity and metabolic disease has had its highs and lows. Many questions still remain about how βARs regulate adipocyte metabolism and the signaling molecules through which they do it.

Role of β-adrenergic receptors in insulin resistance: Induction or protection?

Role of β-adrenergic receptors in insulin resistance: Induction or protection?

The role of β-adrenergic receptors in stress-induced cardiac injury in a rat model of Takotsubo syndrome

Introduction. The pathophysiological mechanisms of cardiac injury in Takotsubo syndrome are currently poorly understood. The role of adrenergic receptor (AR) subtypes in the development of stress-induced myocardial injury (SIMI) remains unclear.Aim. To assess the role of β-ARs in the development of SIMI.Material and Methods. The study was performed using female Wistar rats (n = 84). Rats were subject to 24-hour immobilization in the supine position to simulate SIMI. 99mTc-pyrophosphate radiopharmaceutical was used to determine the degree of cardiac injury.Results. The study showed that β-AR blockade with propranolol reduced the degree of cardiac injury by 38.4%. Selective β1- AR antagonists, atenolol and nebivolol, led to 2.00- and 2.55-fold decreases in 99mTc pyrophosphate accumulation in the heart, respectively. Blockade of β2-ARs by a selective antagonist ICI-118.551 caused an increase in the degree of 99mTc-pyrophosphate accumulation in the heart by 34.6%. A selective β3-AR antagonist L-748337 did not affect 99mTc pyrophosphate accumulation in the heart.Conclusions. The study showed that β1-ARs are involved in the damaging effects of stress on the heart during immobilization stress. β2-AR had a cardioprotective effect in immobilization. β3-AP did not play a significant role in the stress-induced cardiac injury with a single exposure to the stressor.

β2‑adrenergic receptor signaling promotes neuroblastoma cell proliferation by activating autophagy.

Accumulating evidence suggests the pivotal role of the sympathetic nervous system in the initiation and aggressive progression of tumors, whereas the role of β-adrenergic receptor (β-AR) signaling in neuroblastoma (NB) and the underlying regulatory mechanisms have not yet been well elucidated. In the present study, it was demonstrated that the expression of both β1-AR and β2-AR was significantly increased in clinical samples of NB compared with those of ganglioneuroma (GN) and ganglioneuroblastoma (GNB), and that β2-AR is the key β-adrenergic receptor responsible for NB cell growth. Further investigation showed that the expression levels of the autophagy markers LC3-II, beclin-1 and unc-51-like autophagy kinase 1 (ULK1) were also elevated in NB, compared to the cases of GN and GNB. Moreover, β2-AR expression was found to be positively associated with autophagy markers in the clinical NB specimens. Cellular functional assays demonstrated that β2-AR activation promoted NB cell growth and activated the autophagy pathway. Pharmacological inhibition of autophagy with 3-methyladenine abolished β2-AR-induced NB cell growth. Mechanistically, β2-AR signaling triggers autophagy through CREB-mediated ULK1 upregulation. In conclusion, the present study uncovered a novel regulatory mechanism of β2-AR-activated autophagy in NB cell growth and provides a novel potential therapeutic approach for treating NB by targeting autophagy and the β2-AR pathway.

Outcomes of advanced angiosarcoma and hemangioendothelioma on propranolol based regimens from sarcoma medical oncology clinic in North India.

e22539 Background: Angiosarcoma is an extremely rare subtype of soft tissue sarcoma with a dismal prognosis. The response rate with current standard treatment is low and new approaches are needed. Propranolol is a well-known, generic ß-blocker that has recently been approved for the treatment of a benign vascular tumor, hemangioma, with high response rates. Several preclinical studies and case reports suggest that propranolol could also be repurposed to treat malignant vascular tumors like angiosarcoma. Methods: All patients with advanced or unresectable angiosarcoma and hemangioendothelioma that were treated in the Sarcoma medical oncology clinic in North India from January 2016 to August 2018 were included. Patients were treated with 40 mg BID propranolol with or without chemotherapy or targeted agents. Results: Eight patients with angiosarcoma or hemangioendothelioma were treated with propranolol in combination with pazopanib, methotrexate and vinblastine or methotrexate monotherapy. The median follow up period was 15 months, response rates were 14%. Median PFS was not reached, but the 10 months PFS was 60%. Median OS was not reached, but the 10 months OS was 80%. Conclusions: Treatment of angiosarcoma or hemangioendothelioma patients with propranolol in combination with chemotherapy or targeted therapy shows promising results in terms of survival albeit with relatively low response rates .To determine the exact place of propranolol in the treatment of angiosarcoma, more patients need to be treated, the efficacy of propranolol as monotherapy needs to be evaluated and the role of β-adrenergic receptor as a predictive biomarker needs to be clarified further. Additionally, different combination partners should be tested to determine the optimal backbone for the combination therapy with propranolol.

β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

PurposeThe role of β–adrenergic receptor (AR) signaling in neovascular ocular diseases has recently emerged. We have previously reported that intraperitoneal propranolol inhibits choroidal neovascularization (CNV) in vivo and β2-AR blockade reduces vascular endothelial growth factor (VEGF) expression in mouse retinal pigment epithelium and choroidal endothelial cells in culture. Here we tested the hypothesis that the β2-AR regulates CNV through modulation of VEGF and inflammatory cytokine expression.MethodsMice were subjected to laser burns, inducing CNV, and were treated with an intravitreal β2-AR antagonist. After 3 and 5 days, total eye interleukin-6 (IL-6) and VEGF protein levels were measured, respectively. After 14 days, CNV was measured on choroidal–scleral flatmounts. The effects of β-AR signaling on VEGF and IL-6 expression were investigated in various mouse retinal and human RPE cells by using specific β-AR agonists and antagonists.Resultsβ2–Adrenergic receptor signaling increased Vegf mRNA expression by approximately 3- to 4-fold in mouse retinal microglia and pericytes in culture. β2–Adrenergic receptor signaling upregulated IL-6 mRNA expression between 10- and 60-fold in mouse retinal microglia, pericytes, RPE, and choroidal endothelial cells in culture. Intravitreal injection of β2-AR antagonist ICI 118,551 reduced CNV by 35% and decreased IL-6 protein levels by approximately 50%. In primary human RPE cells, β2-AR activation also stimulated VEGF and IL-6 mRNA expression by 2- and 10-fold, respectively.ConclusionsAnti-VEGF therapy for CNV is highly effective; however, some patients are resistant to therapy while others undergo repeated, frequent treatments. β2–Adrenergic receptor signaling is a potential therapeutic target because of its angiogenic and inflammatory properties.

Dosage‐dependent regulation of cell proliferation and adhesion through dual β2‐adrenergic receptor/cAMP signals

The role of β-adrenergic receptors (β-ARs) remains controversial in normal and tumor breast. Herein we explore the cAMP signaling involved in β-AR-dependent control of proliferation and adhesion of nontumor human breast cell line MCF-10A. Low concentrations of a β-agonist, isoproterenol (ISO), promote cell adhesion (87.5% cells remaining adherent to the plastic dishes following specific detachment vs. 35.0% in control, P<0.001), while increasing concentrations further engages an additional 36% inhibition of Erk1/2 phosphorylation (p-Erk1/2)-dependent cell proliferation (P<0.01). Isoproterenol dose response on cell adhesion was fitted to a 2-site curve (EC50(1): 16.5±11.5 fM, EC50(2): 4.08±3.09 nM), while ISO significantly inhibited p-Erk1/2 according to a 1-site model (EC50: 0.25±0.13 nM). Using β-AR-selective agonist/antagonists and cAMP analogs/inhibitors, we identified a dosage-dependent signaling in which low ISO concentrations target a β2-AR population localized in raft microdomains and stimulate a Gs/cAMP/Epac/adhesion-signaling module, while higher concentrations engage a concomitant activation of another β2-AR population outside rafts and inhibit the proliferation by a Gs/cAMP/PKA-dependent signaling module. Our data provide a new molecular basis for the dose-dependent switch of β-AR signaling. This study also sheds light on a new cAMP pathway core mechanism with a single receptor triggering dual cAMP signaling controlled by PKA or Epac but with different cellular outputs.

Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

Exercise promotes cardioprotection in both humans and animals not only by reducing risk factors associated with cardiovascular disease but by reducing myocardial infarction and improving survival following ischemia. This article will define the role that nitric oxide and β-adrenergic receptors play in mediating the cardioprotective effects of exercise in the setting of ischemia-reperfusion injury.

Role of β-Adrenergic Receptors in the Oral Activity of Zinc-α2-Glycoprotein (ZAG)

Zinc-α2-glycoprotein (ZAG) is an adipokine with the potential as a therapeutic agent in the treatment of obesity and type 2 diabetes. In this study we show that human ZAG, which is a 41-kDa protein, when administered to ob/ob mice at 50 μg/d(-1) orally in the drinking water produced a progressive loss of body weight (5 g after 8 d treatment), together with a 0.5 C increase in rectal temperature and a 40% reduction in urinary excretion of glucose. There was also a 33% reduction in the area under the curve during an oral glucose tolerance test and an increased sensitivity to insulin. These results were similar to those after iv administration of ZAG. However, tryptic digestion was shown to inactivate ZAG. There was no evidence of human ZAG in the serum but a 2-fold elevation of murine ZAG, which was also observed in target tissues such as white adipose tissue. To determine whether the effect was due to interaction of the human ZAG with the β-adrenergic (β-AR) in the gastrointestinal tract before digestion, ZAG was coadministered to ob/ob mice together with propanolol (40 mg/kg(-1)), a nonspecific β-AR antagonist. The effect of ZAG on body weight, rectal temperature, urinary glucose excretion, improvement in glucose disposal, and increased insulin sensitivity were attenuated by propanolol, as was the increase in murine ZAG in the serum. These results suggest that oral administration of ZAG increases serum levels through interaction with a β-AR in the upper gastrointestinal tract, and gene expression studies showed this to be in the esophagus.

Role of β-adrenergic receptors in regulation of hepatic fat accumulation during aging

Excessive fat accumulation in liver (hepatic steatosis) predisposes to hepatic functional and structural impairment and overall metabolic risk. Previous studies noted an association between hepatic steatosis and age in humans and rodents. However, the mechanisms leading to age-associated hepatic fat accumulation remain unknown. Earlier work from our group showed that β-adrenergic receptor (β-AR) levels and β-AR-stimulated adenylyl cyclase activity increase in rat liver during aging. Here we investigated whether age-associated increases in β-AR signaling play a role in augmenting hepatic lipid accumulation. We demonstrate an increase in hepatic lipid content during senescence and a significant correlation between hepatic fat content and stimulation of adenylyl cyclase activity by the β-AR agonist isoproterenol in rat liver. Isoproterenol administration to young and old rodents in vivo increased hepatic lipid accumulation. Furthermore, in vitro overexpression of β1- and β2-AR subtypes in hepatocytes from young rodents increased cellular lipid content, whereas inhibition of β-ARs by receptor subtype-specific inhibitors reduced lipid levels in hepatocytes from senescent animals. Isoproterenol-induced hepatic lipid accumulation in vivo was prevented by the β-AR nonselective blocker propranolol, suggesting a novel therapeutic effect of this class of drugs in hepatic steatosis. Acipimox, which inhibits adipose tissue lipolysis, did not alter isoproterenol-mediated hepatic fat accumulation; thus β-AR responsive hepatic lipid accumulation does not appear to be related primarily to altered lipolysis. These findings suggest that augmented hepatic β-AR signaling during aging may increase lipid accumulation in liver and advocate a possible role for β-adrenergic blockers in preventing or retarding the development of hepatic steatosis.

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Objectives: The goal of the current study is to determine whether the β-adrenoreceptor (β-AR) plays a role in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotein (ZAG). Material and methods: This has been investigated in CHO-K1 cells transfected with the human β1-, β2-, β3-AR and in ob/ob mice. Cyclic AMP assays were carried out along with binding studies. Ob/ob mice were treated with ZAG and glucose transportation and insulin were examined in the presence or absence of propranolol. Results: ZAG bound to the β3-AR with higher affinity (Kd 46±1nM) than the β2-AR (Kd 71±3nM) while there was no binding to the β1-AR, and this correlated with the increases in cyclic AMP in CHO-K1 cells transfected with the various β-AR and treated with ZAG. Treatment of ob/ob mice with ZAG increased protein expression of β3-AR in gastrocnemius muscle, and in white and brown adipose tissues, but had no effect on expression of β1- and β2-AR. A reduction of body weight was seen and urinary glucose excretion, increase in body temperature, reduction in maximal plasma glucose and insulin levels in the oral glucose tolerance test, and stimulation of glucose transport into skeletal muscle and adipose tissue, were completely attenuated by the non-specific β-AR antagonist propranolol. Conclusion: The results suggest that the effects of ZAG on body weight and insulin sensitivity in ob/ob mice are manifested through a β-3AR, or possibly a β2-AR.

The Role of β-adrenergic Receptors in the Cardioprotective Effects of Beta-Preconditioning (βPC)

To determine the mechanism whereby transient stimulation of the β-adrenergic receptor subtypes (β-AR) elicit cardioprotection against subsequent ischaemia. Isolated rat hearts were subjected to 35 min regional ischaemia (RI) and reperfusion and infarct size (IS) determined. Hearts were preconditioned with 5 min isoproterenol (β1/β2-AR agonist), denopamine (β1-AR agonist), formoterol hemifumarate (β2-AR agonist) or BRL37344 (β3-AR agonist) and 5 min reperfusion. The roles of the β-ARs, NO, PKA, and PI3-K were explored by using selective antagonists/blockers. Pertussis toxin was administered i.p., 48 h prior to experimentation. IS of hearts preconditioned with either isoproterenol, denopamine or formoterol (% of area at risk: 23.6 ± 1.26; 24.52 ± 0.89; 20.74 ± 0.85 respectively) were significantly smaller than that of non-preconditioned hearts (41.7 ± 1.65) and associated with improvement in postischaemic mechanical performance. The β3-AR agonist BRL37344 could not reduce IS. The β1- and β2-AR blockers CGP-20712A and ICI-118551 abolished the reduction in IS and improvement in mechanical recovery during reperfusion induced by isoproterenol preconditioning, while the β3-AR blocker SR59230A was without effect. Both Rp-8-CPT-cAMPs and wortmannin significantly increased IS when administered before and during β1/β2-AR preconditioning and reduced mechanical recovery. PTX pretreatment had no significant effect on the reduction in IS induced by β1/β2-AR or β2-AR preconditioning, but reduced mechanical recovery in β2-AR preconditioning. Similarly the NOS inhibitors L-NAME and LNNA had no effect on IS in β1/β2-AR preconditioning, but depressed mechanical recovery. Protection afforded by β-ARs stimulation, depends on activation of both β1-AR and β2-ARs but not β3-AR. With functional recovery as endpoint, results suggest involvement of NO in β1/β2-AR preconditioning and the Gi protein in β2-AR preconditioning. Both PKA and PI3-K activation were essential for β1/β2-AR cardioprotection.

The role of β-adrenergic receptors in heart failure: Differential regulation of cardiotoxicity and cardioprotection

β-adrenergic receptor blockers have demonstrated significant survival benefit and have become standard therapy for adults with dilated cardiomyopathy, although their efficacy in pediatric patients is still unproven. Recent data suggests that the two major cardiac β-adrenergic receptor subtypes (β1 and β2) couple differentially to intracellular signaling pathways regulating contractility and remodeling. This has led some to suggest that the β1 receptor is the “cardiotoxic subtype” whereas the β2 receptor is “cardioprotective.” Given this paradigm, there could be situations where subtype selective β-blockade or even subtype selective β-stimulation might be beneficial. However, since most of these studies have been performed in isolated cardiomyocytes, their application to clinical practice is unclear. To better understand the roles of β1- vs. β2-receptors in the pathogenesis of clinical cardiomyopathy, we and others have taken advantage of several well-characterized murine models of cardiovascular disease. These studies demonstrate that β-receptor regulation of the balance between cardioprotection and cardiotoxicity is even more complex than previously appreciated: the role of each β-receptor subtype may vary depending on the specific cardiac stressor involved (e.g. ischemia, pressure overload, genetic mutation, cardiotoxin). Furthermore, the remodeling effects of β-receptor signaling have a temporal component, depending on whether a cardiac stress is acute vs. chronic.

Role of β-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction

Dietary methionine restriction (MR) limits fat deposition and decreases plasma leptin, while increasing food consumption, total energy expenditure (EE), plasma adiponectin, and expression of uncoupling protein 1 (UCP1) in brown and white adipose tissue (BAT and WAT). beta-adrenergic receptors (beta-AR) serve as conduits for sympathetic input to adipose tissue, but their role in mediating the effects of MR on energy homeostasis is unclear. Energy intake, weight, and adiposity were modestly higher in beta(3)-AR(-/-) mice on the Control diet compared with wild-type (WT) mice, but the hyperphagic response to the MR diet and the reduction in fat deposition did not differ between the genotypes. The absence of beta(3)-ARs also did not diminish the ability of MR to increase total EE and plasma adiponectin or decrease leptin mRNA, but it did block the MR-dependent increase in UCP1 mRNA in BAT but not WAT. In a further study, propranolol was used to antagonize remaining beta-adrenergic input (beta(1)- and beta(2)-ARs) in beta(3)-AR(-/-) mice, and this treatment blocked >50% of the MR-induced increase in total EE and UCP1 induction in both BAT and WAT. We conclude that signaling through beta-adrenergic receptors is a component of the mechanism used by dietary MR to increase EE, and that beta(1)- and beta(2)-ARs are able to substitute for beta(3)-ARs in mediating the effect of dietary MR on EE. These findings are consistent with the involvement of both UCP1-dependent and -independent mechanisms in the physiological responses affecting energy balance that are produced by dietary MR.

Role of β-Adrenergic Receptors in Inflammatory Marker Expression in Müller Cells

To determine whether beta-adrenergic receptors are involved in the modulation of inflammatory cytokines in Müller cells in a hyperglycemic environment. Rat Müller cells were grown in high (25 mM)- or low (5 mM)-glucose medium. Müller cells lysates were processed for real-time polymerase chain reaction to measure steady state mRNA expression for the following inflammatory markers: iNOS, TNF-alpha, IL-1B, and ICAM-1. Western blot analysis and ELISA assays were performed to determine the protein levels of these inflammatory markers and PGE2 content. Isoproterenol treatment significantly decreased protein levels of iNOS, TNF-alpha, and IL-1B, in rMC-1 cells cultured in high glucose as early as 1 hour, compared with cells receiving no treatment. PGE2 content was also reduced after isoproterenol treatment. There were no significant changes observed in protein levels of ICAM-1 production after isoproterenol treatment in high glucose. Steady state mRNA levels for iNOS were significantly decreased 1 hour after isoproterenol, whereas ICAM-1 gene expression was significantly increased after 1 hour. Isoproterenol significantly increased gene expression for IL-1B after 24 hours of treatment. These results suggest that stimulation of beta-adrenergic receptors with isoproterenol leads to decreased levels of PGE(2), TNF-alpha, and IL-1B protein content, and in both gene expression and protein levels of iNOS in Müller cells cultured in hyperglycemia. beta-Adrenergic receptor agonists had limited effects on ICAM-1 protein production. These results indicate that isoproterenol treatment reduces cytokine activation in cultured rat Müller cells.

Blockade of β-adrenergic receptors prevents amphetamine-induced behavioural sensitization in rats: a putative role of the bed nucleus of the stria terminalis

Recent findings have given evidence a role for noradrenergic transmission in the mechanisms underlying behavioural sensitization to psychostimulants. This work was undertaken to investigate the possible role of beta-adrenergic receptors in amphetamine-induced behavioural sensitization in rats. Rats were sensitized by a single administration of amphetamine (1 mg/kg s.c.) and challenged with the same dose 7 d later. The beta(1) /beta(2) -adrenergic receptor antagonists timolol (10 mg/kg i.p.) and nadolol (10 mg/kg i.p.), which respectively cross or do not readily cross the blood-brain barrier, were injected prior to the first or second amphetamine administration. Timolol, but not nadolol, prevented the initiation of behavioural sensitization without interfering with the expression of the sensitized response or the acute locomotor response to amphetamine. Since we found amphetamine-induced fos-activated cells closely associated with dopamine beta-hydroxylase immunoreactive varicosities in the bed nucleus of the stria terminalis (BNST), we investigated the effect of a bilateral micro-injection of timolol into this nucleus. Similarly to systemic administration, intra-BNST timolol (2.5 microg/side) prevented the development of behavioural sensitization. These results suggest that central beta-adrenergic receptors could specifically modulate early neuronal changes leading to the development of behavioural sensitization to psychostimulants, and that the BNST could be an important part of the brain circuitry involved in these long-term neuroadaptations.

The effect of α 2-adrenergic receptors on cutaneous water evaporation in the rock pigeon ( Columba livia)

The role of β-adrenergic receptors in regulating cutaneous water evaporation (CWE) in the rock pigeon ( Columba livia) is well documented. Here, we studied the involvement of the α 2-adrenergic receptors in this cooling mechanism of the heat-acclimated (HAc) pigeon. Systemic α 2-adrenergic activation [clonidine, 50 μg kg −1, intramuscular (i.m.)] was found to increase CWE in heat-acclimated pigeons at an ambient temperature ( T a) of 25 °C. Subcutaneous administration of the drug had no significant effect. Preinjection of an α 2-adrenergic antagonist (yohimbine, 10 mg kg −1, i.m.) completely prevented clonidine-induced CWE and attenuated propranolol-induced CWE by 53%. Pretreatment with a β-adrenergic agonist (isoproterenol, 4 mg kg −1, i.m.) abolished the effect of clonidine. None of the above treatments was found to elicit significant CWE in nonacclimated (NAc) pigeons. These findings, in addition to previously reported data, indicate a complex regulatory pathway of CWE in the heat-acclimated pigeon consisting of α 2- and β 2-adrenergic receptors. The possible hierarchical pattern of these receptors is discussed.