Previous work has suggested that N-methyl-d-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)(2A) receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic ...

Adenosine A(?A) receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson's disease (PD). Clinical trials of A(?A) antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of ...

Previous research has suggested that serotonin 5-HT(2A) receptors modulate the functioning of the mesocortical dopamine (DA) pathway. However, the specific role of 5-HT(2A) receptors localized within the medial prefrontal cortex (mPFC) is not known. The present study employed in vivo microdialysis to examine the ...

Acute intramedullary infusion of hyperosmotic NaCl, used to simulate a high-salt diet-induced increase of medullary osmolality, increases urine production and endothelin release from the kidney. To determine whether endothelin mediates this diuretic and natriuretic response, urine flow and Na(+) excretion rate were measured during acute intramedullary infusion of hyperosmotic NaCl in anesthetized ...

Functional roles for C5a receptors in sepsis Daniel Rittirsch1, Michael A Flierl1, Brian A Nadeau1 in the setting of cecal ligation and puncture�induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In `mid-grade' sepsis (30�40% survival), ...

We investigated the effects of mitragynine, a major alkaloid isolated from the leaves of Mitragyna speciosa Korth (Rubiaceae), on the 5-HT2A receptor-mediated head-twitch response in mice. Intraperitoneal injection of mitragynine (5-30 mg/kg), as well as intraperitoneal injection of 5-HT2A receptor antagonist ...

Several lines of evidence support the involvement of serotonergic (5-HT) neurons of the median raphe nucleus (MRN) in anxiety-like behaviour. In this context, it is known that blockade of 5-HT(1A) somatodendritic autoreceptors in the midbrain raphe nuclei increases the firing rate of these neurons, disinhibiting 5-HT release in postsynaptic target areas such as amygdala, ...

Although triiodothyronine (T3) is widely used clinically, preclinical support for its antidepressant-like effects is limited, and the mechanisms are unknown. We evaluated 1) the antidepressant-like effects of T3 in the novelty suppressed feeding test (NSFT), tail suspension test (TST), and forced swim test (FST), 2) the role of presynaptic 5-HT(1A) ...

Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood ...

Despite its clinical use for more than two decades, the mechanisms by which trazodone acts as an antidepressant are not clear, because it has affinity for a variety of 5-hydroxytryptamine (5-HT; serotonin) receptors and the 5-HT transporter. This study examined the effects of sustained trazodone administration on 5-HT neurotransmission. Electrophysiological recordings were conducted in ...

1. Train-of-four fade (TOF(fade) ) is a clinically useful parameter to monitor the degree of neuromuscular transmission block in curarized patients. Experimentally, TOF(fade) has been attributed to the blockade of facilitatory nicotinic receptors on motor nerve terminals. There is less information regarding the involvement of coexistent presynaptic receptors (e.g. muscarinic ...

It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by ...

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D(2)) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT(2A) system in schizophrenia are ...

Complement activation products are known to be generated in the setting of both experimental and human sepsis. C5 activation products (C5a anaphylatoxin and the membrane attack complex [MAC] C5b-9) are generated during sepsis following infusion of endotoxin, or after cecal ligation and puncture (CLP), which produces polymicrobial sepsis. C5a reacts with its receptors C5aR and C5L2 in a manner that ...

We examined the pharmacology of (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride (R-96544), the active form of a novel 5-HT(2A) receptor antagonist, (2R,4R)-4-lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride (R-102444). R-96544 produced a ...

1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses ...

Rationale and objectivesWe previously showed that systemic administration of the prototypical alpha-2 noradrenaline (NA) receptor antagonist yohimbine increases alcohol self-administration and reinstatement. Yohimbine also acts as an agonist of 5-hydroxytryptamine (5-HT) 5-HT1A receptors, which have been shown to be involved in alcohol seeking. Here, we ...

Adenosine is an important paracrine agent regulating renal vascular tone via adenosine A(1) and A(2) receptors. While A(2B) receptor message and protein have been localized to preglomerular vessels, functional evidence on the role of A(2B) receptors in mediating the vasodilator action of adenosine on afferent arterioles is not available. The present study determined the role of A(2B) receptors in ...

The antipsychotic agent haloperidol regulates gene transcription in striatal medium spiny neurons (MSNs) by blocking dopamine D2 receptors (D2Rs). We examined the mechanisms by which haloperidol increases the phosphorylation of histone H3, a key step in nucleosomal response. Using BAC-transgenic mice that express EGFP under the control of the promoter of the dopamine D1 receptor or the D2R, we ...

Myocardial ischaemia activates cardiac sympathetic afferents leading to chest pain and reflex cardiovascular responses. Previous studies have shown that a brief period of myocardial ischaemia increases endothelin in cardiac venous plasma draining ischaemic myocardium and that exogenous endothelin excites cutaneous group III and IV sensory nerve fibres. The present study tested the hypothesis that ...

In previous studies, inhibition of mitogen activated protein kinase (MAP) p38 significantly improved recovery and attenuated apoptosis after retinal ischemia in rats. Yet, ischemic preconditioning (IPC) attenuated the ischemia-induced increase in p38 expression. We hypothesized that p38 was required for induction of ischemic tolerance by IPC. We examined ...

Cannabinoids have been shown to impair cognition in vivo and block long-term potentiation (LTP), a candidate experimental model of learning and memory in vitro, via cannabinoid receptor (CB1) activation. cis-Oleamide (cOA) is an endogenous sleep-inducing lipid with putative cannabinomimetic properties. We hypothesise that cOA is cannabinomimetic and perform a comparative study with synthetic and ...

Blockade of central endothelin ET(B) receptors inhibits fever induced by LPS in conscious rats. The contribution of ET(B) receptor-mediated mechanisms to fever triggered by intracerebroventricular IL-6, PGE2, PGF(2alpha), corticotropin-releasing factor (CRF), and preformed pyrogenic factor derived from LPS-stimulated macrophages (PFPF) was examined. The influence of natural ...

Background and purpose:? Acute nitric oxide synthase (NOS) inhibition in humans and animals is associated with hypersensitivity to nitric oxide (NO) donors. The mechanisms underlying this phenomenon have not been fully elucidated. The purpose of the present study was to assess whether hypersensitivity to NOS-blockade is linked to endothelin-1 (ET-1) signaling. Experimental ...

Recent clinical studies suggest that several antihypertensive drugs, especially angiotensin-converting enzyme inhibitors, reduced bone fractures. To clarify the relationship between hypertension and osteoporosis, we focused on the role of angiotensin II (Ang II) on bone metabolism. In bone marrow-derived mononuclear cells, Ang II (1x10(-6) M) significantly increased tartrate-resistant acid ...

Unilateral transection of the lumbar sympathetic chain attenuated the ... After ganglion blockade, KA produced a pressor response in sham-lesioned but not ...

Unilateral transection of the lumbar sympathetic chain attenuated the ... After ganglion blockade, KA produced a pressor response in sham-lesioned but not ...

Chronic treatment with olanzapine causes desensitization of serotonin2A receptor signaling. The purpose of the current study is to further understand the mechanisms underlying this desensitization response of serotonin2A receptor signaling in vivo. We now report that desensitization of ...

The paraventricular nucleus (PVN) in the hypothalamus is the main integration site that controls the hypothalamic-pituitary-adrenal (HPA) neuroendocrine stress system. Disruption of this system has been linked with alcoholism, but the specific role of the PVN has not been fully explored. Of particular interest is the ability of ?-aminobutyric acid type A receptors (GABA(A) Rs) in the PVN, to ...

Although adenosine has been implicated in penile erection in human males, the receptor subtype responsible for adenosine regulation of human corpus cavernosum (HCC) smooth muscle tone is still a matter of debate. Using selective adenosine agonists and antagonists, we aimed at characterizing the adenosine receptors mediating relaxation of precontracted (with 1 microM phenylephrine) HCC strips. HCC ...

Adenosine A2A receptor antagonists alleviate memory deficits caused by aging or by administration of beta-amyloid peptides in rodents, which is in accordance with the beneficial effects of caffeine consumption (an adenosine receptor antagonist) on memory performance in aged individuals and in preventing Alzheimer's disease. We now tested if ...

ABSTRACT BODY: Recent investigations have linked neurotrophins including NGF, NT-3, and BDNF to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance associated with allergic airway responses in mice. Mice administered an antibody against the low aff...

Recent studies have shown that asthmatics have increased levels of the neurotrophin, NGF, in their lungs. In addition, antibody blockade of NGF in mice attenuates airway resistance associated with allergic airway responses. DEP has been linked to asthma exacerbation in many c...

The present study determined regional serotonin (5-HT) synthesis and metabolism changes associated with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NA) and the influence of 5-HT receptor blockade in the antidepressant-like actions of L-NA in the forced swimming test (FST). Regional effects of L-NA (5,10 and 20mg/kg i.p.) on tryptophan hydroxylase (TPH) ...

Profound alterations in the function of GABA occur over the course of postnatal development. Changes in GABA(A) receptor expression are thought to contribute to these differences in GABAergic function, but how subunit changes correlate with receptor function in individual developing neurons has not been defined precisely. In the current study, we correlate ...

To prevent injury to host tissues, complement activation is regulated by a number of plasma and membrane-associated proteins, most of which limit C3 and C5 activation. An influx of circulating C3 from a syngeneic host into donor kidneys deficient in Crry (a membrane protein that reduces C3 convertase activity) causes spontaneous complement activation, primarily in the tubulointerstitum, leading to ...

Vasopressin V1a receptors in the rat brain have been studied for their role in modulating aggression and anxiety. In the current study blood-oxygen-level-dependent (BOLD) functional MRI was used to test whether V1a receptors modulate neural processing in the maternal brain when dams are exposed to a male intruder. ...

ASC/Icg (Antidepressant Sensitive Catalepsy) mouse strain selected for high predisposition to pinch-induced catalepsy is characterized by depressive-like behavior and impaired immune response. Chronic treatment with SSRI fluoxetine attenuated catalepsy manifestation and normalized a decreased number of rosette-forming cells (RFC) in spleen in ASC mice. Chronic fluoxetine ...

GABAergic neurons in the reticular thalamic nucleus (RTN) synapse onto thalamocortical neurons in the ventrobasal (VB) thalamus, and this reticulo-thalamocortical pathway is considered an anatomic target for general anesthetic-induced unconsciousness. A mutant mouse was engineered to harbor two amino acid substitutions (S270H, L277A) in the GABA(A) ...

Co-administration of caffeine profoundly enhances the acute toxicity of 3,4 methylenedioxymethamphetamine (MDMA) in rats. The aim of this study was to determine the ability of caffeine to impact upon MDMA-induced dopamine release in superfused brain tissue slices as a contributing factor to this drug interaction. MDMA (100 and 300?M) induced a dose-dependent increase in dopamine release in ...

Preconditioning by excitatory stimuli such as N-methyl-d-aspartate (NMDA) offers good neuroprotection against excitotoxic insults, but is potentially limited by the risk of damage associated with the treatment. We report here the potential of an alternative strategy, tested on rat neonatal cerebellar granule neurons, which involves a 48-hour preconditioning step using the potassium channel blocker ...

Osmotic swelling of retinal glial (M�ller) cells may contribute to the development of edema in diabetic retinopathy. Here, we tested whether oxidative stress and mitochondrial dysfunction are pathogenic factors involved in the osmotic swelling of M�ller cells in retinal slices from control and streptozotocin-injected hyperglycemic rats. Hypotonic challenge did not change the size of M�ller ...

Alzheimer's disease (AD) is a neurodegenerative disorder associated with progressive cognitive and memory loss and neuronal cell death. Current therapeutic strategies for AD are very limited; thus, traditional herbal medicines or their active constituents receive much attention. The aim of this study was to investigate the cognitive enhancing effects of salvianolic acid B (SalB) isolated from ...

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy. Elevated circulating endothelin-1 (ET-1) is associated with the disease. However the molecular basis of increased ET-1 production and its role in PE are unknown. This study aimed to investigate the causative factors, pathological role of elevated ET-1 production in PE, and the underlying mechanisms. In this study, we found ...

Dopamine metabolism, as reflected by the concentration of dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex was significantly increased following 30 min immobilisation stress or systemic administration of the benzodiazepine/GABA(A) receptor inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). The response to ...

The blockade of the lateral parabrachial nucleus (LPBN) with GABA(A) receptor agonist muscimol induces robust hypertonic NaCl and water intake by rats. In the present study we investigated the effects of previous injections of losartan (AT(1) angiotensin receptor antagonist) into the LPBN on 0.3M NaCl and water intake induced by ...

We have recently reported that treatment with the 5-HT(2A) receptor antagonist ketanserin in the inflamed paw raises the nociceptive threshold above normal level (hypoalgesia) and this response is naloxone-reversible. The present study aimed to investigate neurochemical changes at the site of inflammation and in dorsal root ganglia (DRG) and the spinal ...

We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell ...

The psychomotor stimulant effects of caffeine, the most widely consumed psychoactive substance, are mediated through its antagonism of extracellular adenosine receptors in the basal ganglia. In the absence of caffeine, adenosine stimulates inhibitory striatopallidal neurons that suppress motor activity by binding to A2A receptors, thereby activating a ...

Activation of central 5-HT(2A) receptor signaling and its subsequent alterations have been implicated in the pathophysiological response to stress and the pathogenesis of stress-associated psychiatric disorders. To further examine the association between alterations in central 5-HT(2A) receptor signaling and the ...

Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated ...

Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated ...

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. ...

Dysregulation of the 5-HT(2A) receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT(2A) receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT(2A) down-regulation to their efficacy is not known. We hypothesized that ...

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the central nervous system. Symptomatic and presymptomatic ALS patients demonstrate cortical hyperexcitability, which raises the possibility that alterations in inhibitory gamma-aminobutyric acid (GABA)ergic system could underlie this dysfunction. Here, we studied the GABAergic system in cortex using patch-clamp ...

Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation o...

Background- [Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the ...

The mechanism(s) involved in the pulmonary vascular and airway responses to pulmonary microembolism have not been clearly defined. Therefore, we determined the effects of specific prostaglandin and histamine blockade on the hemodynamic and arterial blood gas tension responses to particulate microembolism (200 mu glass beads) in intact anesthetized dogs. The marked increases in ...

Oxytocin (OT) and arginine vasopressin (AVP), in their capacities as neuromodulators, are believed to play an important role in mood control, including regulation of the anxiety response. In the present study, the contributions of oxytocin and vasopressin receptor modulation to anxiety-like behaviors were examined in male Sprague-Dawley rats. The behavioral effects of the OT receptor agonist, ...

Resveratrol, which is found in grapes, red wine, and berries, has many beneficial health effects, such as anti-cancer, neuro-protective, anti-inflammatory, and life-prolonging effects. However, the cellular mechanisms by which resveratrol acts are relatively unknown, especially in terms of possible regulation of receptors involved in synaptic transmission. 5-Hydroxytryptamine type 3A ...

Previous studies have shown that 2 h restraint stress induces deficits in open arm exploration of an elevated plus maze 24 h later. This effect was attenuated by a post-stress systemic injection of the 5-HT non-selective agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). To verify a possible involvement of hippocampal 5-HT1A ...

Few studies to date have looked at the effects of caffeine on synaptic plasticity, and those that did used very high concentrations of caffeine, whereas the brain concentrations attained by regular coffee consumption in humans should be in the low micromolar range, where caffeine exerts pharmacological actions mainly by antagonizing adenosine receptors. Accordingly, rats drinking caffeine (1 g/L) ...

A(2A) adenosine receptor antagonists are currently under investigation as potential therapeutic agents for Parkinson's disease (PD). However, the molecular mechanisms underlying this therapeutic effect is still unclear. A functional antagonism exists between A(2A) adenosine and D(2) dopamine (DA) receptors that are coexpressed in striatal medium spiny neurons (MSNs) of the indirect pathway. Since ...

Several recent studies suggest functional and molecular interactions between striatal adenosine A(2A) and cannabinoid CB(1) receptors. Here, we demonstrate that A(2A) receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A(2A) receptor blockade on the ...

3,4-Methylenedioxymethamphetamine (MDMA) or 'ecstasy' has been associated with memory deficits during abstinence and intoxication. The human neuropharmacology of MDMA-induced memory impairment is unknown. This study investigated the role of 5-HT(2A) and 5-HT(1A) receptors in MDMA-induced memory impairment. Ketanserin is a 5-HT(2A) ...

- rodegenerative disorders. Adenosine modulates long-term synaptic plasticity in the hippocampus, and it attenuates, cerebralischaemia, sleep apnoea, pain and inflammation32. A2A receptor antagonists are being investigated beat frequency of airway epithelial cells. Purinergic compounds are being explored for the treatment

PCBs are still ubiquitous pollutants despite the ban on their industrial and commercial use. To date, risk characterization and assessment of non-dioxin-like PCBs (NDL-PCBs), especially with respect to neurotoxicity, is hampered by a lack of data. Therefore, the effects of six common NDL congeners (PCB28, 52, 101, 138, 153 and 180) on human GABA(A) ...

Mechanical unloading and food restriction (FR) are leading causes of bone loss, which increase the risk of fracture later in life. Leptin, a 16kDa cytokine like hormone principally produced by white adipocytes, may be involved in bone metabolism with physiological or mechanical changes causing bone loss. The hypotheses of the first study were aimed at determining if serum leptin is reduced by ...

The effects of intracerebroventricular (icv) injections of angiotensin II (ANG II) on water intake, blood pressure, heart rate, and plasma arginine-vasopressin (AVP) concentration were studied in chronically instrumented adult male Syrian golden hamsters (Mesocricetus auratus). Furthermore, the effects of pharmacological ganglionic blockade, and of vascular AVP receptor ...

Recent research has demonstrated that a variety of sensory stimuli can increase acetylcholine release in the frontal cortex of rats. The aim of the present experiments was to investigate the pharmacological regulation of sensory stimulation-induced increases in the activity of basal forebrain cholinergic neurons. To this end, the effects of agonists and antagonists at a variety of neurotransmitter ...

Recent investigations have linked neurotrophins including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF) to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle...

Hepatic pyruvate, lactate and glycogen concentrations were measured 40 min after gavage of 5 ml 35% fructose or glucose to rats with sham surgery or section of the hepatic branch of the vagus nerve. Other animals were treated with saline or the peripheral anticholinergic drug, atropine methyl nitrate, prior to gavage of fructose. The increase in pyruvate concentration produced by the carbohydrate ...

In healthy motor endplates, tetanic depression is overcome by tonic adenosine A(2A) -receptor-mediated facilitation of transmitter release. The A(2A) receptor operates a coordinated shift from fast-desensitizing Ca(v) 2.1 (P/Q) calcium influx to long-lasting Ca(V) 1 (L) channels on motor nerve terminals. This study ...

Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in ...

Clozapine is an effective atypical antipsychotic agent, with serious side effects. JL13 [5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine] is a potential new atypical antipsychotic, structurally modified from clozapine to resist oxidation so as to reduce haematological and cardiological side effects. To assess the potential clinical potency of JL13 we tested its action in a newly ...

The involvement of the 5-HT-1A receptor in serotoninergic responses of stage 2 expiratory (E-2) neurones was investigated in pentobarbitone-anaesthetized, mechanically ventilated cats. The specific agonist of the 5-HT-1A receptor, 8-hydroxy-diproplaminotetralin (8-OH-DPAT), administered systemically or by ...

Memory consolidation is the process by which acquired information is converted to something concrete to be retrieved later. Here we examined a potential role for brain-derived neurotrophic factor (BDNF) in mediating the enhanced memory consolidation induced by the GABA(A) receptor antagonist, bicuculline methiodide. With the administration of an ...

Diabetic nephropathy is associated with cardiovascular morbidity. ACE inhibitors provide imperfect renoprotection in advanced type 2 diabetes and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here we assessed whether combination therapy with ACE inhibitor and ET(A) receptor antagonist ...

Adenosine A(2) receptors have been suggested to modulate tubuloglomerular feedback (TGF) responses by counteracting adenosine A(1) receptor-mediated vasoconstriction, but the mechanisms are unclear. We tested the hypothesis that A(2A) receptor activation blunts TGF by release of nitric oxide in the juxtaglomerular apparatus (JGA). Maximal TGF responses ...

Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight ...

Experiments were designed to test the hypothesis that activation of forebrain 5-HT1A receptors elicits cardiovascular responses. The microinjection of R-(+)-8-hydroxy-2-(di-n-propylamino) tetralin [(+)-8-OH-DPAT], a selective 5-HT1A receptor agonist, in the preoptic area of conscious rats increased blood pressure ...

Both pro-nociceptive and antinociceptive mediators are released in the tissues during inflammation. Balance of these two types of mediators determines the induction and maintenance of pain or hypernociception. This study was designed to explore whether 5-HT(2A) receptors in the periphery contributed to the maintenance of carrageenan-evoked hyperalgesia. ...

Obstructive sleep apnoea (OSA) is characterized by periods of upper airway collapse accompanied by repeated episodes of hypoxia. In experimental animals repeated bouts of hypoxia may evoke sustained augmentation of phrenic nerve activity, known as phrenic long-term facilitation (pLTF). This form of physiological compensation might contribute to stable breathing, minimizing the occurrence of ...

Adenosine plays a dual role on acetylcholine (ACh) release from myenteric motoneurons via the activation of high-affinity inhibitory A(1) and facilitatory A(2A) receptors. The therapeutic potential of adenosine-related compounds for controlling intestinal motility and inflammation, prompted us to investigate further the role of low-affinity adenosine ...

A co-morbidity of sleep-disordered breathing is hypertension associated with elevated sympathetic nerve activity, which may result from chronic intermittent hypoxia (CIH). CIH evokes plasticity in cardiorespiratory regulating sites, including the paraventricular nucleus (PVN), which acts to sustain increased sympathetic nerve activity. Our working hypothesis is that vasopressin neurons mediate the ...

The antagonism or genetic deletion of adenosine A(2A) receptors has been shown to exacerbate tissue damage in acute lung injury. Caffeine, a widely consumed behavioral drug, acts as a non-selective antagonist of A(2A) receptor and also has additional pharmacological effects. Thus, the protective vs. deleterious ...

Previous reports have shown that diltiazem and TMB, calcium channel antagonists, inhibit 5-hydroxytryptamine type 3A (5-HT(3A)) receptor-mediated currents (I(5-HT)) in cell lines and in heterologously expressed Xenopus oocytes. In the present study, we sought to elucidate the molecular mechanisms underlying diltiazem- and TMB-induced ...

Background and Purpose:? Flavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further. Experimental Approach:? We evaluated 2'MeO6MF (2'-methoxy-6-methylflavone) on native GABA(A) receptors in new-born rat hippocampal neurons and determined specificity from 18 human ...

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective, calcium permeable cation channel expressed by a subpopulation of primary afferent nociceptive nerve fibers. On peripheral nerve endings, TRPA1 channel contributes to transduction of chemical and physical stimuli, whereas on the central endings in the spinal dorsal horn, which is the topic of this brief review, it regulates ...

There is a potential risk that 5-HT(1A) receptor blockade combined with blockade of the 5-HT transporter by an SSRI may cause a toxic increase in 5-HT within the synapse, sparking concern for 'serotonin syndrome', a rare but potentially life threatening condition. We evaluated the safety and pharmacodynamics of the ...

Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a thermostabilized ...

All known GABA-A receptor blocker reverse the inhibitory effect of GABA on /sup 35/S-t-butylphosphorothionate (TBPS) binding to rat brain membranes in vitro. This system has already been used to identify several novel GABA antagonists. The authors now report that 12 out of 52 dipeptides tested (all containing L-amino acids), at 1 mM, significantly reverse ...

Although thiazide diuretics are commonly used to supplement angiotensin receptor blockers for treatment of hypertension, the mechanism underlying the therapeutic effects of this drug combination remains unclear. We investigated the antihypertensive and cardioprotective effects of combination therapy with losartan (LOS) and hydrochlorothiazide (HCTZ), in comparison with those of either drug alone, ...

Previous work has shown that 5-HT(2C) receptor agonists and 5-HT(2A) receptor antagonists reduce impulsive action, as well as the locomotor stimulant effect of psychomotor stimulants. Since psychomotor stimulants also increase impulsive action we examined the effects of the 5-HT(2C) receptor agonist Ro60-0175, and the 5-HT(2A) ...

Eugenosedin-B is able to block serotonin (5-HT) and alpha/beta receptors and to inhibit platelet aggregation. In Wistar rats, intravenous injections of eugenosedin-B (2.4, 7.2, 12 micromoL/kg) caused a dose-dependent decrease in blood pressure and heart rate. In contrast, intracisternal injection of eugenosedin-B (0.3, 0.03 micromoL) and an alpha2-antagonist yohimbine (0.03 micromoL) increased ...

1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced ...

Dehydroepiandrosterone (DHEA) and its metabolites, DHEA-sulphate (DHEA-S) and androsterone, have neurosteroid activity. In this study, we examined whether DHEA, DHEA-S and androsterone, can influence serotonin (5-HT) neuronal firing activity via modulation of ?-aminobutryic acid (GABA(A)) receptors. The firing of presumed 5-HT neurones in a slice ...

Serotonergic (5-HT) systems modulate pain, and drugs acting on 5-HT systems are used with opioids to treat pain. This study examined the effects of 5-HT receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in monkeys. Morphine increased tail-withdrawal latency in a dose-related manner; 5-HT receptor agonists alone increased tail-withdrawal latency at 50?�C but ...

The effect of acute arterial baroreflex dysfunction on cerebral autoregulation (CA) in otherwise healthy humans is unknown. We identified dynamic CA with and without arterial baroreflex-mediated tachycardia and consequent changes in cardiac output during acute hypotension whilst continuously monitoring changes in middle cerebral artery mean blood velocity (MCA V(mean)). Acute hypotension was ...

The effect of acute arterial baroreflex dysfunction on cerebral autoregulation (CA) in otherwise healthy humans is unknown. We identified dynamic CA with and without arterial baroreflex-mediated tachycardia and consequent changes in cardiac output during acute hypotension whilst continuously monitoring changes in middle cerebral artery mean blood velocity (MCA V_mean). Acute ...

The involvement of complement activation products in promoting tumor growth has not yet been recognized. Here we show that generation of complement C5a in the tumor microenvironment enhanced tumor growth by suppressing the anti-tumor CD8⁺ T cell-mediated response. This suppression was associated with the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors and ...

Apnea of prematurity (AOP) is a significant clinical problem manifested by an unstable respiratory rhythm reflecting the immaturity of respiratory control systems. This review will address the pathogenesis of and treatment strategies for AOP. Although the neuronal mechanisms leading to apnea are still not well understood, recent decades have provided better insight into the generation of the ...

The main class of atypical antipsychotic drugs (APDs) in current use includes the protypical atypical APD, clozapine, as well as aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone. At clinically effective doses, these agents produce extensive blockade of serotonin (5-HT)(2A) ...

BACKGROUND: The numbers of [3H]MUS binding sites were reported to be elevated in layers II and III, but not V or VI, in cingulate cortex of schizophrenic brains post mortem. These increases in [3H]MUS binding sites are probably due to compensatory up-regulation of GABA(A) receptors on pyramidal cells as a consequence of a selective loss of GABAergic ...

Background:? Neurosteroids and other ?-aminobutyric acid(A) (GABA(A) ) receptor-modulating compounds have been shown to affect ethanol intake, although their mechanism remains unclear. This study examined how patterns of 24-hour ethanol drinking in mice were altered with the synthetic GABAergic neurosteroid ganaxolone (GAN), with an inhibitor of ...

The neurotoxic potential of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is characterized by disruption of presynaptic processes, including calcium homeostasis and neurotransmitter transport. Recently, using a limited set of congeners, we demonstrated that PCB28 and PCB52 can potentiate postsynaptic GABA(A) receptors. In the present study, effects ...

p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated ...

The aim of the present study was to elucidate the pathogenic role of endogenous 5-HT in pancreatitis. Injections of cerulein at hourly intervals caused edematous pancreatitis in mice characterized by hyperenzymemia and histological alterations. While the cerulein-induced hyperenzymemia was attenuated in mice pretreated with p-CPA, a 5-HT depletor, it was exaggerated by the ...

Apomorphine, a dopamine D(1)/D(2) agonist is effective in the treatment of parkinson's disease; but its long term use is often associated with the dependence and addiction. The development of locomotor sensitization to psychostimulants including apomorphine is considered to be an important contributor to psychostimulant drug abuse. Previous studies have shown that long term administration of drugs ...

1. The actions of serotonin (5-HT) on pyramidal cells of the CA1 region of the rat hippocampus were characterized using intracellular recording in in vitro brain slices. 2. 5-HT typically evokes a biphasic response consisting of a hyperpolarization which is followed by a longer-lasting depolarization. These effects on membrane potential are accompanied by a decrease in the calcium-activated ...

OBJECTIVE: Given reports that (+/-)pindolol, a beta-adrenergic-5-HT1A/1B receptor antagonist, accelerates the onset of the therapeutic effect of certain antidepressant drugs in major depression, the aim of this study was to assess the effect of sustained (+/-)pindolol administration on the sensitivity of pre- and postsynaptic 5-HT1A receptors, terminal ...

Very little is known about constitutive activity in vivo. This study examined whether constitutive activity and inverse agonism contribute to discriminative stimulus effects of drugs acting at serotonin (5-HT)(2A) receptors. Rats were trained to discriminate between saline and either 0.56 mg/kg 5-HT(2) receptor agonist ...

Beta-blockade is widely reported to reduce the incidence of syncope in 75-80% of patients with congenital long QT syndrome (LQTS). However, despite full-dose beta-blockade, 20-25% of patients continue to have syncopal episodes and remain at high risk for sudden cardiac death. In some patients refractory to beta-blockade, the recurrence ...

Selective blockade of CD28 is a promising therapy to inhibit pathogenic alloimmunity. However, evaluation of this approach in transplantation has been very limited. Using a novel nonactivating single-chain Fv-based reagent (?28scFv), we have investigated the role of CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) in a murine cardiac transplant model. ...