1,413 results on '"Receptors, Adrenergic, alpha-2"'
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2. Coronary Spasm During Postoperative Sedation With Dexmedetomidine
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Sato, Yu, Matsumura, Tomoka, Abe, Yushi, Kutsumizu, Chihiro, and Maeda, Shigeru
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Aged, 80 and over ,Fentanyl ,Spasm ,Anesthesiology and Pain Medicine ,Receptors, Adrenergic, alpha-2 ,Coronary Vasospasm ,Humans ,Female ,Case Reports ,Dexmedetomidine - Abstract
This is a case report of an 81-year-old woman who underwent tracheostomy, bilateral cervical dissection, partial tongue resection, radial forearm free flap reconstruction, and split-thickness skin grafting under general anesthesia. After successful surgery, she was moderately sedated postoperatively with intravenous dexmedetomidine (DEX) and fentanyl. The fentanyl was discontinued 5 hours postoperatively. Eight hours after the operation, an atrioventricular junctional rhythm, a 2-mm elevation of the ST segment, and biphasic T waves were detected in lead II that lasted approximately 3 minutes. Hypotension and bradycardia were observed simultaneously with the abnormal electrocardiogram. The next day, a cardiologist examined the patient and suggested that coronary spasm had occurred based on those findings. The transient coronary spasm was likely caused by a combination of various factors including surgical stress and altered autonomic function. However, it is possible that stimulation of α-2 adrenergic receptors induced by DEX may also be linked to the coronary vasospasm that occurred.
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- 2022
3. Genetic biomarkers of life-threatening pheochromocytoma-induced cardiomyopathy
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Jacques Amar, Jeremy Brunel, Catherine Cardot Bauters, Virginie Jacques, Clément Delmas, Marie-Françoise Odou, and Frédérique Savagner
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Cancer Research ,Genotype ,Endocrinology, Diabetes and Metabolism ,Adrenal Gland Neoplasms ,Pheochromocytoma ,Polymorphism, Single Nucleotide ,Paraganglioma ,Catecholamines ,Endocrinology ,Oncology ,Receptors, Adrenergic, alpha-2 ,Humans ,Receptors, Adrenergic, beta-2 ,Receptors, Adrenergic, beta-1 ,Cardiomyopathies ,Biomarkers - Abstract
The release of excessive amounts of catecholamine by pheochromocytoma–paragangliomas (PPGL) can lead to life-threatening catecholamine-induced cardiomyopathy (CIC). Single-nucleotide polymorphisms of the beta1 and alpha-2c adrenergic receptors alter myocyte receptor function and enhanced norepinephrine release. We tested the hypothesis that such genetic variations may impact the risk of developing CIC in the context of PPGL. Thirty-one patients with PPGL, including nine with a history of CIC, were analyzed for alpha-2-adrenergic receptors: ADRA2C, beta-1 and beta-2 adrenergic receptors: ADRB1 and ADRB2 genotyping. CIC was defined either by a history of heart failure or cardiogenic shock associated with dilated or Takotsubo cardiomyopathy. Subjects were genotyped for ADRA2C (rs61767072 for del322_325), ADRB1 (rs1801252 for Ser49Gly and rs1801253 for Arg389Gly) and ADRB2 (rs1042713 for Arg16Gly and rs1042714 for Gln27Glu). Single-locus analysis revealed that variant in ADRA2C (alpha 2CDel322–325) was more common among patients with CIC than among controls (allele frequency, 0.44 vs 0.05; P< 0.001). The lack of alpha 2CDel322–325 polymorphism has a negative predictive value of 95% for the onset of CIC. In a replication cohort including 26 patients with PPGL whom eight have developed a CIC, the association between Alpha 2CDel322–325 and CIC was confirmed (allele frequency, 0.33 vs 0.; P= 0.0001). In conclusion, Alpha 2CDel322–325 through the identification of patients at low risk of developing CIC can help physicians to better determine the most appropriate therapeutic approach, notably in patients at high risk of surgical complications.
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- 2022
4. Measuring neuron-regulated immune cell physiology via the alpha-2 adrenergic receptor in an ex vivo murine spleen model.
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Brooke AK, Murrow DP, Caldwell KCN, Witt CE, and Ross AE
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- Animals, Mice, Cell Physiological Phenomena, Neurons, Interleukin-6, Norepinephrine pharmacology, Spleen, Receptors, Adrenergic, alpha-2
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The communication between the nervous and immune systems plays a crucial role in regulating immune cell function and inflammatory responses. Sympathetic neurons, which innervate the spleen, have been implicated in modulating immune cell activity. The neurotransmitter norepinephrine (NE), released by sympathetic neurons, influences immune cell responses by binding to adrenergic receptors on their surface. The alpha-2 adrenergic receptor (α2AR), expressed predominantly on sympathetic neurons, has received attention due to its autoreceptor function and ability to modulate NE release. In this study, we used fast-scan cyclic voltammetry (FSCV) to provide the first subsecond measurements of NE released in the white pulp region of the spleen and validated it with yohimbine, a known antagonist of α2AR. For further application of FSCV in neuroimmunology, we investigated the extent to which subsecond NE from sympathetic neurons is important for immune cell physiology and cytokine production, focusing on tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and interleukin-6 (IL-6). Our findings provide insights into the regulatory mechanisms underlying sympathetic-immune interactions and show the significance of using FSCV, a traditional neurochemistry technique, to study these neuroimmune mechanisms., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2023
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5. Dexmedetomidine modulates neuronal activity of horizontal limbs of diagonal band via α2 adrenergic receptor in mice.
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Zhang XW, Chen L, Chen CF, Cheng J, Zhang PP, and Wang LC
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- Mice, Animals, Receptors, Adrenergic, alpha-2, Signal Transduction, Neurons, Adrenergic alpha-2 Receptor Agonists pharmacology, Dexmedetomidine pharmacology
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Background and Objectives: Dexmedetomidine (DEX) is widely used in clinical sedation which has little effect on cardiopulmonary inhibition, however the mechanism remains to be elucidated. The basal forebrain (BF) is a key nucleus that controls sleep-wake cycle. The horizontal limbs of diagonal bundle (HDB) is one subregions of the BF. The purpose of this study was to examine whether the possible mechanism of DEX is through the α2 adrenergic receptor of BF (HDB)., Methods: In this study, we investigated the effects of DEX on the BF (HDB) by using whole cell patch clamp recordings. The threshold stimulus intensity, the inter-spike-intervals (ISIs) and the frequency of action potential firing in the BF (HDB) neurons were recorded by application of DEX (2 µM) and co-application of a α
2 adrenergic receptor antagonist phentolamine (PHEN) (10 µM)., Results: DEX (2 µM) increased the threshold stimulus intensity, inhibited the frequency of action potential firing and enlarged the inter-spike-interval (ISI) in the BF (HDB) neurons. These effects were reversed by co-application of PHEN (10 µM)., Conclusion: Taken together, our findings revealed DEX decreased the discharge activity of BF (HDB) neuron via α2 adrenergic receptors., (© 2023. BioMed Central Ltd., part of Springer Nature.)- Published
- 2023
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6. Suppression of P2X3 receptor‐mediated currents by the activation of α 2A ‐adrenergic receptors in rat dorsal root ganglion neurons
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Wen-Long Qiao, Wang-Ping Hu, Chun-Yu Qiu, Ting-Ting Liu, Jia-Wei Hao, Qing Li, and Shuang Wei
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Male ,Nociception ,Agonist ,Adrenergic receptor ,medicine.drug_class ,Pharmacology ,Pertussis toxin ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Dorsal root ganglion ,Receptors, Adrenergic, alpha-2 ,Ganglia, Spinal ,Physiology (medical) ,Adrenergic alpha-2 Receptor Agonists ,medicine ,Animals ,Pharmacology (medical) ,Receptor ,Forskolin ,Behavior, Animal ,Chemistry ,P2X3 receptor ,Original Articles ,nociceptive behavior ,current ,Electrophysiological Phenomena ,Rats ,α2A adrenoceptor ,Psychiatry and Mental health ,Electrophysiology ,medicine.anatomical_structure ,Original Article ,Dexmedetomidine ,Receptors, Purinergic P2X3 ,dorsal root ganglion neuron - Abstract
Aims The α2‐adrenergic receptor (α2‐AR) agonists have been shown to be effective in the treatment of various pain. For example, dexmedetomidine (DEX), a selective α2A‐AR agonist, can be used for peripheral analgesia. However, it is not yet fully elucidated for the precise molecular mechanisms. P2X3 receptor is a major receptor processing nociceptive information in primary sensory neurons. Herein, we show that a functional interaction of α2A‐ARs and P2X3 receptors in dorsal root ganglia (DRG) neurons could contribute to peripheral analgesia of DEX. Methods Electrophysiological recordings were carried out on rat DRG neurons, and nociceptive behavior was quantified in rats. Results The activation of α2A‐ARs by DEX suppressed P2X3 receptor‐mediated and α,β‐methylene‐ATP (α,β‐meATP)‐evoked inward currents in a concentration‐dependent and voltage‐independent manner. Pre‐application of DEX shifted the α,β‐meATP concentration‐response curve downwards, with a decrease of 50.43 ± 4.75% in the maximal current response of P2X3 receptors to α,β‐meATP in the presence of DEX. Suppression of α,β‐meATP‐evoked currents by DEX was blocked by the α2A‐AR antagonist BRL44408 and prevented by intracellular application of the Gi/o protein inhibitor pertussis toxin, the adenylate cyclase activator forskolin, and the cAMP analog 8‐Br‐cAMP. DEX also suppressed α,β‐meATP‐evoked action potentials through α2A‐ARs in rat DRG neurons. Finally, the activation of peripheral α2A‐ARs by DEX had an analgesic effect on the α,β‐meATP‐induced nociception. Conclusions These results suggested that activation of α2A‐ARs by DEX suppressed P2X3 receptor‐mediated electrophysiological and behavioral activity via a Gi/o proteins and cAMP signaling pathway, which was a novel potential mechanism underlying analgesia of peripheral α2A‐AR agonists., The α2A‐adrenergic receptors (α2A‐ARs) primarily couple the Gi/o subtype of G‐protein family, which can inhibit intracellular adenylyl cyclase (AC), resulting in the decrease in cAMP levels and PKA activity. The activation of α2A‐ARs by dexmedetomidine (DEX) suppressed P2X3 receptors via the signaling pathway in rat DRG neurons. As a result of DEX treatment, α,β‐methylene‐ATP (α,β‐meATP), a P2X3 receptor agonist, evoked a reduced membrane current and then a decreased burst of action potentials (APs), leading to a relief of α,β‐meATP‐induced pain.
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- 2021
7. Local activation of α2 adrenergic receptors is required for vagus nerve stimulation induced motor cortical plasticity
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Canice Lei E. Dancel, Catherine A. Thorn, Solomon J. Gaulding, and Ching-Tzu Tseng
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Vagus Nerve Stimulation ,medicine.medical_treatment ,Movement ,Science ,Central nervous system ,Article ,Rats, Sprague-Dawley ,Norepinephrine ,Receptors, Adrenergic, alpha-2 ,Cortex (anatomy) ,Neuroplasticity ,medicine ,Animals ,Multidisciplinary ,α2 adrenergic receptor ,Neocortex ,Neuronal Plasticity ,business.industry ,Motor Cortex ,Stroke Rehabilitation ,Vagus Nerve ,Rats ,Receptors, Adrenergic ,Stroke ,Disease Models, Animal ,medicine.anatomical_structure ,Cortex ,Medicine ,Female ,Forelimb ,business ,Neuroscience ,Vagus nerve stimulation ,Motor cortex - Abstract
Vagus nerve stimulation (VNS) paired with rehabilitation training is emerging as a potential treatment for improving recovery of motor function following stroke. In rats, VNS paired with skilled forelimb training results in significant reorganization of the somatotopic cortical motor map; however, the mechanisms underlying this form of VNS-dependent plasticity remain unclear. Recent studies have shown that VNS-driven cortical plasticity is dependent on noradrenergic innervation of the neocortex. In the central nervous system, noradrenergic α2 receptors (α2-ARs) are widely expressed in the motor cortex and have been critically implicated in synaptic communication and plasticity. In current study, we examined whether activation of cortical α2-ARs is necessary for VNS-driven motor cortical reorganization to occur. Consistent with previous studies, we found that VNS paired with motor training enlarges the map representation of task-relevant musculature in the motor cortex. Infusion of α2-AR antagonists into M1 blocked VNS-driven motor map reorganization from occurring. Our results suggest that local α2-AR activation is required for VNS-induced cortical reorganization to occur, providing insight into the mechanisms that may underlie the neuroplastic effects of VNS therapy.
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- 2021
8. Inhibition of transient receptor potential vanilloid type 1 through α2 adrenergic receptors at peripheral nerve terminals relieves pain
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MATSUSHITA, Yumi, MANABE, Miki, KITAGAWA, Issei, HIGUCHI, Masashi, HOSAKA, Yoshinao Z, and KITAMURA, Naoki
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Nociception ,Full Paper ,Physiology ,adrenergic system ,transient receptor potential vanilloid type 1 ,Pain ,TRPV Cation Channels ,analgesia ,Clonidine ,Rats ,nervous system ,peripheral nervous system ,Receptors, Adrenergic, alpha-2 ,Adrenergic alpha-2 Receptor Agonists ,Animals ,Pain Management ,Peripheral Nerves - Abstract
The activation of α2 adrenergic receptors contributes to analgesia not only in the central nervous system but also in the peripheral nervous system. We reported that noradrenaline inhibits the activity of transient receptor potential vanilloid 1 (TRPV1) evoked by capsaicin through α2 receptors in cultured rat dorsal root ganglion (DRG) neurons. However, it is unclear whether activation of TRPV1 expressed in peripheral nerve terminals is inhibited by α2 receptors and whether this phenomenon contributes to analgesia. Therefore, we examined effects of clonidine, an α2 receptor agonist, on several types of nociceptive behaviors, which may be caused by TRPV1 activity, and subtypes of α2 receptors expressed with TRPV1 in primary sensory neurons in rats. Capsaicin injected into hind paws evoked nociceptive behaviors and clonidine preinjected into the same site inhibited capsaicin-evoked responses. This inhibition was not observed when clonidine was injected into the contralateral hind paws. Preinjection of clonidine into the plantar surface of ipsilateral, but not contralateral, hind paws reduced the sensitivity to heat stimuli. Clonidine partially reduced formalin-evoked responses when it was preinjected into ipsilateral hind paws. The expression level of α2C receptor mRNA quantified by real-time PCR was highest followed by those of α2A and α2B receptors in DRGs. α2A and α2C receptor-like immunoreactivities were detected with TRPV1-like immunoreactivities in the same neurons. These results suggest that TRPV1 and α2 receptors are coexpressed in peripheral nerve terminals and that the functional association between these two molecules causes analgesia.
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- 2021
9. Dexmedetomidine Promotes Angiogenesis and Vasculogenic Mimicry in Human Hepatocellular Carcinoma through α
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Tao, Fang, Li, Lin, Zhi Jian, Ye, Lian, Fang, Shuai, Shi, Ke Da, Yu, Hui Hui, Miao, and Tian Zuo, Li
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Cardiovascular Physiological Phenomena ,Oxygen ,Vascular Endothelial Growth Factor A ,Mice ,Carcinoma, Hepatocellular ,Receptors, Adrenergic, alpha-2 ,Liver Neoplasms ,Adrenergic alpha-2 Receptor Agonists ,Tumor Microenvironment ,Animals ,Humans ,Hypoxia ,Dexmedetomidine - Abstract
Dexmedetomidine (DEX), the most specific αWe used SMMC-7721 cells, MHCC97-H cells, and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry (VM) and its mechanism. Under normoxic (20% OThe results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range, and the addition of yohimbine inhibited this effect. DEX could activate HIF-1α/VEGFA pathway, which was further verified by silencing HIF-1α. Consistently,We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma, whereas α
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- 2022
10. Noradrenergic Signaling Disengages Feedforward Transmission in the Nucleus Accumbens Shell
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Brad A. Grueter, Kevin M. Manz, Carrie A. Grueter, Brenda C Shields, Benjamin C. Coleman, and Michael R. Tadross
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Male ,0301 basic medicine ,Patch-Clamp Techniques ,Interneuron ,Optogenetics ,Nucleus accumbens ,Medium spiny neuron ,Inhibitory postsynaptic potential ,Synaptic Transmission ,Nucleus Accumbens ,Mice ,Norepinephrine ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Interneurons ,Parasympathetic Nervous System ,Receptors, Adrenergic, alpha-2 ,Monoaminergic ,medicine ,Animals ,Research Articles ,Neurons ,Chemistry ,General Neuroscience ,Neural Inhibition ,Electrophysiological Phenomena ,Parvalbumins ,030104 developmental biology ,Monoamine neurotransmitter ,medicine.anatomical_structure ,nervous system ,Female ,Nerve Net ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Using a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice. Surprisingly, NE had little direct effect on modulation of synaptic input at medium spiny projection neurons (MSNs). In contrast, we report that NE transmission selectively modulates glutamatergic synapses onto PV-expressing fast-spiking interneurons (PV-INs) by recruiting postsynaptically-localized α2-adrenergic receptors (ARs). The synaptic effects of α2-AR activity decrease PV-IN-dependent feedforward inhibition onto MSNs evoked via optogenetic stimulation of cortical afferents to the NAcSh. These findings provide insight into a new circuit motif in which NE has a privileged line of communication to tune feedforward inhibition in the NAcSh.SIGNIFICANCE STATEMENTThe nucleus accumbens (NAc) directs reward-related motivational output by integrating glutamatergic input with diverse neuromodulatory input from monoamine centers. The present study reveals a synapse-specific regulatory mechanism recruited by norepinephrine (NE) signaling within parvalbumin-expressing interneuron (PV-IN) feedforward inhibitory microcircuits. PV-IN-mediated feedforward inhibition in the NAc is instrumental in coordinating NAc output by synchronizing the activity of medium spiny projection neurons (MSNs). By negatively regulating glutamatergic transmission onto PV-INs via α2-adrenergic receptors (ARs), NE diminishes feedforward inhibition onto MSNs to promote NAc output. These findings elucidate previously unknown microcircuit mechanisms recruited by the historically overlooked NE system in the NAc.
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- 2021
11. Streamlined Target Deconvolution Approach Utilizing a Single Photoreactive Chloroalkane Capture Tag
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Rachel Friedman Ohana, Keith V. Wood, Robin Hurst, Kristopher Zimmerman, Michael M. Rosenblatt, Sergiy Levin, Thomas Machleidt, and Thomas A. Kirkland
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Proteomics ,0301 basic medicine ,Azides ,Membrane permeability ,Hydrolases ,Ultraviolet Rays ,Dasatinib ,01 natural sciences ,Biochemistry ,Histone Deacetylases ,Mass Spectrometry ,03 medical and health sciences ,Low affinity ,Receptors, Adrenergic, alpha-2 ,Hydrocarbons, Chlorinated ,Humans ,Vorinostat ,010405 organic chemistry ,Chemistry ,Drug discovery ,Affinity Labels ,General Medicine ,Selective isolation ,Propranolol ,0104 chemical sciences ,Transmembrane domain ,Cross-Linking Reagents ,030104 developmental biology ,Membrane ,Diazomethane ,Covalent bond ,Biophysics ,Molecular Medicine ,Deconvolution ,K562 Cells ,Protein Kinases ,Chromatography, Liquid - Abstract
Identification of physiologically relevant targets for lead compounds emerging from drug discovery screens is often the rate-limiting step toward understanding their mechanism of action and potential for undesired off-target effects. To this end, we developed a streamlined chemical proteomic approach utilizing a single, photoreactive cleavable chloroalkane capture tag, which upon attachment to bioactive compounds facilitates selective isolation of their respective cellular targets for subsequent identification by mass spectrometry. When properly positioned, the tag does not significantly affect compound potency and membrane permeability, allowing for binding interactions with the tethered compound (probe) to be established within intact cells under physiological conditions. Subsequent UV-induced covalent photo-cross-linking "freezes" the interactions between the probe and its cellular targets and prevents their dissociation upon cell lysis. Targets cross-linked to the capture tag are then efficiently enriched through covalent capture onto HaloTag coated beads and subsequent selective chemical release from the solid support. The tag's built-in capability for selective enrichment eliminates the need for ligation of a capture tag, thereby simplifying the workflow and reducing variability introduced through additional operational steps. At the same time, the capacity for adequate cross-linking without structural optimization permits modular assembly of photoreactive chloroalkane probes, which reduces the burden of customized chemistry. Using three model compounds, we demonstrate the capability of this approach to identify known and novel cellular targets, including those with low affinity and/or low abundance as well as membrane targets with several transmembrane domains.
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- 2021
12. A pilot study of ADRA2A genotype association with doses of dexmedetomidine for sedation in pediatric patients
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Katherine A. Gallaway, Todd C. Skaar, Ashwin Biju, James Slaven, and Emma M. Tillman
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Adult ,Intensive Care Units ,Genotype ,Receptors, Adrenergic, alpha-2 ,Humans ,Hypnotics and Sedatives ,Pharmacology (medical) ,Pilot Projects ,Child ,Dexmedetomidine - Abstract
Dexmedetomidine is titrated to achieve sedation in the pediatric and cardiovascular intensive care units (PICU and CVICU). In adults, dexmedetomidine response has been associated with an ADRA2A polymorphism (rs1800544); CC genotype is associated with an increased sedative response compared with GC and GG. To date, this has not been studied in children.We conducted a pilot study to determine whether ADRA2A genotype is associated with dexmedetomidine dose in children.Forty intubated PICU or CVICU patients who received dexmedetomidine as a continuous infusion for at least 2 days were genotyped for ADRA2A with a custom-designed TaqMan® Assay. Ten (25%) subjects were wildtype (GG), 15 (37.5%) were heterozygous (GC), and 15 (37.5%) were homozygous (CC) variant. The maximum dexmedetomidine doses (mCg/kg/h) were not different between genotype groups CC (1, 0.3-1.2), GC (1, 0.3-1.3), and GG (0.8, 0.3-1.2), (p = 0.37); neither were mean dexmedetomidine doses for these respective genotype groups 0.68 (0.24-1.07), 0.72 (0.22-0.98), 0.58 (0.3-0.94), (p = 0.67).These findings did not confirm the results from adult studies where ADRA2A polymorphisms correlate with dexmedetomidine response, therefore highlighting the need for pediatric studies to validate PGx findings in adults prior to implementation in pediatrics.
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- 2022
13. Interactive Effects of
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Samuel, Obeng, Francisco, Leon, Avi, Patel, Julio D, Zuarth Gonzalez, Lucas, Chaves Da Silva, Luis F, Restrepo, Lea R, Gamez-Jimenez, Nicholas P, Ho, Maria P, Guerrero Calvache, Victoria L C, Pallares, Justin A, Helmes, Sakura K, Shiomitsu, Paul L, Soto, Christopher R, McCurdy, Lance R, McMahon, Jenny L, Wilkerson, and Takato, Hiranita
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Analgesics, Opioid ,Mitragyna ,Receptors, Adrenergic, alpha-2 ,Adrenergic alpha-2 Receptor Agonists ,Receptors, Opioid, mu ,Animals ,Yohimbine ,Secologanin Tryptamine Alkaloids ,Naltrexone ,Rats - Abstract
The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at
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- 2022
14. The effect of alpha-2A adrenergic receptor (ADRA2A) genetic polymorphisms on the depth of sedation of dexmedetomidine: a genetic observational pilot study
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Ju Yeon Park, Yoon Ji Choi, Won Kee Min, Kyu Hee Park, and Yoon Sook Lee
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medicine.drug_class ,medicine.medical_treatment ,Sedation ,Adrenergic ,Pilot Projects ,Polymorphism, Single Nucleotide ,Receptors, Adrenergic, alpha-2 ,medicine ,Alpha-2 ,Humans ,Hypnotics and Sedatives ,Dexmedetomidine ,Receptor ,Saline ,business.industry ,General Medicine ,Bispectral index ,Sedative ,Anesthesia ,Alpha-2 adrenergic receptor ,medicine.symptom ,business ,Polymorphisms ,medicine.drug - Abstract
Background The genetic polymorphisms of the alpha-2A adrenergic receptor (ADRA2A), which plays a significant role in sedation, anxiety relief, and antinociception, particularly in dexmedetomidine, may differ in the degree of sedation. This study aimed to investigate the effect of the genetic polymorphisms of ADRA2A (rs11195418, rs1800544, rs2484516, rs1800545, rs553668, rs3750625) on the sedative effects of dexmedetomidine. Methods A total of 131 patients aged 50 years or more from May 2018 to August 2019 were included in this study. The ADRA2A gene variants were evaluated using the TaqMan Assay. Dexmedetomidine diluted in normal saline to a concentration of 4 μg.mL-1 was infused at a dose of 2 μg.kg-1 to achieve procedural sedation (modified Ramsay sedation scale 4 [mRSS 4]). Results A total of 131 patients were evaluated. The genetic polymorphisms (rs11195418) of the ADRA2A receptor gene demonstrated no variation in our participants. The ADRA2A receptor gene polymorphisms (rs1800544, rs2484516, rs1800545, rs553668, and rs3750625) exhibited no differences in total dexmedetomidine doses (p > 0.217), bispectral index at mRSS 4 (p > 0.620), and time to obtain mRSS 4 (p > 0.349). Conclusion This study suggested that the genetic polymorphisms of ADRA2A did not affect the sedative efficacy of dexmedetomidine.
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- 2022
15. Human C1orf27 protein interacts with α
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Xin, Xu and Guangyu, Wu
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Protein Transport ,Receptors, Adrenergic, alpha-2 ,Gene Knockdown Techniques ,Golgi Apparatus ,Humans ,Membrane Proteins ,CRISPR-Cas Systems ,RNA, Small Interfering ,Endoplasmic Reticulum ,Receptors, G-Protein-Coupled - Abstract
The molecular mechanisms underlying the anterograde surface transport of G protein-coupled receptors (GPCRs) after their synthesis in the endoplasmic reticulum (ER) are not well defined. In C. elegans, odorant response abnormal 4 has been implicated in the delivery of olfactory GPCRs to the cilia of chemosensory neurons. However, the function and regulation of its human homolog, C1orf27, in GPCR transport or in general membrane trafficking remain unknown. Here, we demonstrate that siRNA-mediated knockdown of C1orf27 markedly impedes the ER-to-Golgi export kinetics of newly synthesized α
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- 2022
16. Dexmedetomidine alleviates inflammatory response and oxidative stress injury of vascular smooth muscle cell via α2AR/GSK-3β/MKP-1/NRF2 axis in intracranial aneurysm
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Ze Zhang, Xiue Mu, and Xiaohui Zhou
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Pharmacology ,Inflammation ,Glycogen Synthase Kinase 3 beta ,NF-E2-Related Factor 2 ,Intracranial Aneurysm ,Hydrogen Peroxide ,Muscle, Smooth, Vascular ,Sincalide ,Rats ,Rats, Sprague-Dawley ,Oxidative Stress ,Receptors, Adrenergic, alpha-2 ,Animals ,Cytokines ,Pharmacology (medical) ,Reactive Oxygen Species ,Dexmedetomidine - Abstract
Vascular smooth muscle cell (VSMC) phenotypic modulation regulates the initiation and progression of intracranial aneurysm (IA). Dexmedetomidine (DEX) is suggested to play neuroprotective roles in patients with craniocerebral injury. Therefore, we investigated the biological functions of DEX and its mechanisms against IA formation and progression in the current study. The rat primary VSMCs were isolated from Sprague–Dawley rats. IA and superficial temporal artery (STA) tissue samples were obtained from patients with IA. Flow cytometry was conducted to identify the characteristics of isolated VSMCs. Hydrogen peroxide (H2O2) was used to mimic IA-like conditions in vitro. Cell viability was detected using CCK-8 assays. Wound healing and Transwell assays were performed to detect cell motility. ROS production was determined by immunofluorescence using DCFH-DA probes. Western blotting and RT-qPCR were carried out to measure gene expression levels. Inflammation responses were determined by measuring inflammatory cytokines. Immunohistochemistry staining was conducted to measure α2-adrenergic receptor levels in tissue samples. DEX alleviated the H2O2-induced cytotoxicity, attenuated the promoting effects of H2O2 on cell malignancy, and protected VSMCs against H2O2-induced oxidative damage and inflammation response. DEX regulated the GSK-3β/MKP-1/NRF2 pathway via the α2AR. DEX alleviates the inflammatory responses and oxidative damage of VSMCs by regulating the GSK-3β/MKP-1/NRF2 pathway via the α2AR in IA.
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- 2022
17. Alpha-2 Adrenoreceptor Antagonist Yohimbine Potentiates Consolidation of Conditioned Fear
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Matthias F J Sperl, Christian Panitz, Nadine Skoluda, Urs M Nater, Diego A Pizzagalli, Christiane Hermann, and Erik M Mueller
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Male ,Pharmacology ,sulpiride ,Fear conditioning ,Fear ,Adrenergic alpha-2 Receptor Antagonists ,Extinction, Psychological ,norepinephrine ,Psychiatry and Mental health ,Receptors, Adrenergic, alpha-2 ,Salivary alpha-Amylases ,Humans ,Pharmacology (medical) ,yohimbine ,dopamine - Abstract
Background Hyperconsolidation of aversive associations and poor extinction learning have been hypothesized to be crucial in the acquisition of pathological fear. Previous animal and human research points to the potential role of the catecholaminergic system, particularly noradrenaline and dopamine, in acquiring emotional memories. Here, we investigated in a between-participants design with 3 groups whether the noradrenergic alpha-2 adrenoreceptor antagonist yohimbine and the dopaminergic D2-receptor antagonist sulpiride modulate long-term fear conditioning and extinction in humans. Methods Fifty-five healthy male students were recruited. The final sample consisted of n = 51 participants who were explicitly aware of the contingencies between conditioned stimuli (CS) and unconditioned stimuli after fear acquisition. The participants were then randomly assigned to 1 of the 3 groups and received either yohimbine (10 mg, n = 17), sulpiride (200 mg, n = 16), or placebo (n = 18) between fear acquisition and extinction. Recall of conditioned (non-extinguished CS+ vs CS−) and extinguished fear (extinguished CS+ vs CS−) was assessed 1 day later, and a 64-channel electroencephalogram was recorded. Results The yohimbine group showed increased salivary alpha-amylase activity, confirming a successful manipulation of central noradrenergic release. Elevated fear-conditioned bradycardia and larger differential amplitudes of the N170 and late positive potential components in the event-related brain potential indicated that yohimbine treatment (compared with a placebo and sulpiride) enhanced fear recall during day 2. Conclusions These results suggest that yohimbine potentiates cardiac and central electrophysiological signatures of fear memory consolidation. They thereby elucidate the key role of noradrenaline in strengthening the consolidation of conditioned fear associations, which may be a key mechanism in the etiology of fear-related disorders.
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- 2022
18. Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence
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Qian, Li, Yuanjun, Deng, Lele, Liu, Chunjiang, Zhang, Yang, Cai, Tianjing, Zhang, Min, Han, and Gang, Xu
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neuroimmune ,Immunology ,urologic and male genital diseases ,Mice ,Receptors, Adrenergic, alpha-2 ,Animals ,Immunology and Allergy ,cellular senescence ,Sympathectomy ,neurometabolic ,Original Research ,renal fibrosis ,RC581-607 ,Fibrosis ,Immunohistochemistry ,Mitochondria ,sympathetic denervation ,Disease Models, Animal ,Gene Expression Regulation ,Cytokines ,Kidney Diseases ,Disease Susceptibility ,Inflammation Mediators ,Immunologic diseases. Allergy ,Energy Metabolism ,Biomarkers ,Signal Transduction - Abstract
ObjectiveContinuous overactivation of the renal sympathetic nerve is considered to be an important cause of renal fibrosis. Accumulated senescent cells in the damaged kidney have metabolic activities and secrete amounts of proinflammatory factors as part of the SASP (the senescence-associated secretory phenotype), which induce chronic inflammation and fibrosis. It is still unclear whether renal sympathetic nerves affect renal inflammation and fibrosis by regulating cellular senescence. Therefore, we hypothesize that sympathetic activation in the injured kidney induces cellular senescence, which contributes to progressive renal inflammation and fibrosis.MethodsRenal denervation was performed 2 days before the UUO (unilateral ureteral obstruction) and UIRI (unilateral ischemia-reperfusion injury) models. The effects of renal denervation on renal fibrosis and cellular senescence were observed. In vitro, cellular senescence was induced in renal proximal tubular epithelial cell lines (TKPTS cells) by treatment with norepinephrine (NE). The selective α2A-adrenergic receptor (α2A-AR) antagonists BRL44408 and β-arrestin2 siRNA, were administered to inhibit NE-induced cellular senescence. A significantly altered pathway was identified through immunoblotting, immunofluorescence, immunocytochemistry, and functional assays involved in mitochondrial function.ResultsRenal fibrosis and cellular senescence were significantly increased in UUO and UIRI models, which were partially reversed by renal denervation. In vitro, NE induced epithelial cells secreting proinflammatory cytokines and promoted cell senescence by activating α2A-AR. Importantly, the effects of NE during cellular senescence were blocked by α2A-AR selective antagonist and β-arrestin2 (downstream of α2A-AR) siRNA.ConclusionRenal sympathetic activation and cellular senescence are important neurometabolic and neuroimmune mechanisms in the development of renal fibrosis. Renal sympathetic neurotransmitter NE acting on the α2A-AR of epithelial cells promotes cellular senescence through the downstream β-arrestin2 signaling, which is a potential preventive target for renal fibrosis.
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- 2022
19. Effect of dexmedetomidine on cardiorespiratory regulation in spontaneously breathing adult rats
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Yoichiro Kitajima, Nana Sato Hashizume, Chikako Saiki, Ryoji Ide, and Toshio Imai
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Male ,Physiology ,Blood Pressure ,Biochemistry ,Vascular Medicine ,Body Temperature ,Heart Rate ,Adrenergic alpha-2 Receptor Agonists ,Medicine and Health Sciences ,Multidisciplinary ,Isoflurane ,Organic Compounds ,Respiration ,Monosaccharides ,Imidazoles ,Hematology ,Adrenergic alpha-2 Receptor Antagonists ,Body Fluids ,Chemistry ,Blood ,Cardiorespiratory Fitness ,Physiological Parameters ,Hematocrit ,Breathing ,Hypertension ,Physical Sciences ,Engineering and Technology ,Medicine ,Anatomy ,Dexmedetomidine ,Research Article ,Biotechnology ,Catheters ,Science ,Carbohydrates ,Bioengineering ,Receptors, Adrenergic, alpha-2 ,Animals ,Arterial Pressure ,Hemoglobin ,Rats, Wistar ,Benzofurans ,Organic Chemistry ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Rats ,Blood Counts ,Glucose ,Medical Devices and Equipment ,Blood Gas Analysis ,Physiological Processes - Abstract
Purpose We examined the cardiorespiratory effect of dexmedetomidine, an α2- adrenoceptor/imidazoline 1 (I1) receptor agonist, in spontaneously breathing adult rats. Methods Male rats (226−301 g, n = 49) under isoflurane anesthesia had their tail vein cannulated for drug administration and their tail artery cannulated for analysis of mean arterial pressure (MAP), pulse rate (PR), and arterial blood gases (PaO2, PaCO2, pH). After recovery, one set of rats received normal saline for control recording and was then divided into three experimental groups, two receiving dexmedetomidine (5 or 50 μg·kg−1) and one receiving normal saline (n = 7 per group). Another set of rats was divided into four groups receiving dexmedetomidine (50 μg·kg−1) followed 5 min later by 0.5 or 1 mg∙kg−1 atipamezole (selective α2-adrenoceptor antagonist) or efaroxan (α2-adrenoceptor/I1 receptor antagonist) (n = 6 or 8 per group). Recordings were performed 15 min after normal saline or dexmedetomidine administration. Results Compared with normal saline, dexmedetomidine (5 and 50 μg·kg−1) decreased respiratory frequency (fR, p = 0.04 and < 0.01, respectively), PR (both p < 0.01), and PaO2 (p = 0.04 and < 0.01), and increased tidal volume (both p = 0.049). Dexmedetomidine at 5 μg·kg−1 did not significantly change minute ventilation (V′E) (p = 0.87) or MAP (p = 0.24), whereas dexmedetomidine at 50 μg·kg−1 significantly decreased V′E (p = 0.03) and increased MAP (p < 0.01). Only dexmedetomidine at 50 μg·kg−1 increased PaCO2 (p < 0.01). Dexmedetomidine (5 and 50 μg·kg−1) significantly increased blood glucose (p < 0.01), and dexmedetomidine at 50 μg·kg−1 increased hemoglobin (p = 0.04). Supplemental atipamezole or efaroxan administration similarly prevented the 50 μg·kg−1 dexmedetomidine-related cardiorespiratory changes. Principal conclusion These results suggest that dexmedetomidine-related hypoventilation and hypertension are observed simultaneously and occur predominantly through activation of α2-adrenoceptors, but not I1 receptors, in spontaneously breathing adult rats.
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- 2022
20. Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation
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Chen Qu, Hao Wang, Shuang Peng, Xue Ning, Jian Hong, Aimin Li, Wenyu Lin, Yue Luo, Peng Chen, Xiaojun Luo, Penghui Xie, Guanqi Dai, and Yuchuan Jiang
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0301 basic medicine ,Liver Cirrhosis ,Male ,Clinical Biochemistry ,Biochemistry ,Cell growth ,0302 clinical medicine ,polycyclic compounds ,Neoplasm Metastasis ,Receptor ,Liver Neoplasms ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Disease Progression ,Medicine ,Molecular Medicine ,Chemokines ,hormones, hormone substitutes, and hormone antagonists ,Dexmedetomidine ,Cancer microenvironment ,STAT3 Transcription Factor ,endocrine system ,Carcinoma, Hepatocellular ,QD415-436 ,Malignancy ,Article ,03 medical and health sciences ,Receptors, Adrenergic, alpha-2 ,Cell Line, Tumor ,Carcinoma ,medicine ,Hepatic Stellate Cells ,Animals ,Humans ,Molecular Biology ,Cell Proliferation ,business.industry ,Interleukin-6 ,medicine.disease ,Hepatic stellate cell activation ,digestive system diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Cell culture ,Tumor progression ,Cancer research ,Hepatic stellate cell ,business - Abstract
Dexmedetomidine (DEX) is an anesthetic that is widely used in the clinic, and it has been reported to exhibit paradoxical effects in the progression of multiple solid tumors. In this study, we sought to explore the mechanism by which DEX regulates hepatocellular carcinoma (HCC) progression underlying liver fibrosis. We determined the effects of DEX on tumor progression in an orthotopic HCC mouse model of fibrotic liver. A coculture system and a subcutaneous xenograft model involving coimplantation of mouse hepatoma cells (H22) and primary activated hepatic stellate cells (aHSCs) were used to study the effects of DEX on HCC progression. We found that in the preclinical mouse model of liver fibrosis, DEX treatment significantly shortened median survival time and promoted tumor growth, intrahepatic metastasis and pulmonary metastasis. The DEX receptor (ADRA2A) was mainly expressed in aHSCs but was barely detected in HCC cells. DEX dramatically reinforced HCC malignant behaviors in the presence of aHSCs in both the coculture system and the coimplantation mouse model, but DEX alone exerted no significant effects on the malignancy of HCC. Mechanistically, DEX induced IL-6 secretion from aHSCs and promoted HCC progression via STAT3 activation. Our findings provide evidence that the clinical application of DEX may cause undesirable side effects in HCC patients with liver fibrosis., Liver cancer: Common anesthetic can accelerate tumor progression Researchers warn against using the anesthetic dexmedetomidine (DEX) in liver cancer patients after indications that it promotes tumor growth. Concerns have been raised that certain anesthetics, including DEX, can accelerate the progression of cancerous tumors, but the precise effects of DEX on liver cancer tumors are unclear. Most liver cancers develop in patients who already have fibrosis, a build-up of scarred tissue in the liver. This tissue accumulation stems from the activation of hepatic stellate cells (HSCs) during liver damage. Using human cancer cell lines and mouse models, Aimin Li and Xue Ning at the Southern Medical University, Guangzhou, China and co-workers demonstrated that DEX interacts with HSCs via a receptor protein on their cell surface, further enhancing activation levels. Activated HSCs in turn secrete factors that accelerate tumor growth and invasion.
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- 2020
21. Evidence that the multiflorine‐derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α 2 ‐adrenoceptors in mice
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Immanuel Adorjan, Leonhardt Bauer, Clemens Fürnsinn, Karin Stadlbauer, B. Brunmair, Thomas Scherer, Miroslav Genov, Zsuzsanna Lehner, Alexandra Kautzky-Willer, and Mika Scheinin
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Blood Glucose ,Male ,insulin secretion ,medicine.medical_specialty ,Adrenergic receptor ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Adrenergic ,030209 endocrinology & metabolism ,Stimulation ,030204 cardiovascular system & hematology ,Mice ,03 medical and health sciences ,Alkaloids ,0302 clinical medicine ,Endocrinology ,Receptors, Adrenergic, alpha-2 ,In vivo ,Internal medicine ,drug mechanism ,Internal Medicine ,Animals ,Insulin ,Medicine ,animal pharmacology ,antidiabetic drug ,Glucose tolerance test ,medicine.diagnostic_test ,business.industry ,Original Articles ,drug development ,Mechanism of action ,Original Article ,medicine.symptom ,business ,Vasoconstriction - Abstract
Aims To investigate the mechanism of action of 55P0251, a novel multiflorine‐derived substituted quinazolidine that augments insulin release and lowers blood glucose in rodents, but does not act via mechanisms addressed by any antidiabetic agent in clinical use. Materials and Methods Using male mice, we determined the effects of 55P0251 on glucose tolerance, insulin secretion from isolated islets and blood oxygen saturation, including head‐to‐head comparison of 55P0251 to its inverted enantiomer 55P0250, as well as to other anti‐hyperglycaemic multiflorine derivatives discovered in our programme. Results 55P0251 was clearly superior to its inverted enantiomer in the glucose tolerance test (area under the curve: 11.3 mg/kg 55P0251, 1.19 ± 0.04 min*mol/L vs 55P0250, 1.80 ± 0.04 min*mol/L; P
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- 2019
22. The Predictive Role of ADRA2A rs1800544 and HTR3B rs3758987 Polymorphisms in Motion Sickness Susceptibility
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Xinchen Zhang and Yeqing Sun
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Heterozygote ,vomiting ,Genotype ,Motion Sickness ,motion sickness susceptibility ,ADRA2A rs1800544 ,HTR3B rs3758987 ,sailing environment ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Polymorphism, Single Nucleotide ,Article ,Receptors, Adrenergic, alpha-2 ,Humans ,Medicine ,Genetic Predisposition to Disease ,Receptors, Serotonin, 5-HT3 - Abstract
Motion sickness is a common central nervous system response, the primary sign of which is vomiting. Its susceptibility varies between individuals. To find predictive factors, we investigated the association of ADRA2A rs1800544 and HTR3B rs3758987 with motion sickness susceptibility and examined their mRNA changes during actual voyages. A total of 315 healthy college students were enrolled for SNP genotyping by the PCR-RFLP method. Blood samples were collected from another 42 subjects during two separate voyages to detect their mRNA expression changes at three time points. The frequency of the rs1800544 GG genotype in the susceptibility group was significantly higher (52.26%), and allele G increased the risk of motion sickness (OR = 1.585, 95% CI = 1.136–2.208). In the logistic regression model, the rs3758987 CC+TC genotype and rs1800544 GG genotype increased the risk of motion sickness-induced vomiting (OR = 2.105, 95% CI = 1.112–3.984; OR = 1.992, 95% CI = 1.114–3.571). The ADRA2A mRNA baseline was lower in the GG carriers and the HTR3B mRNA baseline was lower in the TC/CC carriers before sailing, then increased significantly within 24 h and then decreased after a long-term voyage. People carrying the rs1800544 GG genotype seem more susceptible to motion sickness. In combination with the incidence of vomiting during the actual-voyage experiments, our results indicate the involvement of rs1800544 and rs3758987 in motion sickness-induced vomiting.
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- 2021
23. Dexmedetomidine Promotes Lipopolysaccharide-Induced Differentiation of Cardiac Fibroblasts and Collagen I/III Synthesis through α2A Adrenoreceptor-Mediated Activation of the PKC-p38-Smad2/3 Signaling Pathway in Mice
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Jiashuo Teng, Xiaomeng Dai, Jia Liao, Yiyang Wang, Hongmei Li, Huadong Wang, Xiuxiu Lv, Xiangxu Tang, Yingwei Wang, Xingyu Su, Kaiying Li, Yun Xing, Yaqian Xu, and Yihua Chen
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Lipopolysaccharides ,Male ,Cardiac fibrosis ,Stimulation ,Smad2 Protein ,p38 Mitogen-Activated Protein Kinases ,Mice ,polycyclic compounds ,Adrenergic alpha-2 Receptor Agonists ,Biology (General) ,Myofibroblasts ,Spectroscopy ,Protein Kinase C ,Chemistry ,lipopolysaccharide ,virus diseases ,dexmedetomidine ,Cell Differentiation ,General Medicine ,differentiation ,cardiac fibroblast ,α2 adrenergic receptor ,Computer Science Applications ,Knockout mouse ,Tumor necrosis factor alpha ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,Agonist ,musculoskeletal diseases ,medicine.medical_specialty ,QH301-705.5 ,medicine.drug_class ,p38 mitogen-activated protein kinases ,Catalysis ,Article ,Collagen Type I ,Inorganic Chemistry ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,medicine ,Animals ,Smad3 Protein ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Protein kinase C ,Organic Chemistry ,medicine.disease ,nervous system diseases ,Mice, Inbred C57BL ,Endocrinology ,Collagen Type III ,Gene Expression Regulation - Abstract
Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.
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- 2021
24. The α
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Leonardo, Sandrini, Patrizia, Amadio, Alessandro, Ieraci, Alessandro, Malara, José P, Werba, Paolo M, Soprano, Alessandra, Balduini, Marta, Zarà, Alice, Bonomi, Fabrizio, Veglia, Gualtiero I, Colombo, Maurizio, Popoli, Francis S, Lee, Elena, Tremoli, and Silvia S, Barbieri
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Aged, 80 and over ,Male ,Depression ,Brain-Derived Neurotrophic Factor ,Desipramine ,Thrombosis ,Coronary Artery Disease ,Middle Aged ,Polymorphism, Single Nucleotide ,Mice ,Norepinephrine ,Receptors, Adrenergic, alpha-2 ,Animals ,Humans ,Female ,Blood Coagulation ,Aged - Abstract
Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNF
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- 2021
25. Preclinical evaluation of new C-11 labeled benzo-1,4-dioxane PET radiotracers for brain α2C adrenergic receptors
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Santosh Alluri, Seth M. Eisenberg, Laurel A. Grisanti, Miles Tanner, Nora D. Volkow, Sung Won Kim, and Kun-Eek Kil
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Pharmacology ,Receptors, Adrenergic, alpha-2 ,Positron-Emission Tomography ,Organic Chemistry ,Drug Discovery ,Brain ,Carbon Radioisotopes ,General Medicine ,Piperazines - Abstract
As one of the nine subtypes of adrenergic receptors (ARs) in the brain, α2C-ARs play essential roles in emotion and memory, and are implicated in neuropsychiatric disorders, including depression, Alzheimer's disease, substance use disorder, and schizophrenia. A recently developed α2C-AR specific positron emission tomography (PET) radiotracer, [
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- 2022
26. 2-pentadecyl-2-oxazoline prevents cognitive and social behaviour impairments in the Amyloid β-induced Alzheimer-like mice model: Bring the α2 adrenergic receptor back into play
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R, Infantino, S, Boccella, D, Scuteri, M, Perrone, F, Ricciardi, R M, Vitale, R, Bonsale, A, Parente, I, Allocca, A, Virtuoso, C, De Luca, C, Belardo, P, Amodeo, V, Gentile, G, Cirillo, G, Bagetta, L, Luongo, S, Maione, F, Guida, Infantino, R., Boccella, S., Scuteri, D., Perrone, M., Ricciardi, F., Vitale, R. M., Bonsale, R., Parente, A., Allocca, I., Virtuoso, A., De Luca, C., Belardo, C., Amodeo, P., Gentile, V., Cirillo, G., Bagetta, G., Luongo, L., Maione, S., Guida, F., Infantino, R, Boccella, S, Scuteri, D, Perrone, M, Ricciardi, F, Vitale, R M, Bonsale, R, Parente, A, Allocca, I, Virtuoso, A, De Luca, C, Belardo, C, Amodeo, P, Gentile, V, Cirillo, G, Bagetta, G, Luongo, L, Maione, S, and Guida, F
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Pharmacology ,Mice ,Disease Models, Animal ,Amyloid beta-Peptides ,Cognition ,Receptors, Adrenergic, alpha-2 ,Alzheimer Disease ,Amyloid β (1−42) ,α2 adrenergic receptor ,Animals ,General Medicine ,2-pentadecyl-2-oxazoline ,Social Behavior - Abstract
The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind α2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid β 1-42 (sAβ1-42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the α2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sAβ injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of α2AR in neuropsychiatric illness and therapies.
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- 2022
27. Noradrenaline increases intracellular Ca
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Tomoko, Kimyo, Takuji, Machida, Kenji, Iizuka, Masaru, Minami, and Masahiko, Hirafuji
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Mice ,Norepinephrine ,Ileum ,Receptors, Adrenergic, alpha-2 ,Animals ,Calcium ,Epithelial Cells ,Calcium Channels ,Cells, Cultured - Abstract
The stimulation of α
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- 2021
28. Noradrenergic genes polymorphisms and response to methylphenidate in children with ADHD: A systematic review and meta-analysis
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Manxue Zhang, Yi Huang, Danfeng Yuan, Xinwei Wang, Yan Huang, and Jian Jiao
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Oncology ,Candidate gene ,medicine.medical_specialty ,rs5569 ,methylphenidate ,Norepinephrine ,Neurodevelopmental disorder ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,mental disorders ,medicine ,Humans ,noradrenergic gene polymorphism ,Allele ,child ,Norepinephrine Plasma Membrane Transport Proteins ,Polymorphism, Genetic ,Methylphenidate ,business.industry ,General Medicine ,Odds ratio ,medicine.disease ,Treatment Outcome ,Attention Deficit Disorder with Hyperactivity ,Pharmacogenetics ,Meta-analysis ,Pharmacogenomics ,adolescent ,Central Nervous System Stimulants ,Attention-deficit hyperactivity disorder ,business ,Systematic Review and Meta-Analysis ,medicine.drug ,Research Article - Abstract
Background: Attention-deficit hyperactivity disorder (ADHD) is the most common childhood-onset neurodevelopmental disorder, and methylphenidate (MPH) is considered one of the first-line medicine for ADHD. Unfortunately, this medication is only effective for some children with ADHD. This meta-analysis was conducted to evaluate whether noradrenergic gene polymorphisms impact the efficacy of MPH in children with ADHD. Methods: Candidate gene studies published in English until March 1, 2020, were identified through literature searches on PubMed, Web of Science, and Embase. Data were pooled from individual clinical trials considering MPH pharmacogenomics. According to the heterogeneity, the odds ratio and mean differences were calculated by applying fixed-effects or random-effects models. Results: This meta-analysis includes 15 studies and 1382 patients. Four polymorphisms of the NET gene (rs5569, rs28386840, rs2242446, rs3785143) and 2 polymorphisms of the α2A-adrenergic receptor gene (ADRA2A) gene (MspI and DraI) were selected for the analysis. In the pooled data from all studies, T allele carriers of the rs28386840 polymorphism were significantly more likely to respond to MPH (P
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- 2021
29. Crystal structure of the α
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Mattia, Deluigi, Lena, Morstein, Matthias, Schuster, Christoph, Klenk, Lisa, Merklinger, Riley R, Cridge, Lazarus A, de Zhang, Alexander, Klipp, Santiago, Vacca, Tasneem M, Vaid, Peer R E, Mittl, Pascal, Egloff, Stefanie A, Eberle, Oliver, Zerbe, David K, Chalmers, Daniel J, Scott, and Andreas, Plückthun
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Models, Molecular ,Binding Sites ,Crystallography, X-Ray ,Ligands ,Molecular conformation ,Lipids ,Article ,HEK293 Cells ,G protein-coupled receptors ,Receptors, Adrenergic, alpha-2 ,Quinoxalines ,Receptors, Adrenergic, alpha-1 ,Quinazolines ,Humans ,X-ray crystallography - Abstract
α-adrenergic receptors (αARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential of αARs, however, is largely unexploited and hampered by the scarcity of subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to αARs or fail to interact with the desired subtype. Here, we report the crystal structure of human α1BAR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The α1BAR structure allows the identification of two unique secondary binding pockets. By structural comparison of α1BAR with α2ARs, and by constructing α1BAR-α2CAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of α1BAR-selective ligands and may guide the optimization of aminergic drugs to prevent off-target binding to αARs, or to elicit a selective interaction with the desired subtype., This study reports the X-ray structure of the α1B-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects.
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- 2021
30. Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease
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Paul J. Fitzgerald
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0301 basic medicine ,Adrenergic Neurons ,cholinesterase inhibitors ,Synaptic Transmission ,Mice ,Norepinephrine ,0302 clinical medicine ,Phosphorylation ,Biology (General) ,Spectroscopy ,guanfacine ,Nootropic Agents ,Melatonin ,Neurotransmitter Agents ,Neurodegeneration ,neurodegeneration ,Drug Synergism ,General Medicine ,Hypothesis ,Computer Science Applications ,Chemistry ,Signal transduction ,Acetylcholine ,Selective Serotonin Reuptake Inhibitors ,medicine.drug ,Signal Transduction ,Cell signaling ,QH301-705.5 ,Models, Neurological ,tau Proteins ,Biology ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Adrenergic Agents ,Dopamine ,Alzheimer Disease ,Receptors, Adrenergic, alpha-2 ,medicine ,Animals ,Humans ,propranolol ,Physical and Theoretical Chemistry ,clonidine ,Molecular Biology ,QD1-999 ,5-HT receptor ,cognitive impairment ,Brain Chemistry ,prazosin ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,locus coeruleus ,Organic Chemistry ,medicine.disease ,Rats ,Disease Models, Animal ,030104 developmental biology ,noradrenaline ,Locus coeruleus ,Neuroscience ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,terazosin ,dementia - Abstract
While much of biomedical research since the middle of the twentieth century has focused on molecular pathways inside the cell, there is increasing evidence that extracellular signaling pathways are also critically important in health and disease. The neuromodulators norepinephrine (NE), serotonin (5-hydroxytryptamine, 5HT), dopamine (DA), acetylcholine (ACH), and melatonin (MT) are extracellular signaling molecules that are distributed throughout the brain and modulate many disease processes. The effects of these five neuromodulators on Alzheimer’s disease (AD) are briefly examined in this paper, and it is hypothesized that each of the five molecules has a u-shaped (or Janus-faced) dose-response curve, wherein too little or too much signaling is pathological in AD and possibly other diseases. In particular it is suggested that NE is largely functionally opposed to 5HT, ACH, MT, and possibly DA in AD. In this scenario, physiological “balance” between the noradrenergic tone and that of the other three or four modulators is most healthy. If NE is largely functionally opposed to other prominent neuromodulators in AD, this may suggest novel combinations of pharmacological agents to counteract this disease. It is also suggested that the majority of cases of AD and possibly other diseases involve an excess of noradrenergic tone and a collective deficit of the other four modulators.
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- 2021
31. Acetaminophen Exerts an Analgesic Effect on Muscular Hyperalgesia in Repeated Cold-Stressed Rats through the Enhancement of the Descending Pain Inhibitory System Involving Spinal 5-HT
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Chiharu, Yamaguchi, Daisuke, Yamamoto, Yukiko, Fujimaru, Toshiki, Asano, and Akiko, Takaoka
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Male ,Pain Threshold ,Serotonin ,Cold-Shock Response ,Ibuprofen ,Myalgia ,Analgesics, Non-Narcotic ,Hindlimb ,Cold Temperature ,Rats, Sprague-Dawley ,Disease Models, Animal ,Spinal Cord ,Hyperalgesia ,Receptors, Adrenergic, alpha-2 ,Receptors, Serotonin ,Animals ,Neuralgia ,Cyclooxygenase Inhibitors ,Muscle, Skeletal ,Acetaminophen - Abstract
Musculoskeletal and psychological complaints have increased with the widespread use of visual display terminals, and musculoskeletal pain is known to be closely related to stress. One method of experimentally inducing persistent muscle pain is repeated cold stress (RCS), and animals exposed to such stress exhibit a dysfunction in the descending pain inhibitory system. Acetaminophen (N-acetyl-p-aminophenol; APAP) is widely used to relieve several types of pain, including musculoskeletal pain, and is available as an OTC drug. However, the mechanism underlying its analgesic action has not yet been fully elucidated. In this study, we compared the analgesic effect of APAP on RCS-induced muscular hyperalgesia with those of other analgesics to identify its mechanism of action. The daily oral administration of APAP significantly suppressed the decrease in the mechanical withdrawal threshold caused by RCS, similar to the results for neurotropin but not for the cyclooxygenase inhibitor ibuprofen (IBP). Moreover, the intrathecal administration of antagonists of the 5-hydroxytryptamine (5-HT)
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- 2021
32. Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties
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Anna Dziubina, Patryk Kasza, Matylda Stefaniak, Beata Duszyńska, Xavier Bantreil, Agata Siwek, Vittorio Canale, Krzysztof Marciniec, Magdalena Kotańska, Gabriela Starowicz, Frédéric Lamaty, Jacek Sapa, Marek Bednarski, Grzegorz Satała, Paweł Zajdel, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Medical University of Silesia (SUM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Medical University of Silesia, and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Pharmaceutical Science ,Organic chemistry ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Pharmacology ,Ligands ,medicinal mechanochemistry ,01 natural sciences ,α2 adrenoceptor antagonist ,Analytical Chemistry ,5-HT7 receptor ,Mice ,Norepinephrine ,QD241-441 ,Piperidines ,Drug Discovery ,Receptor ,Chemistry ,Adrenergic alpha-2 Receptor Antagonists ,Receptor antagonist ,Antidepressive Agents ,3. Good health ,Chemistry (miscellaneous) ,Dopamine receptor ,depression ,Molecular Medicine ,Antidepressant ,5-HT7 receptor antagonist ,medicine.drug ,Serotonin ,medicine.drug_class ,Mirtazapine ,Motor Activity ,010402 general chemistry ,Article ,Receptors, Adrenergic, alpha-2 ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Swimming ,forced swim test ,010405 organic chemistry ,5-HT 7 receptor antagonist ,α 2 adrenoceptor antagonist ,0104 chemical sciences ,Rats ,HEK293 Cells ,Receptors, Serotonin ,Behavior Rating Scale ,Behavioural despair test - Abstract
The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.
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- 2021
33. Adrenergic α2 receptors are implicated in seizure-induced respiratory arrest in DBA/1 mice
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Rui Zhang, Jianguo Niu, Hua-Jun Feng, and Zheren Tan
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Agonist ,medicine.drug_class ,Pharmacology ,Atomoxetine Hydrochloride ,General Biochemistry, Genetics and Molecular Biology ,Clonidine ,Article ,chemistry.chemical_compound ,Norepinephrine reuptake inhibitor ,Receptors, Adrenergic, alpha-2 ,Seizures ,medicine ,Prazosin ,Adrenergic alpha-2 Receptor Agonists ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Adrenergic alpha-Antagonists ,business.industry ,Respiration ,Atomoxetine ,Antagonist ,Imidazoles ,General Medicine ,Cirazoline ,Yohimbine ,chemistry ,Mice, Inbred DBA ,business ,medicine.drug - Abstract
Aims Sudden unexpected death in epilepsy (SUDEP) is a serious and underestimated public health burden. Both clinical and animal studies show that seizure-induced respiratory arrest (S-IRA) is the primary cause of death in SUDEP. Our previous studies demonstrated that atomoxetine, a norepinephrine reuptake inhibitor (NRI), suppresses S-IRA in DBA/1 mice, suggesting that noradrenergic neurotransmission modulates S-IRA. However, it remains unclear which adrenoceptors are implicated in S-IRA in DBA/1 mice. Materials and methods Naive DBA/1 mice exhibit a low incidence of S-IRA, but after primed by acoustic stimulation, they become consistently susceptible to S-IRA. Atomoxetine, adrenoceptor agonists, antagonists or vehicle was intraperitoneally (i.p.) administered alone or in combination, and the effects of drug treatments on S-IRA incidence and seizure behaviors were examined. Key findings The incidence of S-IRA in primed DBA/1 mice was significantly reduced by clonidine, an α2 adrenoceptor agonist, as compared with that of the vehicle control. However, compared with the vehicle control, S-IRA was not altered by cirazoline, an α1 agonist. Consistent with previous reports, atomoxetine reduced S-IRA in primed DBA/1 mice. The suppressing effect of atomoxetine on S-IRA was prevented by injection of an α2 adrenoceptor antagonist, yohimbine or atipamezole, but not by prazosin, an α1 antagonist. Administration of α1 or α2 antagonists alone did not promote the incidence of S-IRA in nonprimed DBA/1 mice. Significance These data demonstrate that noradrenergic neurotransmission modulates S-IRA predominantly via α2 adrenoceptors in DBA/1 mice, indicating that selective activation of α2 adrenoceptors can potentially prevent SUDEP.
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- 2021
34. Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies
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Cody L Slater and Qi Wang
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0301 basic medicine ,Adrenergic Neurons ,Medicine (General) ,medicine.medical_treatment ,Medicine (miscellaneous) ,Reviews ,Stimulation ,Electric Stimulation Therapy ,Neuropathology ,Review ,Neuroprotection ,03 medical and health sciences ,Norepinephrine ,R5-920 ,0302 clinical medicine ,Alzheimer Disease ,Receptors, Adrenergic, alpha-2 ,Receptors, Adrenergic, beta ,medicine ,electroceuticals ,the locus coeruleus – norepinephrine (LC‐NE) system ,Animals ,Humans ,Cholinergic neuron ,neural stimulation ,business.industry ,Alzheimer's disease ,Cholinergic Neurons ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Locus coeruleus ,Cholinergic ,business ,Neuroscience ,Vagus nerve stimulation ,medicine.drug - Abstract
Alzheimer's disease (AD) poses a significant global health concern over the next several decades. Multiple hypotheses have been put forth that attempt to explain the underlying pathophysiology of AD. Many of these are briefly reviewed here, but to‐date no disease‐altering therapy has been achieved. Despite this, recent work expanding on the role of noradrenergic system dysfunction in both the pathogenesis and symptomatic exacerbation of AD has shown promise. The role norepinephrine (NE) plays in AD remains complicated but pre‐tangle tau has consistently been shown to arise in the locus coeruleus (LC) of patients with AD decades before symptom onset. The current research reviewed here indicates NE can facilitate neuroprotective and memory‐enhancing effects through β adrenergic receptors, while α2A adrenergic receptors may exacerbate amyloid toxicity through a contribution to tau hyperphosphorylation. AD appears to involve a disruption in the balance between these two receptors and their various subtypes. There is also a poorly characterized interplay between the noradrenergic and cholinergic systems. LC deterioration leads to maladaptation in the remaining LC‐NE system and subsequently inhibits cholinergic neuron function, eventually leading to the classic cholinergic disruption seen in AD. Understanding AD as a dysfunctional noradrenergic system, provides new avenues for the use of advanced neural stimulation techniques to both study and therapeutically target the earliest stages of neuropathology. Direct LC stimulation and non‐invasive vagus nerve stimulation (VNS) have both demonstrated potential use as AD therapeutics. Significant work remains, though, to better understand the role of the noradrenergic system in AD and how electroceuticals can provide disease‐altering treatments., In this review, we provide a brief overview of several of the most thoroughly researched pathogenic hypotheses for Alzheimer's disease (AD) and assess their clinical impact to‐date. We focus specifically on recent research into the role of the locus coeruleus norepinephrine (LC‐NE) system, in both AD pathogenesis and symptom exacerbation, as well as the potential to use advanced neural stimulation techniques as a novel therapeutic option in the earliest stages of neuropathology.
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- 2021
35. Chronic Administrations of Guanfacine on Mesocortical Catecholaminergic and Thalamocortical Glutamatergic Transmissions
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Motohiro Okada, Takashi Shiroyama, Kouji Fukuyama, and Tomosuke Nakano
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Male ,Synaptic Transmission ,Rats, Sprague-Dawley ,GABA ,Thalamus ,Adrenergic alpha-2 Receptor Agonists ,Medicine ,Biology (General) ,Spectroscopy ,gamma-Aminobutyric Acid ,guanfacine ,Catecholaminergic ,musculoskeletal, neural, and ocular physiology ,General Medicine ,Computer Science Applications ,Guanfacine ,Ventral tegmental area ,Chemistry ,medicine.anatomical_structure ,L-glutamate ,dopamine ,psychological phenomena and processes ,medicine.drug ,QH301-705.5 ,Glutamic Acid ,Prefrontal Cortex ,attention-deficit/hyperactivity disorder ,Catalysis ,Article ,norepinephrine ,Inorganic Chemistry ,Norepinephrine ,Glutamatergic ,Dopamine ,Receptors, Adrenergic, alpha-2 ,mental disorders ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,QD1-999 ,business.industry ,Organic Chemistry ,Rats ,α2A adrenoceptor ,nervous system ,Attention Deficit Disorder with Hyperactivity ,Catecholamine ,Locus coeruleus ,business ,Neuroscience - Abstract
It has been established that the selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine are considered to involve the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the frontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions associated with the orbitofrontal cortex (OFC) are yet to be clarified. The actions of guanfacine on catecholaminergic transmission, the effects of acutely local and systemically chronic (for 7 days) administrations of guanfacine on catecholamine release in pathways from the locus coeruleus (LC) to OFC, the ventral tegmental area (VTA) and reticular thalamic-nucleus (RTN), from VTA to OFC, from RTN to the mediodorsal thalamic-nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Additionally, the effects of chronic guanfacine administration on the expression of the α2A adrenoceptor in the plasma membrane fraction of OFC, VTA and LC were examined using a capillary immunoblotting system. The acute local administration of therapeutically relevant concentrations of guanfacine into the LC decreased norepinephrine release in the OFC, VTA and RTN without affecting dopamine release in the OFC. Systemically, chronic administration of therapeutically relevant doses of guanfacine for 14 days increased the basal release of norepinephrine in the OFC, VTA, RTN, and dopamine release in the OFC via the downregulation of the α2A adrenoceptor in the LC, OFC and VTA. Furthermore, systemically, chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission. The present study demonstrated the dual actions of guanfacine on catecholaminergic transmission—acute attenuation of noradrenergic transmission and chronic enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission. These dual actions of guanfacine probably contribute to the clinical effects of guanfacine against ADHD.
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- 2021
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36. Role of α2-Adrenoceptor Subtypes in Suppression of L-Type Ca2+ Current in Mouse Cardiac Myocytes
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Sungjo Park, Oleg Yu. Pimenov, Alexey E. Alekseev, Edward V. Evdokimovskii, and Ryoung-Hoon Jeon
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0301 basic medicine ,Gene isoform ,Cell signaling ,Calcium Channels, L-Type ,QH301-705.5 ,left ventricle ,Heart Ventricles ,Action Potentials ,Biology ,BRL 44408 ,Catalysis ,Article ,Inorganic Chemistry ,Contractility ,guanabenz ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Receptors, Adrenergic, alpha-2 ,medicine ,Animals ,Protein Isoforms ,Myocyte ,cell signaling ,Myocytes, Cardiac ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Cells, Cultured ,Spectroscopy ,G protein-coupled receptor ,BRL-44408 ,Organic Chemistry ,Cardiac muscle ,JP 1302 ,General Medicine ,Computer Science Applications ,Cell biology ,Mice, Inbred C57BL ,Chemistry ,030104 developmental biology ,medicine.anatomical_structure ,G-protein coupled receptors ,ARC 239 ,Ventricle ,030217 neurology & neurosurgery - Abstract
Sarcolemmal α2 adrenoceptors (α2-AR), represented by α2A, α2B and α2C isoforms, can safeguard cardiac muscle under sympathoadrenergic surge by governing Ca2+ handling and contractility of cardiomyocytes. Cardiomyocyte-specific targeting of α2-AR would provide cardiac muscle-delimited stress control and enhance the efficacy of cardiac malfunction treatments. However, little is known about the specific contribution of the α2-AR subtypes in modulating cardiomyocyte functions. Herein, we analyzed the expression profile of α2A, α2B and α2C subtypes in mouse ventricle and conducted electrophysiological antagonist assay evaluating the contribution of these isoforms to the suppression of L-type Ca2+ current (ICaL). Patch-clamp electro-pharmacological studies revealed that the α2-agonist-induced suppression of ICaL involves mainly the α2C, to a lesser extent the α2B, and not the α2A isoforms. RT-qPCR evaluation revealed the presence of adra2b and adra2c (α2B and α2C isoform genes, respectively), but was unable to identify the expression of adra2a (α2A isoform gene) in the mouse left ventricle. Immunoblotting confirmed the presence only of the α2B and the α2C proteins in this tissue. The identified α2-AR isoform-linked regulation of ICaL in the mouse ventricle provides an important molecular substrate for the cardioprotective targeting.
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- 2021
37. Clonidine, an α2 adrenergic receptor agonist, disrupts reconsolidation of a cocaine-paired environmental memory
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Ellen M. Unterwald and Rachel R Denny
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Male ,Agonist ,medicine.drug_class ,Conditioning, Classical ,Adrenergic ,Pharmacology ,Clonidine ,norepinephrine ,Rats, Sprague-Dawley ,Cocaine-Related Disorders ,03 medical and health sciences ,0302 clinical medicine ,Cocaine ,Reward ,Short Reports ,Memory ,Receptors, Adrenergic, alpha-2 ,Adrenergic alpha-2 Receptor Agonists ,Animals ,Medicine ,rat ,Receptor ,Memory Consolidation ,α2 adrenergic receptor ,business.industry ,morphine ,Adrenergic Agonists ,conditioned place preference ,Conditioned place preference ,Rats ,030227 psychiatry ,Psychiatry and Mental health ,Morphine ,Memory consolidation ,Cues ,adrenergic receptors ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Environmental cues can elicit robust cocaine reward memories, contributing to relapse to cocaine abuse. Memories can be manipulated pharmacologically by interfering with reconsolidation after reactivation. Clonidine, an α2 noradrenergic receptor agonist, was tested for its ability to block reconsolidation of cocaine environmental-paired memory. Male Sprague-Dawley rats completed an 8-day cocaine place conditioning procedure to establish a cocaine place preference. Cocaine memory was reactivated by exposure to the cocaine-paired environment in a drug-free state, followed immediately by administration of clonidine (10 or 50 µg/kg) or vehicle. Cocaine place preference was retested 24 h and 1 week later. Clonidine significantly attenuated the previously established cocaine place preference when tested 1 or 7 days later. To investigate the generalizability of this effect to other drug classes, morphine conditioned place preference was tested. Clonidine administration after morphine memory reactivation did not significantly alter the expression of morphine place preference. These results suggest that clonidine can interfere with reconsolidation of cocaine memory and may be a useful approach to reduce relapse.
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- 2019
38. Prognostic significance of α‐ and β2‐adrenoceptor gene expression in breast cancer patients
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Lucía Gargiulo, Carlos David Bruque, Ezequiel Mariano Rivero, Ariana Bruzzone, Leandro M Martinez, and Isabel Alicia Luthy
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BREAST CANCER PATIENTS ,Oncology ,medicine.medical_specialty ,CIENCIAS MÉDICAS Y DE LA SALUD ,Adrenergic receptor ,Datasets as Topic ,Breast Neoplasms ,Medicina Clínica ,030226 pharmacology & pharmacy ,Disease-Free Survival ,Oncología ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,purl.org/becyt/ford/3.2 [https] ,Gene expression ,PROGNOSTIC FACTORS ,Biomarkers, Tumor ,medicine ,Humans ,Pharmacology (medical) ,Breast ,030212 general & internal medicine ,Oligonucleotide Array Sequence Analysis ,Pharmacology ,business.industry ,Gene Expression Profiling ,Hazard ratio ,purl.org/becyt/ford/3.1 [https] ,Original Articles ,Bioquímica y Biología Molecular ,Middle Aged ,Prognosis ,medicine.disease ,ADRENOCEPTORS ,Medicina Básica ,Hormone receptor ,Immunohistochemistry ,purl.org/becyt/ford/3 [https] ,Female ,Receptors, Adrenergic, beta-2 ,Lymph ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
Breast cancer is the most frequently diagnosed and leading cause of cancer death among women worldwide. It was classified within molecular intrinsic subtypes: luminal A, luminal B, human epidermal growth factor receptor 2‐enriched and basal‐like. Epinephrine and norepinephrine, released during stress, bind to adrenoceptors. α2‐adrenoceptors are encoded by the ADRA2A , ADRA2B and ADRA2C genes and β2 by ADRB2 . Fil: Rivero, Ezequiel Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Martinez, Leandro Marcelo. Hospital for Special Surgery; Estados Unidos Fil: Bruque, Carlos David. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina Fil: Gargiulo, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Bruzzone, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Luthy, Isabel Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
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- 2019
39. Sarcolemmal α2-adrenoceptors in feedback control of myocardial response to sympathetic challenge
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Andre Terzic, Alexey E. Alekseev, Sungjo Park, Santiago Reyes, and Oleg Yu. Pimenov
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0301 basic medicine ,Cell signaling ,Heart Diseases ,Adrenergic receptor ,03 medical and health sciences ,Norepinephrine ,Sarcolemma ,0302 clinical medicine ,Receptors, Adrenergic, alpha-2 ,Postsynaptic potential ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Feedback, Physiological ,Pharmacology ,Cardioprotection ,business.industry ,Cardiac muscle ,Heart ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Signal transduction ,business ,Neuroscience ,medicine.drug - Abstract
α2-adrenoceptor (α2-AR) isoforms, abundant in sympathetic synapses and noradrenergic neurons of the central nervous system, are integral in the presynaptic feed-back loop mechanism that moderates norepinephrine surges. We recently identified that postsynaptic α2-ARs, found in the myocellular sarcolemma, also contribute to a muscle-delimited feedback control capable of attenuating mobilization of intracellular Ca2+ and myocardial contractility. This previously unrecognized α2-AR-dependent rheostat is able to counteract competing adrenergic receptor actions in cardiac muscle. Specifically, in ventricular myocytes, nitric oxide (NO) and cGMP are the intracellular messengers of α2-AR signal transduction pathways that gauge the kinase-phosphatase balance and manage cellular Ca2+ handling preventing catecholamine-induced Ca2+ overload. Moreover, α2-AR signaling counterbalances phospholipase C - PKC-dependent mechanisms underscoring a broader cardioprotective potential under sympathoadrenergic and angiotensinergic challenge. Recruitment of such tissue-specific features of α2-AR under sustained sympathoadrenergic drive may, in principle, be harnessed to mitigate or prevent cardiac malfunction. However, cardiovascular disease may compromise peripheral α2-AR signaling limiting pharmacological targeting of these receptors. Prospective cardiac-specific gene or cell-based therapeutic approaches aimed at repairing or improving stress-protective α2-AR signaling may offer an alternative towards enhanced preservation of cardiac muscle structure and function.
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- 2019
40. Stress augments the rewarding memory of cocaine via the activation of brainstem-reward circuitry
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Masabumi Minami, Yuta Asaoka, Hironori Kamii, Katsuyuki Kaneda, and Fumiya Shinohara
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Adrenergic Neurons ,Male ,Restraint, Physical ,Tegmentum Mesencephali ,Dopamine ,Medicine (miscellaneous) ,Addiction ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Dopamine receptor D1 ,Cocaine ,Dopamine Uptake Inhibitors ,Reward ,Idazoxan ,Memory ,Receptors, Adrenergic, alpha-2 ,Conditioning, Psychological ,Receptors, Adrenergic, beta ,Medicine ,Animals ,Adrenergic alpha-Antagonists ,Pharmacology ,business.industry ,musculoskeletal, neural, and ocular physiology ,Laterodorsal tegmental nucleus ,Medial prefrontal cortex ,Conditioned place preference ,030227 psychiatry ,Ventral tegmental area ,Psychiatry and Mental health ,medicine.anatomical_structure ,Nicotinic agonist ,nervous system ,Timolol ,Noradrenaline ,Locus coeruleus ,business ,Neuroscience ,Excitatory Amino Acid Antagonists ,psychological phenomena and processes ,030217 neurology & neurosurgery ,Acetylcholine ,Stress, Psychological ,medicine.drug ,Brain Stem - Abstract
金沢大学医薬保健研究域薬学系, Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30-minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a β or α2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a β or α2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value. © 2018 Society for the Study of Addiction., Embargo Period 12 months
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- 2019
41. Post-treatment with JP-1302 protects against renal ischemia/reperfusion-induced acute kidney injury in rats
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Tomoyuki Terada, Tokihito Yukimura, Toru Nishinaka, Masayo Yamagata, Kohei Hayashi, Hidenobu Tsutsui, Kozo Yoneda, Masashi Takama, Takeshi Miura, and Takaomi Shimokawa
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Male ,0301 basic medicine ,medicine.medical_specialty ,Ischemia ,Urology ,Renal function ,Drug Administration Schedule ,Piperazines ,Blood Urea Nitrogen ,Rats, Sprague-Dawley ,Norepinephrine (medication) ,03 medical and health sciences ,Receptors, Adrenergic, alpha-2 ,medicine ,Animals ,Blood urea nitrogen ,Pharmacology ,Kidney ,Renal ischemia ,business.industry ,lcsh:RM1-950 ,Acute kidney injury ,Acute Kidney Injury ,Adrenergic alpha-2 Receptor Antagonists ,medicine.disease ,Rats ,Up-Regulation ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Therapeutics. Pharmacology ,Creatinine ,Reperfusion Injury ,Acridines ,Cytokines ,Molecular Medicine ,business ,Reperfusion injury ,medicine.drug - Abstract
Ischemia/reperfusion injury is the most common cause of acute kidney injury. We previously revealed that pre-treatment with yohimbine or JP-1302 attenuated renal ischemia/reperfusion injury by inhibition of α2C-adrenoceptor antagonist. The aim of the present study is to investigate the effects of post-treatment with JP-1302 on renal ischemia/reperfusion injury in rats. Male Sprague Dawley rats were randomly divided into four groups: sham operation, ischemia/reperfusion, pre-treatment with JP-1302 (3.0 mg/kg) and post-treatment with JP-1302 groups. In ischemia/reperfusion injury, renal functional parameters, such as blood urea nitrogen, plasma creatinine and creatinine clearance, deteriorated after reperfusion. Renal venous norepinephrine concentrations, as well as inflammatory molecules in the kidney increased after reperfusion. Both pre- and post-treatment with JP-1302 improved renal dysfunction, tissue damage, renal venous norepinephrine concentrations and inflammatory molecules expression in the kidney. In conclusion, these results suggest that post-treatment with JP-1302 protects on ischemia/reperfusion-induced acute kidney injury by suppressing cytokine upregulation via α2C-adrenoceptors. Keywords: JP-1302, Ischemia/reperfusion, Acute kidney injury, α2C-adrenoceptor, Norepinephrine
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- 2019
42. The relationship between MMP9 and ADRA2A gene polymorphisms and mothers–newborns’ nutritional status: an exploratory path model (STROBE compliant article)
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Lorena Elena Meliţ, Florin Tripon, Cristina Oana Mărginean, Claudia Bănescu, Claudiu Mărginean, and Mihaela Iancu
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Adult ,Male ,medicine.medical_specialty ,Birth weight ,Nutritional Status ,Single-nucleotide polymorphism ,MMP9 ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pregnancy ,Receptors, Adrenergic, alpha-2 ,030225 pediatrics ,Genotype ,medicine ,Birth Weight ,Humans ,Infant Nutritional Physiological Phenomena ,Maternal-Fetal Exchange ,Clinical Research Article ,Models, Genetic ,business.industry ,Obstetrics ,Romania ,Infant, Newborn ,Gestational age ,Maternal Nutritional Physiological Phenomena ,medicine.disease ,Gestational Weight Gain ,body regions ,Cross-Sectional Studies ,Matrix Metalloproteinase 9 ,Pediatrics, Perinatology and Child Health ,Female ,Gene polymorphism ,medicine.symptom ,business ,Weight gain ,030217 neurology & neurosurgery - Abstract
Background The aim of this study was to evaluate the direct effects of matrix metalloproteinase (MMP9 rs17577, MMP9 rs17576) and alfa 2 adrenergic receptor (ADRA2A rs553668) gene polymorphisms investigated in mothers and their newborns on maternal weight gain (MWG) during pregnancy and the newborn’s birth weight (BW), taking into account the presence of other related factors. Methods We performed a cross-sectional study in 197 mother–newborn pairs in an Obstetrics Gynecology Clinic, in order to evaluate the demographic and anthropometric parameters, and gene polymorphism. Results BW was positively correlated with maternal age (p = 0.021) and the educational level (p = 0.002), and negatively correlated with smoking status in pregnant women (p
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- 2019
43. Interrelation of cardiovascular risk factors with high albuminury among patients with arterial hypertension living in Mountain Shoriya
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Т А, Mulerova, E S, Filimonov, S A, Maksimov, V N, Maksimov, М I, Voevoda, and М Yu, Ogarkov
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Genetic Markers ,History ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Population ,lcsh:Medicine ,Urine ,Peptidyl-Dipeptidase A ,Polymerase Chain Reaction ,Receptor, Angiotensin, Type 1 ,albuminuria ,Russia ,chemistry.chemical_compound ,Receptors, Adrenergic, alpha-2 ,Risk Factors ,Albumins ,Internal medicine ,Epidemiology ,Ethnicity ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Methylenetetrahydrofolate Reductase (NADPH2) ,Triglycerides ,Abdominal obesity ,education.field_of_study ,Polymorphism, Genetic ,biology ,Cholesterol ,business.industry ,ethnos ,lcsh:R ,General Medicine ,polymorphism of candidate genes ,medicine.disease ,Obesity ,factors of cardiovascular risk ,chemistry ,Cardiovascular Diseases ,Obesity, Abdominal ,Methylenetetrahydrofolate reductase ,Hypertension ,Albuminuria ,biology.protein ,medicine.symptom ,Lipoproteins, HDL ,Family Practice ,business - Abstract
Aim: to evaluate the association of a complex of cardiovascular risk factors and genetic markers with the development of high albuminuria among patients with arterial hypertension in the population of Mountain Shoriya, taking into account ethnicity. Materials and methods. A clinical epidemiological study of a compactly residing population in remote areas of Mountain Shoria was carried out. 1409 people were examined [901 people - representatives of the indigenous nationality (Shorians), 508 people - representatives of non-indigenous nationality (90% of them are Caucasians)]. Hypertension was diagnosed according to the National Guidelines of the Russian Society of Cardiology/the Russian Medical Society on Arterial Hypertension (2010). All patients underwent clinical, laboratory and instrumental investigation. To study the state of the kidneys, the concentration (the presence of elevated levels) of albumin (albuminuria) in the morning portion of urine by an immunoturbidimetric method was analyzed. Polymorphisms of genes ACE (I/D, rs4340), АGT (c.803T>C, rs699), AGTR1 (А1166С, rs5186), ADRB1 (с.145A>G, Ser49Gly, rs1801252), ADRA2B (I/D, rs28365031), MTHFR (c.677С>Т, Ala222Val, rs1801133) and NOS3 (VNTR, 4b/4a) were tested using PCR. Results. In the group of shors with arterial hypertension, high albuminuria was associated with polymorphisms of the ACE genes (OR=2.05), ADRA2B (OR=6.00), elevated triglyceride level (OR=2.86), decreased index of cholesterol of high density lipoproteins (OR=5.57) and increased index of low density lipoproteins (OR=2.49); in the new population - with polymorphisms of the AGTR1 genes (OR=8.66), ADRA2B (OR=6.53), MTHFR (OR=7.16), obesity (OR=2.72), and abdominal obesity (OR=3.14). Conclusion. The primary predictors determining the development of high albuminuria among patients with arterial hypertension in both ethnic groups were genetic ones. In addition to them, non-genetic risk factors also contributed to the development of this organ damage to the kidneys: age and lipid metabolism disorders in representatives of indigenous nationality; age and abdominal obesity in the examined patients non-indigenous nationality.
- Published
- 2019
44. An investigation into the noradrenergic and serotonergic contributions of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis
- Author
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Kirsty Bannister, Stevie Lockwood, and Anthony H. Dickenson
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Male ,Serotonin ,medicine.medical_specialty ,Physiology ,Action Potentials ,Osteoarthritis ,Serotonergic ,Inhibitory postsynaptic potential ,050105 experimental psychology ,Tonic (physiology) ,Diffuse Noxious Inhibitory Control ,Rats, Sprague-Dawley ,Norepinephrine ,03 medical and health sciences ,0302 clinical medicine ,Receptors, Adrenergic, alpha-2 ,Ganglia, Spinal ,Internal medicine ,medicine ,Animals ,0501 psychology and cognitive sciences ,RNA, Messenger ,Neurons ,Chemistry ,General Neuroscience ,Diffuse noxious inhibitory control ,05 social sciences ,Neural Inhibition ,Adrenergic alpha-2 Receptor Antagonists ,medicine.disease ,Iodoacetic Acid ,Disease Models, Animal ,Endocrinology ,Spinal Cord ,Receptors, Serotonin ,Disease Progression ,Serotonin Antagonists ,Descending modulation ,030217 neurology & neurosurgery ,Research Article - Abstract
Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.
- Published
- 2019
45. Deleterious effects of levamisole, a cocaine adulterant, in rabbit aorta
- Author
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Sol Guerra-Ojeda, Patricia Marchio, Martin Aldasoro, Soraya L. Valles, Patricia Genovés, Maria D. Mauricio, and José M. Vila
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Pharmacology ,Norepinephrine ,Adrenergic Agents ,Cocaine ,Levamisole ,Receptors, Adrenergic, alpha-2 ,Physiology ,Animals ,Molecular Medicine ,Rabbits ,Aorta - Abstract
Levamisole, a veterinary anthelmintic drug, is one of the most widely used and dangerous cocaine adulterants. Like cocaine, levamisole acutely blocks noradrenaline reuptake but with much less potency, although its vascular effects are not well known. In this study, we evaluated the vascular effects of levamisole and cocaine in rabbit aortic rings used for isometric recording of tension in organ baths and protein expression by western blot. Our results indicated that levamisole (10
- Published
- 2022
46. Dexmedetomidine-Induced Aortic Contraction Involves Transactivation of the Epidermal Growth Factor Receptor in Rats
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Soo Hee Lee, Seong-Chun Kwon, Seong-Ho Ok, Seung Hyun Ahn, Sung Il Bae, Ji-Yoon Kim, Yeran Hwang, Kyeong-Eon Park, Mingu Kim, and Ju-Tae Sohn
- Subjects
Transcriptional Activation ,Muscle, Smooth, Vascular ,Catalysis ,Inorganic Chemistry ,Receptors, Adrenergic, alpha-2 ,Receptors, Adrenergic, alpha-1 ,Adrenergic alpha-2 Receptor Agonists ,Animals ,Phosphorylation ,Physical and Theoretical Chemistry ,Molecular Biology ,Aorta ,Spectroscopy ,Organic Chemistry ,Yohimbine ,Prazosin ,General Medicine ,Rats ,dexmedetomidine ,contraction ,epidermal growth factor receptor ,transactivation ,alpha-2 adrenoceptor ,Computer Science Applications ,ErbB Receptors ,src-Family Kinases ,Tyrosine ,sense organs ,Dexmedetomidine ,hormones, hormone substitutes, and hormone antagonists - Abstract
In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal growth factor receptor (EGFR) in isolated endothelium-denuded rat aortas. Additionally, we aimed to elucidate the associated underlying cellular mechanisms. The effects of the alpha-2 adrenoceptor inhibitor rauwolscine, EGFR tyrosine kinase inhibitor AG1478, Src kinase inhibitors PP1 and PP2, and matrix metalloproteinase inhibitor GM6001 on EGFR tyrosine phosphorylation and c-Jun NH2-terminal kinase (JNK) phosphorylation induced by dexmedetomidine in rat aortic smooth muscles were examined. In addition, the effects of these inhibitors on dexmedetomidine-induced contraction in isolated endothelium-denuded rat aorta were examined. Dexmedetomidine-induced contraction was inhibited by the alpha-1 adrenoceptor inhibitor prazosin, rauwolscine, AG1478, PP1, PP2, and GM6001 alone or by a combined treatment with prazosin and AG1478. AG1478 (3 × 10−6 M) inhibited dexmedetomidine-induced contraction in isolated endothelium-denuded rat aortas pretreated with rauwolscine. Dexmedetomidine-induced EGFR tyrosine and JNK phosphorylation were inhibited by rauwolscine, PP1, PP2, GM6001, and AG1478. Furthermore, dexmedetomidine-induced JNK phosphorylation reduced upon EGFR siRNA treatment. Therefore, these results suggested that the transactivation of EGFR associated with dexmedetomidine-induced contraction, mediated by the alpha-2 adrenoceptor, Src kinase, and matrix metalloproteinase, caused JNK phosphorylation and increased calcium levels.
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- 2022
47. Noradrenergic and Cholinergic Modulation of Belief Updating
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Sander Nieuwenhuis, Peter R. Murphy, Stephen B. R. E. Brown, Marieke Jepma, Stephany C. Koelewijn, Arn M. J. M. van den Maagdenberg, Boukje de Vries, Ontwikkelingspsychologie (Psychologie, FMG), and Institute of Interdisciplinary Studies
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0301 basic medicine ,Adult ,Male ,Adolescent ,Cognitive Neuroscience ,Rate regulation ,media_common.quotation_subject ,Scopolamine ,Electroencephalography ,Cholinergic modulation ,Cholinergic Antagonists ,Clonidine ,03 medical and health sciences ,Norepinephrine ,Young Adult ,0302 clinical medicine ,Double-Blind Method ,Receptors, Adrenergic, alpha-2 ,medicine ,Adrenergic alpha-2 Receptor Agonists ,Humans ,Learning ,Genetic Association Studies ,media_common ,Cross-Over Studies ,Norepinephrine Plasma Membrane Transport Proteins ,medicine.diagnostic_test ,Uncertainty ,Brain ,Anticipation, Psychological ,Acetylcholine ,Surprise ,030104 developmental biology ,Anticipation (artificial intelligence) ,Catecholamine ,Cholinergic ,Female ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
To make optimal predictions in a dynamic environment, the impact of new observations on existing beliefs—that is, the learning rate—should be guided by ongoing estimates of change and uncertainty. Theoretical work has proposed specific computational roles for various neuromodulatory systems in the control of learning rate, but empirical evidence is still sparse. The aim of the current research was to examine the role of the noradrenergic and cholinergic systems in learning rate regulation. First, we replicated our recent findings that the centroparietal P3 component of the EEG—an index of phasic catecholamine release in the cortex—predicts trial-to-trial variability in learning rate and mediates the effects of surprise and belief uncertainty on learning rate (Study 1, n = 17). Second, we found that pharmacological suppression of either norepinephrine or acetylcholine activity produced baseline-dependent effects on learning rate following nonobvious changes in an outcome-generating process (Study 1). Third, we identified two genes, coding for α2A receptor sensitivity (ADRA2A) and norepinephrine reuptake (NET), as promising targets for future research on the genetic basis of individual differences in learning rate (Study 2, n = 137). Our findings suggest a role for the noradrenergic and cholinergic systems in belief updating and underline the importance of studying interactions between different neuromodulatory systems.
- Published
- 2018
48. Selective adrenergic alpha2C receptor antagonist ameliorates acute phencyclidine-induced schizophrenia-like social interaction deficits in rats
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Aaaro J Jalkanen, Katja Savolainen, Jouni Ihalainen, and Markus M. Forsberg
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Olanzapine ,Agonist ,Male ,medicine.drug_class ,Phencyclidine ,Pharmacology ,Partial agonist ,Atypical antipsychotics ,03 medical and health sciences ,0302 clinical medicine ,α2C adrenergic receptor antagonist ,Receptors, Adrenergic, alpha-2 ,Medicine ,Animals ,Interpersonal Relations ,Rats, Wistar ,Social Behavior ,Clozapine ,Adrenergic alpha-Antagonists ,Original Investigation ,Dose-Response Relationship, Drug ,business.industry ,Social interaction deficit ,Antagonist ,Receptor antagonist ,medicine.disease ,030227 psychiatry ,α7 nicotinic acetylcholine receptor partial agonist ,Rats ,Schizophrenia ,Rat ,business ,Excitatory Amino Acid Antagonists ,030217 neurology & neurosurgery ,medicine.drug ,Antipsychotic Agents - Abstract
Rationale Social withdrawal is a core feature of the negative symptoms of schizophrenia. Currently available pharmacotherapies have only limited efficacy towards the negative symptoms, i.e., there is a significant unmet medical need in the treatment of these symptoms. Objective We wanted to confirm whether selective adrenergic α2C receptor (AR) antagonist therapy could ameliorate acute phencyclidine (PCP)-induced schizophrenia-like social interaction deficits in rats, and to compare the effects of an α2C AR antagonist to another putative therapeutic alternative, an α7 nicotinic acetylcholine receptor (nAChR) partial agonist, as well against three commonly used atypical antipsychotics. Methods Here, we used acute PCP administration and modified a protocol for testing social interaction deficits in male Wistar rats and then used this model to compare the effects of an α2C AR antagonist (ORM-13070 0.3 and 1.0 mg/kg s.c.) with an α7 nAChR partial agonist (EVP-6124 0.3 mg/kg s.c.) and three atypical antipsychotics (clozapine 2.5 mg/kg i.p., risperidone 0.04 and 0.08 mg/kg s.c., olanzapine 0.125 and 0.5 mg/kg s.c.) on social interaction behavior. Results Acute PCP (1.5 mg/kg s.c.) produced robust and reproducible deficits in social interaction behavior without affecting locomotor activity. The selective α2C AR antagonist significantly ameliorated PCP-induced social interaction deficits. In contrast, neither the partial α7 nAChR agonist nor any of the three atypical antipsychotics were able to reverse the behavioral deficits at the selected doses. Conclusion Our findings confirm that α2C AR antagonism is a potential mechanism for the treatment of the negative symptoms of schizophrenia.
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- 2018
49. The influence of the noradrenergic/stress system on perceptual biases for reward
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Colin J. D. Ross, Mana R. Ehlers, and Rebecca M. Todd
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Adult ,Male ,Visual adaptation ,Stress system ,Cognitive Neuroscience ,media_common.quotation_subject ,Happiness ,Anger ,050105 experimental psychology ,Norepinephrine ,Young Adult ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Reward ,Receptors, Adrenergic, alpha-2 ,Perception ,Adaptation, Psychological ,Humans ,0501 psychology and cognitive sciences ,Valence (psychology) ,Acute stress ,media_common ,Two-alternative forced choice ,05 social sciences ,Ambiguity ,16. Peace & justice ,Facial Expression ,Female ,Positive bias ,Psychology ,Facial Recognition ,Stress, Psychological ,psychological phenomena and processes ,030217 neurology & neurosurgery ,Personality ,Cognitive psychology - Abstract
Previous research has established a role for the norepinephrine (NE)/stress system in individual differences in biases to attend to reward or punishment. Outstanding questions concern its role in the flexibility with which such biases can be changed. The goal of this preregistered study was to examine the role of the NE/stress system in the degree to which biases can be trained along the axis of valence in the direction of reward. Participants genotyped for a common deletion variant of ADRA2b (linked to altered NE availability) experienced either an acute stress induction or a control procedure. Following stress induction, a "bias probe" task was presented before and after training. In the bias probe task, participants made forced choice judgments (happy or angry) on emotional faces with varying degrees of ambiguity. For bias training, participants viewed unambiguously angry faces in a task exploiting visual adaptation effects. The results revealed an overall shift from a slightly positive bias in categorizing faces pretraining to a more positive bias after training. Carriers of the deletion variant overall showed a more positive bias than did the noncarriers. Follow-up analyses showed that pretraining bias was a significant predictor of bias change, with those who showed a more negative bias preadaptation changing more in a positive direction. Critically, this effect was observed under control but not under stress conditions. These results suggest that the NE/stress system plays an important role in influencing trait-like biases as well as short-term changes in the tendency to perceive ambiguous stimuli as being more rewarding than threatening.
- Published
- 2018
50. 2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors
- Author
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Serena Boccella, Ida Marabese, Pietro Amodeo, Vito de Novellis, Antonio Calignano, Fabio Arturo Iannotti, Salvatore Paino, Flavia Ricciardi, Rosa Maria Vitale, Claudia Cristiano, Enza Palazzo, Francesca Guida, Livio Luongo, Vincenzo Di Marzo, Sabatino Maione, Carmela Belardo, Rosmara Infantino, Monica Iannotta, Boccella, Serena, Guida, Francesca, Iannotta, Monica, Iannotti, Fabio Arturo, Infantino, Rosmara, Ricciardi, Flavia, Cristiano, Claudia, Vitale, Rosa Maria, Amodeo, Pietro, Marabese, Ida, Belardo, Carmela, de Novellis, Vito, Paino, Salvatore, Palazzo, Enza, Calignano, Antonio, Di Marzo, Vincenzo, Maione, Sabatino, Luongo, Livio, and Luongo, Livio.
- Subjects
Male ,0301 basic medicine ,Long-Term Potentiation ,Anxiety ,Neuropathic pain ,Oxazole ,lcsh:RC346-429 ,Norepinephrine ,H3 receptors ,Mice ,Cognition ,0302 clinical medicine ,Chlorocebus aethiops ,Locus coeruleus ,Entorhinal Cortex ,Medicine ,Oxazoles ,gamma-Aminobutyric Acid ,Behavior, Animal ,Depression ,Chronic pain ,Long-term potentiation ,Cognitive impairment ,Allodynia ,Hyperalgesia ,COS Cells ,Histamine H3 receptor ,medicine.symptom ,Cognitive impairments ,Human ,Memory Disorder ,Glutamic Acid ,Chlorocebus aethiop ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Neurochemical ,Receptors, Adrenergic, alpha-2 ,COS Cell ,Animals ,Humans ,Receptors, Histamine H3 ,Amino Acid Sequence ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Memory Disorders ,Dentate Gyru ,Animal ,business.industry ,Research ,Correction ,Nerve injury ,medicine.disease ,H3 receptor ,Mice, Inbred C57BL ,030104 developmental biology ,Structural Homology, Protein ,Dentate Gyrus ,Locus coeruleu ,Neuralgia ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine altered levels after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.
- Published
- 2021
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