Nicotinic Cholinergic Receptors Research Articles

The Novel Antipsychotic Drug Cariprazine and Cognition Enhancing Drugs: Indications for their Use as the Add-on Therapy in Schizophrenia.

Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some patients show treatment-resistant forms of psychotic disorders, and in this case, they can be treated with clozapine. Based on the previous reviews on novel antipsychotic drugs, it is important to know whether the add-on therapy with the new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score. The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant forms of psychotic disorders. A combination of the currently available antipsychotic drugs with novel antipsychotic or modulating drugs might improve negative schizophrenic symptoms and cognitive function and thereby social functioning and quality of life. The mechanisms of action, the therapeutic effects, and the pharmacokinetic profiles of novel antipsychotic drugs such as cariprazine, brexipiprazole, and lumateperone have been updated. Published case reports of patients with treatment-resistant psychoses have also been discussed in this study. These patients were treated only with clozapine, as a result of which a high PANSS total score was observed. Only the add-on therapy with cariprazine improved the score, and above all, the negative schizophrenic symptoms and cognitive functions were improved. For the ensurance of a constant antipsychotic drug concentration, long-acting injectable antipsychotic drugs might be a choice for the maintenance therapy in schizophrenia. New modulating drugs, such as receptor positive allosteric modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic receptor) and encenicline, an alpha7 nicotinic cholinergic receptor agonist, have been investigated in preclinical and clinical trials. In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In schizophrenia, long-acting injectable antipsychotic drugs are safe and tolerable maintenance therapy. In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative schizophrenic symptoms and cognitive functions by the add-on therapy with cognitionenhancing drugs.

Pupillary behavior during wakefulness, non-REM sleep, and REM sleep in birds is opposite that of mammals

Mammalian pupils respond to light1,2 and dilate with arousal, attention, cognitive workload, and emotions,3 thus reflecting the state of the brain. Pupil size also varies during sleep, constricting during deep non-REM sleep4-7 and dilating slightly during REM sleep.4-6 Anecdotal reports suggest that, unlike mammals, birds constrict their pupils during aroused states, such as courtship and aggression,8-10 raising the possibility that pupillary behavior also differs between mammals and birds during sleep. Here, we measured pupil size in awake pigeons and used their translucent eyelid to investigate sleep-state-dependent changes in pupil size. Male pigeons constricted their pupils during courtship and other male-female interactions but not while engaging in other waking behaviors. Unlike mouse pupils, the pigeons' pupils were dilated during non-REM sleep, while over 1,000 bursts of constriction and relaxation, which we call rapid iris movements (RIMs), occurred primarily during REM sleep. Consistent with the avian iris being composed largely of striated muscles,11-15 rather than smooth muscles, as in mammals, pharmacological experiments revealed that RIMs are mediated by nicotinic cholinergic receptors in the iris muscles. Despite receiving input from a parasympathetic nucleus, but consistent with its striated nature, the avian iris sphincter muscle behaves like skeletal muscles controlled by the somatic nervous system, constricting during courtship displays, relaxing during non-REM sleep, and twitching during REM sleep. We speculate that during wakefulness, pupillary constrictions are involved in social communication, whereas RIMs occurring during REM sleep might maintain the efficacy of this motor system and/or reflect the processing of associated memories.

The Cholinergic Lateral Line Efferent Synapse: Structural, Functional and Molecular Similarities With Those of the Cochlea.

Vertebrate hair cell (HC) systems are innervated by efferent fibers that modulate their response to external stimuli. In mammals, the best studied efferent-HC synapse, the cholinergic medial olivocochlear (MOC) efferent system, makes direct synaptic contacts with HCs. The net effect of MOC activity is to hyperpolarize HCs through the activation of α9α10 nicotinic cholinergic receptors (nAChRs) and the subsequent activation of Ca2+-dependent SK2 potassium channels. A serious obstacle in research on many mammalian sensory systems in their native context is that their constituent neurons are difficult to access even in newborn animals, hampering circuit observation, mapping, or controlled manipulation. By contrast, fishes and amphibians have a superficial and accessible mechanosensory system, the lateral line (LL), which circumvents many of these problems. LL responsiveness is modulated by efferent neurons which aid to distinguish between external and self-generated stimuli. One component of the LL efferent system is cholinergic and its activation inhibits LL afferent activity, similar to what has been described for MOC efferents. The zebrafish (Danio rerio) has emerged as a powerful model system for studying human hearing and balance disorders, since LL HC are structurally and functionally analogous to cochlear HCs, but are optically and pharmacologically accessible within an intact specimen. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of HC biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired HC dysfunction. With the rise of the zebrafish LL as a model in which to study auditory system function and disease, there has been an increased interest in studying its efferent system and evaluate the similarity between mammalian and piscine efferent synapses. Advances derived from studies in zebrafish include understanding the effect of the LL efferent system on HC and afferent activity, and revealing that an α9-containing nAChR, functionally coupled to SK channels, operates at the LL efferent synapse. In this review, we discuss the tools and findings of these recent investigations into zebrafish efferent-HC synapse, their commonalities with the mammalian counterpart and discuss several emerging areas for future studies.

Neuron-specific responses to acetylcholine within the spinal dorsal horn circuits of rodent and primate

Excitatory and inhibitory neurotransmission within the spinal dorsal horn is tightly controlled to regulate transmission of nociceptive signals to the brain. One aspect of this control is modulation of neuronal activity through cholinergic signaling. Nociceptive neurons in the dorsal horn express both nicotinic and muscarinic cholinergic receptors and activation of these receptors reduces pain in humans, while inhibition leads to nociceptive hypersensitivity. At a cellular level, acetylcholine (ACh) has diverse effects on excitability which is dependent on the receptor and neuronal subtypes involved. In the present study we sought to characterize the electrophysiological responses of specific subsets of lamina II interneurons from rat and marmoset spinal cord. Neurons were grouped by morphology and by action potential firing properties. Whole-cell voltage-clamp recordings from lamina II dorsal horn neurons of adult rats showed that bath applied acetylcholine increased, decreased or had no effect on spontaneous synaptic current activity in a cell-type specific manner. ACh modulated inhibitory synaptic activity in 80% of neurons, whereas excitatory synaptic activity was affected in less than 50% of neurons. In whole-cell current clamp recordings, brief somatic application of ACh induced cell-type specific responses in 79% of rat lamina II neurons, which included: depolarization and action potential firing, subthreshold membrane depolarization, biphasic responses characterized by transient depolarization followed by hyperpolarization and membrane hyperpolarization alone. Similar responses were seen in marmoset lamina II neurons and the properties of each neuron group were consistent across species. ACh-induced hyperpolarization was blocked by the muscarinic antagonist atropine and all forms of acetylcholine-induced depolarization were blocked by the nicotinic antagonist mecamylamine. The cholinergic system plays an important role in regulating nociception and this study contributes to our understanding of how circuit activity is controlled by ACh at a cellular level in primate and rodent spinal cord.

Omega-3 Supplementation Prevents Short-Term High-Fat Diet Effects on the α7 Nicotinic Cholinergic Receptor Expression and Inflammatory Response

The study is aimed at investigating if PUFA supplementation could prevent the effects of a short-term HFD on α7nAChR expression and on the severity of sepsis. Swiss mice were used for the in vivo experiments. For the in vitro experiments, we used a microglia cell line (BV-2) and a hepatoma cell line (Hepa-1c1c7) derived from mice. The animals were either fed standard chow, fed a short-term HFD (60%), or given supplementation with omega-3 fatty acid (2 g/kg or 4 g/kg bw) for 17 days, followed by a short-term HFD. Endotoxemia was induced with an intraperitoneal (i.p.) lipopolysaccharide injection (LPS, 5 or 12 mg/kg), and sepsis was induced by subjecting the animals to cecal ligation and puncture (CLP). BV-2 and Hepa-1c1c7 cells were treated with LPS (100 and 500 ng/mL, respectively) for 3 hours. RT-PCR or Western blotting was used to evaluate α7nAChR expression, inflammatory markers, DNMT1, and overall ubiquitination. LPS and HFD reduced the expression of α7nAChR and increased the expression of inflammatory markers. Omega-3 partially prevented the damage caused by the HFD to the expression of α7nAChR in the bone marrow and hypothalamus, decreased the inflammatory markers, and reduced susceptibility to sepsis-induced death. Exposing the BV-2 cells to LPS increased the protein content of DNMT1 and the overall ubiquitination and reduced the expression of α7nAChR. The inflammation induced by LPS in the BV-2 cell decreased α7nAChR expression and concomitantly increased DNMT1 expression and the ubiquitinated protein levels, indicating the participation of pre- and posttranscriptional mechanisms.

Synaptic Contributions to Cochlear Outer Hair Cell Ca2+ Dynamics.

For normal cochlear function, outer hair cells (OHCs) require a precise control of intracellular Ca2+ levels. In the absence of regulatory elements such as proteinaceous buffers or extrusion pumps, OHCs degenerate, leading to profound hearing impairment. Influx of Ca2+ occurs both at the stereocilia tips and the basolateral membrane. In this latter compartment, two different origins for Ca2+ influx have been poorly explored: voltage-gated L-type Ca2+ channels (VGCCs) at synapses with Type II afferent neurons, and α9α10 cholinergic nicotinic receptors at synapses with medio-olivochlear complex (MOC) neurons. Using functional imaging in mouse OHCs, we dissected Ca2+ influx individually through each of these sources, either by applying step depolarizations to activate VGCC, or stimulating MOC axons. Ca2+ ions originated in MOC synapses, but not by VGCC activation, was confined by Ca2+-ATPases most likely present in nearby synaptic cisterns. Although Ca2+ currents in OHCs are small, VGCC Ca2+ signals were comparable in size to those elicited by α9α10 receptors, and were potentiated by ryanodine receptors (RyRs). In contrast, no evidence of potentiation by RyRs was found for MOC Ca2+ signals over a wide range of presynaptic stimulation strengths. Our study shows that despite the fact that these two Ca2+ entry sites are closely positioned, they differ in their regulation by intracellular cisterns and/or organelles, suggesting the existence of well-tuned mechanisms to separate the two different OHC synaptic functions.SIGNIFICANCE STATEMENT Outer hair cells (OHCs) are sensory cells in the inner ear operating under very special constraints. Acoustic stimulation leads to fast changes both in membrane potential and in the intracellular concentration of metabolites such as Ca2+ Tight mechanisms for Ca2+ control in OHCs have been reported. Interestingly, Ca2+ is crucial for two important synaptic processes: inhibition by efferent cholinergic neurons, and glutamate release onto Type II afferent fibers. In the current study we functionally imaged Ca2+ at these two different synapses, showing close positioning within the basolateral compartment of OHCs. In addition, we show differential regulation of these two Ca2+ sources by synaptic cisterns and/or organelles, which could result crucial for functional segregation during normal hearing.

Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders.

Cholinergic α7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5–7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a, resulting in a hybrid gene known as CHRFAM7A, unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer’s diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca2+ conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/dupα7 interfaces. Based on these models, we used protein–protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aβ42. Our findings show that the optimal stoichiometry of dupα7/α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aβ42 effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in ‘Alzheimer’s disease research.

The Non‐Neuronal Cholinergic System is Causal for Cardioprotection by Hypoxic Preconditioning in Isolated Adult Rat Cardiomyocytes

Introduction Brief episodes of non-lethal myocardial ischemia/reperfusion preceding more sustained ischemia reduce lethal ischemia/reperfusion injury in all species tested so far, including humans. Although this phenomenon is known for more than 3 decades, the underlying signaling mechanisms are unclear in their details. Among various cardioprotective mediators, neuronal acetylcholine (ACh) and its signaling through cholinergic receptors is certainly involved. However, a non-neuronal cardiac cholinergic system (NNCCS) has been recently identified, suggesting a nervous system-independent, cardiomyocyte-derived ACh signaling with signal amplification by autocrine cholinergic receptor activation. Aim We aimed to examine the role of NNCCS-derived ACh as a mediator of cardioprotection. We therefore in a reductionist approach used isolated adult cardiomyocytes with hypoxic preconditioning (HPC). Methods Hearts from male Lewis rats were harvested, and adult ventricular cardiomyocytes were isolated. In suspended cardiomyocytes HPC was induced by one cycle of 10 min brief hypoxia and 20 min reoxygenation. Thirty min normoxia served as control. Afterwards, cardiomyocytes were exposed to 30 min sustained hypoxia and 5 min reoxygenation (H/R) or to 35 min normoxia as time control (TC). Cardiomyocyte viability was quantified before and after H/R or TC, respectively, as the percent fraction of rod-shaped, unstained (0.5% trypan blue) cells over all cells. In parallel experiments, physostigmine (0.2 mmol/L) was added to cardiomyocyte suspensions to block the ubiquitous ACh esterase. Intracellular ACh was quantified with and without HPC via liquid chromatography-coupled tandem mass spectrometry. In subsets, the nicotinic cholinergic receptor antagonists hexamethonium (1.0 µmol/L) and α-bungarotoxine (0.1 µmol/L) or the muscarinic cholinergic receptor antagonist atropine (0.1 µmol/L) were added to cardiomyocyte suspensions with and without HPC, respectively, and exposure to H/R or TC, respectively, afterwards. Again, cardiomyocyte viability was quantified. Results With HPC, the viability of cardiomyocytes subjected to H/R was better preserved than without (24±1% vs. 7±1%, figure A). Also, intracellular ACh was slightly (n.s.) increased after sustained hypoxia (6±2 pmol/mg protein), but significantly with HPC (13±3 pmol/mg protein) in comparison to baseline (3±1 pmol/mg protein) or TC (3±1 pmol/mg protein, figure B). However, this increase was only detectable in the presence of physostigmine (figure B). Addition of nicotinic and muscarinic cholinergic receptor antagonists attenuated the protection by HPC to the same extent (hexamethonium: 12±2%, α-bungarotoxine: 11±1%, atropine: 10±1%, figure A). Conclusion The NNCCS is activated by HPC and causal for HPC´s protection. HPC increases intracellular ACh, and cardiomyocyte protection is mediated via both nicotinic and muscarinic cholinergic receptors, suggesting an autocrine signal amplification on the cardiomyocyte level.

Roles of the Functional Interaction between Brain Cholinergic and Dopaminergic Systems in the Pathogenesis and Treatment of Schizophrenia and Parkinson's Disease.

Most physiologic processes in the brain and related diseases involve more than one neurotransmitter system. Thus, elucidation of the interaction between different neurotransmitter systems could allow for better therapeutic approaches to the treatments of related diseases. Dopaminergic (DAergic) and cholinergic neurotransmitter system regulate various brain functions that include cognition, movement, emotion, etc. This review focuses on the interaction between the brain DAergic and cholinergic systems with respect to the pathogenesis and treatment of schizophrenia and Parkinson’s disease (PD). We first discussed the selection of motor plans at the level of basal ganglia, the major DAergic and cholinergic pathways in the brain, and the receptor subtypes involved in the interaction between the two signaling systems. Next, the roles of each signaling system were discussed in the context of the negative symptoms of schizophrenia, with a focus on the α7 nicotinic cholinergic receptor and the dopamine D1 receptor in the prefrontal cortex. In addition, the roles of the nicotinic and dopamine receptors were discussed in the context of regulation of striatal cholinergic interneurons, which play crucial roles in the degeneration of nigrostriatal DAergic neurons and the development of L-DOPA-induced dyskinesia in PD patients. Finally, we discussed the general mechanisms of nicotine-induced protection of DAergic neurons.

Exposure System Dependent Calcium Influx in Chromaffin Cells by Nanosecond Electric Pulse- Field Reflections at Dielectric Interface

Nanosecond electric pulses have been successfully used as a novel electrical stimulus for evoking a dependent catecholamine release from the bovine adrenal chromaffin cells. It was observed that the duration of calcium influx varies depending on the exposure system. For example, cells exposed to 5 ns and 5MV/m pulses by a gold strip exposure chamber elicited calcium responses similar to the physiological stimulus, nicotinic cholinergic receptor activation. On the other hand, recent exposure systems utilizing tungsten rod electrodes evoke an undesired calcium response that is relatively long-lived even by exposure of the same pulse.

Синаптичні відповіді нейронів верхнього шийного ганглія у щурів при експериментальному цукровому діабеті

Excitatory postsynaptic potentials (EPSP) were recorded from the superior cervical ganglion neurons (SCG) in the rats with experimental streptozotocininduced diabetes (ESD). EPSP was inducted by electrical stimulation of the cervical sympathetic trunk. It was founded that the average value of the EPSP time constant decay in the rats with ESD was 15% higher. At the same time, the amplitudes of EPSP of SCG neurons and the hexamethonium blocking effect in the rats with ESD on 30th day after streptozotocin injection didn’t differ significantly from those in control rats. This may indicate specific functional disorders associated as with steady-state elevated blood glucose level in rats as SCG neurons nicotinic cholinergic receptors.

Molecular mechanisms of α7-nAchR-mediated anti-inflammatory effects

The cholinergic anti-inflammatory pathway is described as an interaction between the nervous system and the immune system. This interaction is regulated by the α7 subtype of cholinergic nicotinic Ach receptors (α7-nAchR), which leads to a marked decrease in the inflammatory cytokines, such as interleukin (IL)-1β, IL-6 and tumour necrosis factor α. Several ligands that interact with α7-nAchR have been recently discovered. These ligands vary in their source, chemical structure, selectivity, potency and efficacy. Activation of α7-nAchR either selectively or non-selectively showed an anti-inflammatory effect that could be due to the inhibition of inflammatory signalling pathways such as Toll-like receptor 4/nuclear factor kappa B inflammasome and mammalian target of rapamycin-mediated autophagy pathways. In addition, it was proved that continuous activation of α7-nAchR could stimulate several anti-inflammatory signalling mechanisms, including Janus activated kinase-2/signal transducer and activator of transcription 3, nuclear factor erythroid 2-related factor 2/HO-1 and adenosine monophosphate-activated protein kinase signalling. In this review, we focused on the recent discoveries of α7-nAchR agonists and antagonists and their anti-inflammatory mechanisms.

Introduction to the Theme "Old and New Toxicology: Interfaces with Pharmacology".

The theme of Volume 61 is "Old and New Toxicology: Interfaces with Pharmacology." Old toxicology is exemplified by the authors of the autobiographical articles: B.M. Olivera's work on toxins and venoms from cone snails and P. Taylor's studies of acetylcholinesterase and the nicotinic cholinergic receptor, which serve as sites of action for numerous pesticides and venoms. Other articles in this volume focus on new understanding and new types of toxicology, including (a) arsenic toxicity, which is an ancient poison that, through evolution, has caused most multicellular organisms to express an active arsenic methyltransferase to methylate arsenite, which accelerates the excretion of arsenic from the body; (b) small molecules that react with lipid dicarbonyls, which are now considered the most toxic oxidative stress end products; (c) immune checkpoint inhibitors (ICIs), which have revolutionized cancer therapy but have numerous immune-related adverse events, including cardiovascular complications; (d) autoimmunity caused by the environment; (e) idiosyncratic drug-induced liver disease, which together with the toxicity of ICIs represents new toxicology interfacing with pharmacology; and (f) sex differences in the development of cardiovascular disease, with men more susceptible than women to vascular inflammation that initiates and perpetuates disease. These articles and others in Volume 61 reflect the interface and close integration of pharmacology and toxicology that began long ago but continues today.

Study of properties and applications nicotine alkaloids

Nicotine = Nicotine may be a plant alkaloid, found within the tobacco plant, and addictive focal sensory system (CNS) energizer that causes either ganglionic incitement in low portions or ganglionic blockage in high dosages. Nicotine goes about as an agonist at the nicotinic cholinergic receptors within the autonomic ganglia, at neuromuscular intersections, and within the medulla and therefore the mind. Nicotine's CNS-animating exercises could be intervened through the arrival of a couple of synapses, including acetylcholine, beta-endorphin, dopamine, norepinephrine, serotonin, and ACTH. Subsequently, fringe vasoconstriction, tachycardia, and raised pulse could be seen with nicotine admission. This specialist may likewise animate the chemoreceptor trigger zone, subsequently instigating queasiness and spewing.

Efficacy of iv infusion of magnesium sulphate and dromperidol on the management of neuropathic and somatosensory chronic pain - a two pain center study

Introduction: Droperidol as a medicine has unique properties and it has been successfully used as analgesic, antipsychotic, antiemetic and as a sedative [1]. It is an antagonist for d2-dopamine, serotonin, histamine, and nicotinic and muscarinic cholinergic receptors. It is also a dose-dependent agonist/antagonist of GABA receptors and an agonist of a2 adrenergic receptors. Moreover, is a sodium channel blocker such as lidocaine and potentiate μ opioid receptors. Its multi-receptor action justifies its use as analgesic, antiemetic and antiphycotic medication [2]. Magnesium seems to function as an antagonist for NMDA receptors and it has been used for relief of acute and chronic pain [3, 4]. The aim of the current study is the evaluation of the efficacy of droperidol and magnesium co-administration on the patients with chronic pain. Method: All patients that attended the pain clinic for chronic pain and aged over 18 years old were included in the study. Patients with atrioventricular block any grade and patients with chronic renal failure were excluded from the study. All included patients received droperidol to the dose 2.5 mg maximum and 1 gr magnesium sulphate iv. DN4 questionnaire was used to assess the presence of neuropathic pain. VAS scale and NPS scale were used to assess the intensity of pain before and after the administration. Change in the pain scales calculated as a percentage. Results: 48 patients included in the study. 23 of them had neuropathic pain. There was a 40–50% reduction of the intensity of pain after iv administration of droperidol and magnesium. There weren’t any complications. Conclusions: The co-administration of magnesium and droperidol can relieve neuropathic and somatosensory pain. Long-term evaluation is needed.

Холинергическая модуляция секреции ацетилхолина в нервно-мышечном соединении

The effect of cholinergic compounds (activators and blockers of nicotinic cholinergic receptors) on the acetylcholine secretion from motor nerve endings is of interest in connection with the questions of the feedback mechanism in the neuromuscular synapse. It is assumed that acetylcholine autoreceptors may exist on the nerve endings. Them activity changes be able affects the release of the transmitter in response to a nerve stimulus. However, numerous of experimental data do not give an unambiguous idea of the direction and mechanisms of action of both endogenous acetylcholine and other cholinergic compounds on the evoked transmitter quantal secretion at the neuromuscular synapse. The relevance of such studies is due to the need to decipher the effects of these compounds, since many of them are used in clinical practice. The review is devoted to the analysis of the results of studies carried out on objects classical for neurophysiology - neuromuscular preparations of warm-blooded animals using a radioisotope method for assessing the amount of a transmitter secreted from nerve endings and an electrophysiological method for determining the number of quanta released in response to a nervous stimulus. Numerous data obtained using activators and blockers of ionotropic nicotinic receptors, as well as the probable mechanisms of action of cholinergic compounds modulating the secretory process, are compared. A scheme for the regulation of quantum secretion was proposed, taking into account new information about the possible participation of the Schwann cell and about presynaptic homeostatic plasticity.

The role of α7-nicotinic acetylcholine receptor in a rat model of chronic nicotine-induced mechanical hypersensitivity

Smokers have a higher incidence of chronic pain than non-smokers, but the neural mechanism is not yet fully understood. Nicotine is the main component of tobacco and acts as an agonist for nicotinic cholinergic receptors (nAChRs) in the nervous system.This study was approved by the IACUC of UM. The effects of chronic nicotine administration on mechanical sensitivity were studied using a rat model. The changes in the expression levels of the α7 isoform of nAChR (α7-nAChR), inflammatory cytokines TNFα and COX-2, as well as the density of neuro-immune cells (astrocytes and microglia) were measured concurrently.The results indicate that long-term nicotine administration induces hypersensitivity to mechanical stimuli, as demonstrated by a significant reduction in the pain perception threshold. In response to nicotine, the expression levels of α7-nAChR increased in the periaqueductal gray matter (PAG) and decreased in the spinal cord. Acute administration of the selective α7-nAChR agonist CDP-Choline reversed this hypersensitivity. Chronic nicotine administration led to an increase of microglial cells in the dorsal horn of the spinal cord and increased expression levels of the cytokines TNFα and COX-2.This study suggests that decreased α7-nAChR expression in the spinal cord, as a result of long-term exposure to nicotine, may be causatively linked to chronic pain. Simultaneously, the increase of neuro-immune factors in the spinal cord is also a potential factor leading to chronic pain.

Identification of CHRNB4 as a Diagnostic/Prognostic Indicator and Therapeutic Target in Human Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors and there is a lack of biomarkers for ESCC diagnosis and prognosis. Family subunits of cholinergic nicotinic receptor genes (CHRNs) are involved in smoking behavior and tumor cell proliferation. Previous researches have shown similar molecular features and pathogenic mechanisms among ESCC, head and neck squamous cell carcinoma (HNSC), and lung squamous cell carcinoma (LUSC). Using edgeR, three mutual differentially expressed genes of CHRNs were found to be significantly upregulated at the mRNA level in ESCC, LUSC, and HNSC compared to matched normal tissues. Kaplan–Meier survival analysis showed that high expression of CHRNB4 was associated with unfavorable prognosis in ESCC and HNSC. The specific expression analysis revealed that CHRNB4 is highly expressed selectively in squamous cell carcinomas compared to adenocarcinoma. Cox proportional hazards regression analysis was performed to find that just the single gene CHRNB4 has enough independent prognostic ability, with the area under curve surpassing the tumor-node-metastasis (TNM) staging-based model, the most commonly used model in clinical application in ESCC. In addition, an effective prognostic nomogram was established combining the TNM stage, gender of patients, and expression of CHRNB4 for ESCC patients, revealing an excellent prognostic ability when compared to the model of CHRNB4 alone or TNM. Gene Set Enrichment Analysis results suggested that the expression of CHRNB4 was associated with cancer-related pathways, such as the mTOR pathway. Cell Counting Kit-8, cloning formation assay, and western blot proved that CHRNB4 knockdown can inhibit the proliferation of ESCC cells via the Akt/mTOR and ERK1/2/mTOR pathways, which might facilitate the prolonged survival of patients. Furthermore, we conducted structure-based molecular docking, and potential modulators against CHRNB4 were screened from FDA approved drugs. These findings suggested that CHRNB4 specifically expressed in SCCs, and may serve as a promising biomarker for diagnosis and prognosis prediction, and it can even become a therapeutic target of ESCC patients.

Neonicotinoids disrupt circadian rhythms and sleep in honey bees

Honey bees are critical pollinators in ecosystems and agriculture, but their numbers have significantly declined. Declines in pollinator populations are thought to be due to multiple factors including habitat loss, climate change, increased vulnerability to disease and parasites, and pesticide use. Neonicotinoid pesticides are agonists of insect nicotinic cholinergic receptors, and sub-lethal exposures are linked to reduced honey bee hive survival. Honey bees are highly dependent on circadian clocks to regulate critical behaviors, such as foraging orientation and navigation, time-memory for food sources, sleep, and learning/memory processes. Because circadian clock neurons in insects receive light input through cholinergic signaling we tested for effects of neonicotinoids on honey bee circadian rhythms and sleep. Neonicotinoid ingestion by feeding over several days results in neonicotinoid accumulation in the bee brain, disrupts circadian rhythmicity in many individual bees, shifts the timing of behavioral circadian rhythms in bees that remain rhythmic, and impairs sleep. Neonicotinoids and light input act synergistically to disrupt bee circadian behavior, and neonicotinoids directly stimulate wake-promoting clock neurons in the fruit fly brain. Neonicotinoids disrupt honey bee circadian rhythms and sleep, likely by aberrant stimulation of clock neurons, to potentially impair honey bee navigation, time-memory, and social communication.

Nicotine and the nicotinic cholinergic system in COVID-19.

There is an urgent need to address the devastating pandemic, COVID‐19, caused by SARS‐CoV‐2. The efforts to understand the details of this disease in hope of providing effective treatments are commendable. It is clear now that the virus can cause far more damage in patients with comorbid conditions—particularly in those with respiratory, cardiovascular, or immune‐compromised system—than in patients without such comorbidities. Drug use can further exacerbate the condition. In this regard, the ill effects of smoking are amply documented, and no doubt can be a confounding factor in COVID‐19 progression. Although conflicting hypotheses on the potential role of nicotine in COVID‐19 pathology have recently been offered, we believe that nicotine itself, through its interaction with the nicotinic cholinergic system, as well as ACE2, may not only be of use in a variety of neuropsychiatric and neurodegenerative diseases, but may also be of potential use in COVID‐19. Thus, on one hand, while we strongly support smoking cessation as a means of harm reduction associated with COVID‐19, on the other hand, we support a potential therapeutic role for nicotine, nicotinic agonists, or positive allosteric modulators of nicotinic cholinergic receptors in COVID‐19, owing to their varied effects including mood regulation, anti‐inflammatory, and purported interference with SARS‐CoV‐2 entry and/or replication.