Adrenoceptor Research Articles

The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons

Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and α2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal-to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na+ leak channel NALCN in mice and found that its presence was required for spontaneous firing in cartwheel cells. Activation of α2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, α2-dependent enhancement of synaptic strength was also absent in the knockout. GABAB receptors mediated inhibition through NALCN as well, acting on the same population of channels as α2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.

The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons.

Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and α2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal-to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na+ leak channel NALCN in mice and found that its presence was required for spontaneous firing in cartwheel cells. Activation of α2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, α2-dependent enhancement of synaptic strength was also absent in the knockout. GABAB receptors mediated inhibition through NALCN as well, acting on the same population of channels as α2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.

The Dual Cardiovascular Effect of Centrally Administered Clonidine: A Comparative Study between Pentobarbital- and Ketamine/Xylazine-Anesthetized Rats

The administration of the α2-adrenergic receptor agonist clonidine via intracerebroventricular route produces hypotension in pentobarbital-anesthetized rats and pressor responses in conscious normotensive rats. We explored the impact of different anesthetics on the central nervous system-dependent cardiovascular effects of clonidine. Normotensive male Wistar rats with guide cannulas previously implanted in the cerebroventricular system were anesthetized with pentobarbital or ketamine/xylazine and prepared for blood pressure measurement. The animals received intracerebroventricular injections of 10 μg clonidine or 0.6 μg dexmedetomidine, and the effects on the systolic, diastolic, mean arterial pressure, and heart rate were evaluated. The influence of 5 μg yohimbine, a selective α2-adrenergic receptor antagonist, was also assessed. The i.c.v. microinjection of clonidine decreased all three components of systemic arterial pressure and the heart rate of pentobarbital-anesthetized rats. On the other hand, clonidine increased the blood pressure and generated a less intense reduction in the heart rate of ketamine/xylazine-anesthetized rats. The pressor and bradycardic effects of clonidine in ketamine/xylazine-anesthetized animals were reproduced by dexmedetomidine, a more selective α2-adrenergic receptor agonist. Notably, the previous intracerebroventricular injection of yohimbine significantly inhibited the hypertensive effect of clonidine and dexmedetomidine. This study discloses that while normotensive rats anesthetized with pentobarbital show hypotensive responses, the stimulation of α2-adrenergic receptors increases the blood pressure in rats under ketamine/xylazine-induced anesthesia, reproducing the effects seen in conscious normotensive animals. Recognizing the mechanisms involved in these differences may allow us to understand better the final effects of clonidine and other α2-adrenergic receptor agonists in the central nervous system, contributing to the repurposing of these drugs.

Optimal clinical dose of medetomidine for sedation of young cows during dehorning surgery.

The present paper reports on the clinical efficacy and optimal clinical dose of medetomidine for sedation of young cows during dehorning surgery. Medical records of 24 female Holstein cows that underwent dehorning surgery were used in this study. In four groups, the sedation of animals wascarried out by one of the four intravenous treatments: 0.1 mg kg-1 xylazine (Xyl group, n = 6), 5.0 μg kg-1 medetomidine (5.0 Med group, n = 6), 10.0 μg kg-1 medetomidine (10.0 Med group, n = 6) or 20.0 μg kg-1 medetomidine (20.0 Med group, n = 6). The clinical sedation score (CSS) and heart rate (HR) were recorded. The CSSs after intravenous administration of each α2-adrenergic receptor agonistincreased rapidly and peaked at 12.5 (10.0-16.0) at t = 20 min in the Xyl group, 11.5 (10.0-15.0) at t = 10 min in the 5.0 Med group, 16.0 (14.0-16.0) at t = 20 min in the 10.0 Med group and 16.0(14.0- 16.0) at t = 20 min in the 20.0 Med group. A similar degree of bradycardia was observed after every sedative treatment. We conclude that the intravenous administration of 10.0-20.0 μg kg-1 medetomidine is appropriate for sedation of young cows without severe side effects.

Effect of thymoquinone on acetic acid-induced visceral nociception in rats: role of central cannabinoid and α2-adrenergic receptors.

Thymoquinone (TQ) is the main biologically active substance of Nigella sativa (black seeds). It has anti-cancer, anti-inflammatory, anti-diabetic, anti-oxidative and anti-nociceptive properties. This study was aimed to explore the effect of TQ on acetic acid-induced visceral nociception. The central mechanisms of the effect of TQ were investigated using cannabinergic (AM251) and α2-adrenergic (yohimbine [Yoh]) antagonists. The lateral ventricle of the brain was cannulated for intracerebroventricular (ICV) injections. Visceral nociception was induced by intra-peritoneal (IP) injection of acetic acid (1.00% in a volume of 1.00 mL). Measuring the latency time to the first writhing appearance and counting the number of writhing in 5-min intervals for a period of 60 min were performed. Locomotor activity was determined using an open-field test. Oral administration (PO) of 2.50 and 10.00 mg kg-1 TQ increased the latency time to the first writhing appearance and decreased the number of writhing. The AM251 (5.00 µg per rat; ICV) and Yoh (5.00 µg per rat; ICV) partially prevented TQ (10.00 mg kg-1; PO)-induced anti-nociception. Locomotor activity was not altered by these treatments. The results of the present study showed that TQ had the ability to reduce visceral nociception caused by IP injection of acetic acid. The central mechanisms of this action of TQ might be partially mediated by cannabinergic and α2-adrenegic receptors.

Adrenoceptor Expression and Function in the Endocrine Pancreas.

The sympathetic nervous system plays an important role in the regulation of endocrine pancreatic function, most importantly insulin release. Among the nine adrenoceptor (AR) subtypes, the α2A-AR appears to be the subtype most abundantly expressed in the human pancreas. While α2- and β-AR have opposing effects, the net response to sympathetic stimulation is inhibition of insulin secretion mediated by α2-AR located in the plasma membrane of pancreatic β cells. This inhibition may be present physiologically as evidenced by increased insulin secretion in healthy and diabetic humans and animals in response to α2-AR antagonists, a finding that was confirmed in all studies. Based on such data and on an association of an α2A-AR polymorphism, that increases receptor expression levels, with an elevated risk for diabetes, increased α2A-AR signaling in the pancreatic β cells has been proposed as a risk factor for the development of type 2 diabetes. Thus, the α2A-AR was proposed as a drug target for the treatment of some forms of type 2 diabetes. Drug research and development programs leveraging this mechanism have reached the clinical stage, but none have resulted in an approved medicine due to a limited efficacy. While β-AR agonists can increase circulating insulin levels in vivo, it remains controversial whether this includes a direct effect on β cells or occurs secondary to general metabolic effects. Therefore, the regulation of endocrine pancreatic function is physiologically interesting but may be of limited therapeutic relevance.

Dexmedetomidine protects against sepsis-induced lung injury through autophagy and Smad2/3 signaling pathway.

Dexmedetomidine (Dex) is a potent α2-adrenergic receptor(α2-AR) agonist that has been shown to protect against sepsis-induced lung injury, however, the underlying mechanisms of this protection are not fully understood. Autophagy and the Smad2/3 signaling pathway play important roles in sepsis-induced lung injury, but the relationship between Dex and Smad2/3 is not clear. This study aimed to investigate the role of autophagy and the Smad2/3 signaling pathway in Dex-mediated treatment of sepsis-induced lung injury. Sepsis was performed using cecal ligation and puncture (CLP) in C57BL/6J mice. Mice were randomly assigned to four groups (n=6 per group): sham, CLP, CLP-Dex, and CLP-Dex-YOH, Yohimbine hydrochloride (YOH) is an α2-AR blocker. The cecum was carefully separated to avoid blood vessel damage and was identified and punctured twice with an 18-gauge needle. The pathological changes, inflammatory factor levels, oxidative stress, autophagy, Smad2/3 signaling pathway-related protein levels in lung tissues, and the activity of superoxide dismutase (SOD) and malonaldehyde (MDA) in the serum were measured. CLP-induced lung injury was reflected by increased levels of inflammatory cytokines, apoptosis, and oxidative stress, along with an increase in the expression of autophagy and Smad2/3 signaling pathway-related proteins. Dex could reverse these changes and confer a protective effect on the lung during sepsis. However, the administration of YOH significantly reduced the positive effects of Dex in mice with sepsis. Dex exerts its beneficial effects against sepsis-induced lung injury through the regulation of autophagy and the Smad2/3 signaling pathway.

Management of severe delirium with dexmedetomidine in a palliative care patient—a case report

Dexmedetomidine is used as an adjunct to anaesthesia or as a stand-alone agent for conscious sedation. It is a potent α2-adrenergic receptor agonist, with a fast onset of action and peak effects in 30 minutes to 1 hour after application, depending on the route of administration. It is metabolized in the liver and excreted in urine as a glucuronide. It potentiates analgesia and is effective in opioid sparing. Clinical trials show its efficacy in the treatment of Intensive Care Unit (ICU) delirium with an effect comparable to antipsychotics and benzodiazepines. It has also been used at the Eye Clinic of the University Medical Centre Ljubljana to sedate patients undergoing intraocular surgery. It proved to be an excellent alternative to other sedatives and analgesics, such as midazolam and remifentanil. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine and to investigate its potential use in the palliative care population, particularly in the management of delirium. This area of application is still largely unexplored and opens up a new field of application. At the Institute of Oncology (IO) Ljubljana, we have used it with success in several palliative patients with delirium, when all other modalities were failing. At the IO Ljubljana, anaesthesiologists are involved in the palliative management of patients, especially in pain management, but also in sedation and delirium treatment. Given its favourable pharmacokinetic and pharmacodynamic effects, dexmedetomidine could be used more frequently and perhaps alternative and less complex routes of administration, such as intranasal administration, could be explored. In this paper, we present a case of a palliative care patient in whom dexmedetomidine was used successfully.

Nicotine Diminishes Alpha2-Adrenergic Receptor-Dependent Protection Against Oxidative Stress in H9c2 Cardiomyocytes.

Nicotine is a major component of cigarette smoke with various detrimental cardiovascular effects, including increased oxidative stress in the heart. Agonism of α2-adrenergic receptors (ARs), such as with dexmedetomidine, has been documented to exert cardioprotective effects against oxidative stress and related apoptosis and necroptosis. α2-ARs are membrane-residing G protein-coupled receptors (GPCRs) that primarily activate Gi/o proteins. They are also subjected to GPCR-kinase (GRK)-2-dependent desensitization, which entails phosphorylation of the agonist-activated receptor by GRK2 to induce its decoupling from G proteins, thus terminating α2AR-mediated G protein signaling. In the present study, we sought to examine the effects of nicotine on α2AR signaling and effects in H9c2 cardiomyocytes exposed to H2O2 to induce oxidative cellular damage. As expected, treatment of H9c2 cardiomyocytes with H2O2 significantly decreased cell viability and increased oxidative stress, as assessed by reactive oxygen species (ROS)-associated fluorescence levels (DCF assay) and superoxide dismutase activity. Both H2O2 effects were partly rescued by α2AR activation with brimonidine in control cardiomyocytes but not in cells pretreated with nicotine for 24 hours, in which brimonidine was unable to reduce H2O2-induced cell death and oxidative stress. This was due to severe α2AR desensitization, manifested as very low Gi protein activation by brimonidine, and accompanied by GRK2 upregulation in nicotine-treated cardiomyocytes. Finally, pharmacological inhibition of adenylyl cyclase (AC) blocked H2O2-dependent oxidative damage in nicotine-pretreated H9c2 cardiomyocytes, indicating that α2AR activation protects against oxidative injury via its classic coupling to Gai-mediated AC inhibition. Nicotine can negate the cardioprotective effects of α2AR agonists against oxidative injury, which may have important implications for patients treated with this class of drugs that are chronic tobacco smokers.

Phentolamine Protects against Apoptosis and Inflammation in a Neonatal Pneumonia Cell Model Induced by LPS by Regulating the TrkA/Akt Signaling Pathways.

Phentolamine is an α-adrenergic receptor blocker that can be used to treat neonatal pneumonia, but its underlying mechanism is unclear. The purpose of this study is to probe the function of phentolamine on lipopolysaccharide (LPS)-induced inflammation and cell death in an in vitro model of neonatal pneumonia. Human MRC-5 cells were incubated with varying doses of phentolamine in vitro to evaluate cell viability. Subsequently, LPS was introduced to further investigate the combined effects of phentolamine and LPS on cell viability and apoptosis in MRC-5 cells. The effect of phentolamine/LPS treatment on the Neurotrophic Tyrosine Kinase Receptor A (TrkA)/Protein Kinase B (Akt) signaling pathway and the phosphorylation of pathway proteins in MRC-5 cells was further analyzed via western blot. Additionally, knockout of TrkA and Akt genes in MRC-5 cells was performed to explore the effects of phentolamine/LPS treatment on cell viability, apoptosis levels, and inflammatory factor levels in MRC-5 cells. Preincubation of MRC-5 cells with a low concentration of phentolamine (≤6 μg/mL) protected against LPS-induced cell inflammatory injury. Phentolamine promoted both TrkA and Akt phosphorylation and Akt activation induced by LPS in MRC-5 cells. The protective effect of phentolamine against LPS-induced apoptosis and inflammation was significantly reduced in response to TrkA or Akt gene knockdown in MRC-5 cells. Phentolamine may protect LPS-induced apoptosis and inflammation by activating the TrkA and Akt signaling pathways.

Trazodone associated with Clomiphene a proposal treatment for post finasteride syndrome

Erectile dysfunction caused by medications are probably caused by the disconnection of synaptic circuits responsible for linking libido to erection. For instance, it is well known that sexual dysfunction may occur in patients treated with finasteride, an inhibitor of the enzyme 5alpha-reductase, prescribed for androgenetic alopecia and benign prostatic hyperplasia. Interestingly, sexual dysfunction persists after drug discontinuation. Clomiphene citrate is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men. It acts centrally to increase secretion of luteinizing hormone. Trazodone is a multifunctional drug with hypnotic actions at low doses due to blockade of 5-HT2A receptors, as well as H1 histamine receptors and α1 adrenergic receptors, therefore this drug can cause severe priapism and in many cases causing penile necrosis or permanent loss of erectile function. Therefore, we propose that trazodone and clomiphene can restore libido synaptic circuits, thus these associated drugs can be a treatment for post-finasteride syndrome.

Fibromyalgia Animal Models Using Intermittent Cold and Psychological Stress.

Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions. Both models show long-lasting and generalized pain and female-predominant sex differences after gonadectomy. Like many other neuropathic pain models, ICGP and IPGP were abolished in lysophosphatidic acid receptor 1 (LPAR1) knock-out mice or by LPAR1 antagonist treatments, although deciding the clinical importance of this mechanism depends on waiting for the development of a clinically available LPAR1 antagonist. On the other hand, the nonsteroidal anti-inflammatory drug diclofenac with morphine did not suppress hyperalgesia in these models, and this is consistent with the clinical findings. Pharmacological studies suggest that the lack of morphine analgesia is associated with opioid tolerance upon the stress-induced release of endorphins and subsequent counterbalance through anti-opioid NMDA receptor mechanisms. Regarding pharmacotherapy, hyperalgesia in both models was suppressed by pregabalin and duloxetine, which have been approved for FM treatment in clinic. Notably, repeated treatments with mirtazapine, an α2 adrenergic receptor antagonist-type antidepressant, and donepezil, a drug for treating Alzheimer's disease, showed potent therapeutic actions in these models. However, the pharmacotherapeutic treatment should be carried out 3 months after stress, which is stated in the FM guideline, and many preclinical studies, such as those analyzing molecular and cellular mechanisms, as well as additional evidence using different animal models, are required. Thus, the ICGP and IPGP models have the potential to help discover and characterize new therapeutic medicines that might be used for the radical treatment of FM, although there are several limitations to be overcome.

Cold nociception as a measure of hyperalgesia during spontaneous heroin withdrawal in mice

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests—thermal gradient ring (5–30 °C, 5–50 °C, 15–40 °C, and 25–50 °C), dynamic cold plate (4 °C to −1 °C at −1 °C/min, −1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)—to measure hyperalgesia in a mouse protocol of heroin dependence. On the thermal gradient ring, mice in the heroin withdrawal group preferred warmer temperatures, and the results depended on the ring's temperature range. On the dynamic cold plate, heroin withdrawal increased the number of nociceptive responses, with a temperature ramp from 4 °C to −1 °C yielding the largest response. On the stable cold plate, heroin withdrawal increased the number of nociceptive responses, and a plate temperature of 2 °C yielded the most significant increase in responses. Among the three tests, the stable cold plate elicited the most robust change in behavior between heroin-dependent and nondependent mice and had the highest throughput. To pharmacologically characterize the stable cold plate test, we used μ-opioid and non-opioid receptor-targeting drugs that have been previously shown to reverse OWIH in mechanical and heat nociception assays. The full μ-opioid receptor agonist methadone and μ-opioid receptor partial agonist buprenorphine decreased OWIH, whereas the preferential μ-opioid receptor antagonist naltrexone increased OWIH. Two N-methyl-d-aspartate receptor antagonists (ketamine, MK-801), a corticotropin-releasing factor 1 receptor antagonist (R121919), a β2-adrenergic receptor antagonist (butoxamine), an α2-adrenergic receptor agonist (lofexidine), and a 5-hydroxytryptamine-3 receptor antagonist (ondansetron) had no effect on OWIH. These data demonstrate that the stable cold plate at 2 °C yields a robust, reliable, and concise measure of OWIH that is sensitive to opioid agonists.

Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate Tcell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.

Activation of α 2A and α 2B -adrenergic receptors inhibits tactile stimulation-evoked parallel fiber-Purkinje cell synaptic transmission in mouse cerebellar cortex.

The mechanism by which α2-adrenergic receptors (ARs) modulate the cerebellar parallel fiber-Purkinje cell (PF-PC) synaptic transmission is unclear. We investigated this issue using electrophysiological and neuropharmacological methods. Six- to eight-week-old ICR mice were used in the study. Under in vivo conditions, PF-PC synaptic transmission was evoked by facial stimulation of ipsilateral whisker pad, and recorded using cell-attached patch from PCs. Under in-vitro conditions, PF-PC synaptic transmission was evoked by electrical stimulation of the molecular layer in cerebellar slices, and was recorded using whole-cell recording from PCs. SR95531 (20 µM) was added to the ACSF during all recordings to prevent GABAA receptor-mediated inhibition. Air-puff stimulation of the ipsilateral whisker pad in-vivo evoked simple spike (eSS) firing of cerebellar PCs. Microapplication of noradrenaline (15 µM) to the molecular layer significantly decreased the numbers and frequency of eSS, an effect abolished by the α2-AR antagonist. Microapplication of an α2-AR agonist, UK14304 (1 µM), significantly decreased the numbers of eSS in PCs, which was abolished by either α2A- or α2B-AR antagonist, but not by α2C-AR antagonist. Under in-vitro conditions, application of UK 14304 significantly decreased the amplitude of PF-PC EPSCs and increased the paired-pulse ratio, which were abolished by either α2A- or α2B-AR antagonist. The present results indicate that activation of presynaptic α2A- and α2B-AR downregulates PF-PC synaptic transmission in mouse cerebellar cortex.

Hypersexuality during treatment with cariprazine in a patient with schizophrenia? A case report

BackgroundCariprazine is a third-generation antipsychotic with a unique mechanism of action. It functions as a partial agonist with high affinity for dopamine D2 and D3 and serotonin 5-HT1A receptors, an antagonist for 5-HT2A (moderate affinity) and 5-HT2B (high affinity) receptors. It binds to histamine H1 receptors and has a low affinity for 5-HT2C and alpha 1A-adrenergic receptors and no affinity for muscarinic (cholinergic) receptors. Among the troubling side effects, symptoms related to impulse control, such as hypersexuality, pathological gambling, compulsive shopping, compulsive eating etc., have been reported with the use of antipsychotic medications. However, no reports have been published regarding impulse control symptoms associated with cariprazine. We report a case of cariprazine-induced hypersexuality in a patient with schizophrenia, which was resolved by discontinuation of the medication.Case presentationA 67-year-old Caucasian woman with schizophrenia was admitted to the hospital inpatient unit after she discontinued olanzapine and psychotic symptoms reappeared. Prior to that, she was in remission, taking olanzapine for approximately one year. After discontinuation, she experienced auditory hallucinations with persecutory delusions and became anergic and withdrawn, with blunted affect. Olanzapine was reintroduced, as it was proven successful in her past treatments. However, since there were no changes, especially in negative symptoms, cariprazine was added. Seven days after the introduction of cariprazine, the patient developed compulsive sexual behaviour. Therefore, cariprazine was discontinued, and the hypersexual behaviour was resolved.ConclusionsIn this case report, we describe hypersexual behaviour that could potentially be induced by cariprazine. As a single case study, conclusions cannot be drawn. Controlled studies are warranted to better determine causality and the significance of this possible side-effect of cariprazine.

Norepinephrine regulates calcium signals and fate of oligodendrocyte precursor cells in the mouse cerebral cortex

Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, contributing to myelination and myelin repair. OPCs contact axons and respond to neuronal activity, but how the information relayed by the neuronal activity translates into OPC Ca2+ signals, which in turn influence their fate, remains unknown. We generated transgenic mice for concomitant monitoring of OPCs Ca2+ signals and cell fate using 2-photon microscopy in the somatosensory cortex of awake-behaving mice. Ca2+ signals in OPCs mainly occur within processes and confine to Ca2+ microdomains. A subpopulation of OPCs enhances Ca2+ transients while mice engaged in exploratory locomotion. We found that OPCs responsive to locomotion preferentially differentiate into oligodendrocytes, and locomotion-non-responsive OPCs divide. Norepinephrine mediates locomotion-evoked Ca2+ increases in OPCs by activating α1 adrenergic receptors, and chemogenetic activation of OPCs or noradrenergic neurons promotes OPC differentiation. Hence, we uncovered that for fate decisions OPCs integrate Ca2+ signals, and norepinephrine is a potent regulator of OPC fate.

Interaction between Kölliker-Fuse/A7 and the parafacial respiratory region on the control of respiratory regulation

Respiration is regulated by various types of neurons located in the pontine-medullary regions. The Kölliker-Fuse (KF)/A7 noradrenergic neurons play a role in modulating the inspiratory cycle by influencing the respiratory output. These neurons are interconnected and may also project to brainstem and spinal cord, potentially involved in regulating the post-inspiratory phase. In the present study, we hypothesize that the parafacial (pF) neurons, in conjunction with adrenergic mechanisms originating from the KF/A7 region, may provide the neurophysiological basis for breathing modulation. We conducted experiments using urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Injection of L-glutamate into the KF/A7 region resulted in inhibition of inspiratory activity, and a prolonged and high-amplitude genioglossal activity (GGEMG). Blockade of the α1 adrenergic receptors (α1-AR) or the ionotropic glutamatergic receptors in the pF region decrease the activity of the GGEMG without affecting inspiratory cessation. In contrast, blockade of α2-AR in the pF region extended the duration of GG activity. Notably, the inspiratory and GGEMG activities induced by KF/A7 stimulation were completely blocked by bilateral blockade of glutamatergic receptors in the Bötzinger complex (BötC). While our study found a limited role for α1 and α2 adrenergic receptors at the pF level in modulating the breathing response to KF/A7 stimulation, it became evident that BötC neurons are responsible for the respiratory effects induced by KF/A7 stimulation.

Dexmedetomidine Alleviates Ischemia/Reperfusion-Associated Acute Kidney Injury by Enhancing Autophagic Activity via the α2-AR/AMPK/mTOR Pathway.

Dexmedetomidine (DEX) reportedly protects against ischemia-reperfusion (I/R) injury and associated damage to the kidneys, but the underlying mechanisms have yet to be established. Unilateral nephrectomy was performed in Wistar rats, and the remaining kidney was clamped for 1 h prior to reperfusion to establish an experimental model system. These animals were then randomized into Sham, DEX + Sham, DEX + I/R, ATI (Altepamizole, α2-adrenergic receptor inhibitor) + DEX + I/R, and 3-MA (3-methyladenine, autophagy inhibitor) + DEX + I/R groups. Serum renal function biomarkers, acute kidney injury (AKI) histopathological scores, serum inflammatory factors, redox biomarkers, markers of autophagic flux, and autophagosome numbers were assessed. Levels of proteins related to the autophagic pathway, including mTOR and AMPK, were also analyzed. Serum creatinine and urea nitrogen levels in the I/R group were significantly elevated over those in sham control rats, as were AKI scores, serum inflammatory cytokine concentrations (IL-6, IL-1β, and TNF-α), and serum levels of the oxidative stress biomarker malondialdehyde (MDA). All of these parameters were significantly reduced in the DEX + I/R group relative to I/R model rats. I/R group rats also exhibited significant decreases in renal levels of autophagic flux-related biomarkers and autophagosome numbers relative to sham controls, while DEX administration partially restored normal autophagic flux in these rats. Acute I/R also suppress the expression of AMPK in the kidney while increasing mTOR expression, and DEX reversed these effects. The beneficial impact of DEX on I/R-associated AKI was ablated by ATI or 3-MA administration. These analyses provide strong evidence for the ability of DEX to protect against I/R-associated AKI via the α2-AR/AMPK/mTOR pathway-mediated enhancement of autophagic activity.

Features of α2-Adrenergic Regulation of Isolated Rat Heart after Hypokinesia.

We studied the effect of the α2-adrenergic receptor agonist clonidine hydrochloride (10-9-10-6 M) on the isolated heart of adult rats after 30-day restriction of motor activity. In hypokinetic rats, in comparison with control animals, clonidine caused a positive inotropic effect; the dynamics of coronary flow was changed after stimulation of α2-adrenergic receptors by clonidine in the minimum and maximum concentrations. Moreover, clonidine in concentrations of 10-8 and 10-7 M reduced coronary flow both in the control group and against the background of hypokinesia. Clonidine (10-8-10-6 M) had a negative chronotropic effect in control and hypokinetic animals, while the dynamics of HR was multidirectional, i.e. either an increase or decrease in the effects was observed depending of the agonist concentration. Overall, the data obtained indicate the participation of α2-adrenergic receptors in adaptive processes after motor activity limitation.