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acetylcholine chloride [keywords]
- ABT-089, but not ABT-107, ameliorates nicotine withdrawal-induced cognitive deficits in C57BL6/J mice. [JOURNAL ARTICLE]
- Behav Pharmacol 2014 Nov 25.
Nicotine withdrawal produces cognitive deficits that can predict relapse. Amelioration of these cognitive deficits emerges as a target in current smoking cessation therapies. In rodents, withdrawal from chronic nicotine disrupts contextual fear conditioning (CFC), whereas acute nicotine enhances this hippocampus-specific learning and memory. These modifications are mediated by β2-subunit-containing (β2*) nicotinic acetylcholine receptors in the hippocampus. We aimed to test ABT-089, a partial agonist of α4β2*, and ABT-107, an α7 nicotinic acetylcholine receptor agonist, for amelioration of cognitive deficits induced by withdrawal from chronic nicotine in mice. Mice underwent chronic nicotine administration (12.6 mg/kg/day or saline for 12 days), followed by 24 h of withdrawal. At the end of withdrawal, mice received 0.3 or 0.6 mg/kg ABT-089 or 0.3 mg/kg ABT-107 (doses were determined through initial dose-response experiments and prior studies) and were trained and tested for CFC. Nicotine withdrawal produced deficits in CFC that were reversed by acute ABT-089, but not ABT-107. Cued conditioning was not affected. Taken together, our results suggest that modulation of hippocampal learning and memory using ABT-089 may be an effective component of novel therapeutic strategies for nicotine addiction.
- Imidacloprid and thiacloprid neonicotinoids bind more favourably to cockroach than to honeybee α6 nicotinic acetylcholine receptor: Insights from computational studies. [JOURNAL ARTICLE]
- J Mol Graph Model 2014 Nov 8.:1-12.
The binding interactions of two neonicotinoids, imidacloprid (IMI) and thiacloprid (THI) with the extracellular domains of cockroach and honeybee α6 nicotinic acetylcholine receptor (nAChR) subunits in an homomeric receptor have been studied through docking and molecular dynamics (MD) simulations. The binding mode predicted for the two neonicotinoids is validated through the good agreement observed between the theoretical results with the crystal structures of the corresponding complexes with Ac-AChBP, the recognized structural surrogate for insects nAChR extracellular ligand binding domain. The binding site of the two insect α6 receptors differs by only one residue of loop D, a serine residue (Ser83) in cockroach being replaced by a lysine residue (Lys108) in honeybee. The docking results show very close interactions for the two neonicotinoids with both α6 nAChR models, in correspondence to the trends observed in the experimental neonicotinoid-Ac-AChBP complexes. However, the docking parameters (scores and energies) are not significantly different between the two insect α6 nAChRs to draw clear conclusions. The MD results bring distinct trends. The analysis of the average interaction energies in the two insects α6 nAChRs shows indeed better affinity of neonicotinoids bound to α6 cockroach compared to honeybee nAChR. This preference is explained by tighter contacts with aromatic residues (Trp and Tyr) of the binding pocket. Interestingly, the non-conserved residue Lys108 of loop D of α6 honeybee nAChR interacts through van der Waals contacts with neonicotinoids, which appear more favourable than the direct or water mediated hydrogen-bond interaction between the OH group of Ser83 of α6 cockroach nAChR and the electronegative terminal group of the two neonicotinoids (nitro in IMI and cyano in THI). Finally, in both insects nAChRs, THI is consistently found to bind more favourably than IMI.
- Transcriptome Analysis of Neonatal Larvae after Hyperthermia-Induced Seizures in the Contractile Silkworm, Bombyx mori. [JOURNAL ARTICLE]
- PLoS One 2014; 9(11):e113214.
The ability to respond quickly and efficiently to transient extreme environmental conditions is an important property of all biota. However, the physiological basis of thermotolerance in different species is still unclear. Here, we found that the cot mutant showed a seizure phenotype including contraction of the body, rolling, vomiting gut juice and a momentary cessation of movement, and the heartbeat rhythm of the dorsal vessel significantly increases after hyperthermia. To comprehensively understand this process at the molecular level, the transcriptomic profile of cot mutant, which is a behavior mutant that exhibits a seizure phenotype, was investigated after hyperthermia (42°C) that was induced for 5 min. By digital gene expression profiling, we determined the gene expression profile of three strains (cot/cot ok/ok, +/+ ok/ok and +/+ +/+) under hyperthermia (42°C) and normal (25°C) conditions. A Venn diagram showed that the most common differentially expressed genes (DEGs, FDR<0.01 and log2 Ratio≥1) were up-regulated and annotated with the heat shock proteins (HSPs) in 3 strains after treatment with hyperthermia, suggesting that HSPs rapidly increased in response to high temperature; 110 unique DEGs, could be identified in the cot mutant after inducing hyperthermia when compared to the control strains. Of these 110 unique DEGs, 98.18% (108 genes) were up-regulated and 1.82% (two genes) were down-regulated in the cot mutant. KEGG pathways analysis of these unique DEGs suggested that the top three KEGG pathways were "Biotin metabolism," "Fatty acid biosynthesis" and "Purine metabolism," implying that diverse metabolic processes are active in cot mutant induced-hyperthermia. Unique DEGs of interest were mainly involved in the ubiquitin system, nicotinic acetylcholine receptor genes, cardiac excitation-contraction coupling or the Notch signaling pathway. Insights into hyperthermia-induced alterations in gene expression and related pathways could yield hints for understanding the relationship between behaviors and environmental stimuli (hyperthermia) in insects.
- A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of the Augmentation of a Nicotinic Acetylcholine Receptor Partial Agonist in Depression: Is There a Relationship to Leptin Levels? [JOURNAL ARTICLE]
- J Clin Psychopharmacol 2014 Nov 24.
This randomized, double-blind, placebo-controlled trial evaluated the efficacy of CP-601,927, an α4β2 nicotinic acetylcholine receptor partial agonist and an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to selective serotonin reuptake inhibitors (SSRIs). After open-label treatment with an SSRI for 8 weeks, subjects with a Hamilton Depression Scale 17 score greater than or equal to 16 were entered into a double-blind phase and randomized to CP-601,927 2 mg twice daily or placebo for 6 weeks. The primary end point was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from double-blind baseline to week 14. There was no significant difference in change from baseline to week 14 in the MADRS score for CP-610,927 versus placebo (least square mean difference [80% confidence interval], -1.30 [-3.32-0.71]). Post hoc analyses revealed that the drug-placebo difference in change from baseline (SE) to week 14 in MADRS score was greater in subjects with body mass index (BMI) less than or equal to 35 kg/m (-3.43 [1.87], P = 0.069) than those with BMI greater than 35 kg/m (3.37 [2.8], P = 0.230). Analysis of biomarkers associated with increased BMI suggests that baseline leptin had a significant effect on treatment outcome. P values for the effect of treatment on mean change in MADRS score for subjects with baseline leptin levels below and above the median were 0.055 and 0.0055, respectively. CP-601,927 was equivalent to placebo as an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to SSRIs. However, post hoc analyses suggest that BMI, particularly elevated leptin levels, may have affected the response to CP-601,927; however, further study may be needed to confirm these results.
- Key changes in denervated muscles and their impact on regeneration and reinnervation. [REVIEW]
- Neural Regen Res 2014 Oct 15; 9(20):1796-1809.
The neuromuscular junction becomes progressively less receptive to regenerating axons if nerve repair is delayed for a long period of time. It is difficult to ascertain the denervated muscle's residual receptivity by time alone. Other sensitive markers that closely correlate with the extent of denervation should be found. After a denervated muscle develops a fibrillation potential, muscle fiber conduction velocity, muscle fiber diameter, muscle wet weight, and maximal isometric force all decrease; remodeling increases neuromuscular junction fragmentation and plantar area, and expression of myogenesis-related genes is initially up-regulated and then down-regulated. All these changes correlate with both the time course and degree of denervation. The nature and time course of these denervation changes in muscle are reviewed from the literature to explore their roles in assessing both the degree of detrimental changes and the potential success of a nerve repair. Fibrillation potential amplitude, muscle fiber conduction velocity, muscle fiber diameter, mRNA expression levels of myogenic regulatory factors and nicotinic acetylcholine receptor could all reflect the severity and length of denervation and the receptiveness of denervated muscle to regenerating axons, which could possibly offer an important clue for surgical choices and predict the outcomes of delayed nerve repair.
- Functional differences between neurotransmitter binding sites of muscle acetylcholine receptors. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2014 Nov 24.
A muscle acetylcholine receptor (AChR) has two neurotransmitter binding sites located in the extracellular domain, at αδ and either αε (adult) or αγ (fetal) subunit interfaces. We used single-channel electrophysiology to measure the effects of mutations of five conserved aromatic residues at each site with regard to their contribution to the difference in free energy of agonist binding to active versus resting receptors (ΔGB1). The two binding sites behave independently in both adult and fetal AChRs. For four different agonists, including ACh and choline, ΔGB1 is ∼-2 kcal/mol more favorable at αγ compared with at αε and αδ. Only three of the aromatics contribute significantly to ΔGB1 at the adult sites (αY190, αY198, and αW149), but all five do so at αγ (as well as αY93 and γW55). γW55 makes a particularly large contribution only at αγ that is coupled energetically to those contributions of some of the α-subunit aromatics. The hydroxyl and benzene groups of loop C residues αY190 and αY198 behave similarly with regard to ΔGB1 at all three kinds of site. ACh binding energies estimated from molecular dynamics simulations are consistent with experimental values from electrophysiology and suggest that the αγ site is more compact, better organized, and less dynamic than αε and αδ. We speculate that the different sensitivities of the fetal αγ site versus the adult αε and αδ sites to choline and ACh are important for the proper maturation and function of the neuromuscular synapse.
- Epidermal Growth Factor Receptor Transactivation Is Required for Mitogen-Activated Protein Kinase Activation by Muscarinic Acetylcholine Receptors in HaCaT Keratinocytes. [Journal Article]
- Int J Mol Sci 2014; 15(11):21433-54.
Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M1 and M3 are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation.
- Origins of variation in conducted vasomotor responses. [JOURNAL ARTICLE]
- Pflugers Arch 2014 Nov 26.
Regulation of blood flow in the microcirculation depends on synchronized vasomotor responses. The vascular conducted response is a synchronous dilatation or constriction, elicited by a local electrical event that spreads along the vessel wall. Despite the underlying electrical nature, however, the efficacy of conducted responses varies significantly between different initiating stimuli within the same vascular bed as well as between different vascular beds following the same stimulus. The differences have stimulated proposals of different mechanisms to account for the experimentally observed variation. Using a computational approach that allows for introduction of structural and electrophysiological heterogeneity, we systematically tested variations in both arteriolar electrophysiology and modes of stimuli. Within the same vessel, our simulations show that conduction efficacy is influenced by the type of cell being stimulated and, in case of depolarization, by the stimulation strength. Particularly, simultaneous stimulation of both endothelial and vascular smooth muscle cells augments conduction. Between vessels, the specific electrophysiology determines membrane resistance and conduction efficiency-notably depolarization or radial currents reduce electrical spread. Random cell-cell variation, ubiquitous in biological systems, only cause small or no reduction in conduction efficiency. Collectively, our simulations can explain why CVRs from hyperpolarizing stimuli tend to conduct longer than CVRs from depolarizing stimuli and why agonists like acetylcholine induce CVRs that tend to conduct longer than electrical injections. The findings demonstrate that although substantial heterogeneity is observed in conducted responses, it can be largely ascribed to the origin of electrical stimulus combined with the specific electrophysiological properties of the arteriole. We conclude by outlining a set of "principles of electrical conduction" in the microcirculation.
- Oleoyl-Lysophosphatidylcholine Limits Endothelial Nitric Oxide Bioavailability by Induction of Reactive Oxygen Species. [JOURNAL ARTICLE]
- PLoS One 2014; 9(11):e113443.
Previously we reported modulation of endothelial prostacyclin and interleukin-8 production, cyclooxygenase-2 expression and vasorelaxation by oleoyl- lysophosphatidylcholine (LPC 18:1). In the present study, we examined the impact of this LPC on nitric oxide (NO) bioavailability in vascular endothelial EA.hy926 cells. Basal NO formation in these cells was decreased by LPC 18:1. This was accompanied with a partial disruption of the active endothelial nitric oxide synthase (eNOS)- dimer, leading to eNOS uncoupling and increased formation of reactive oxygen species (ROS). The LPC 18:1-induced ROS formation was attenuated by the superoxide scavenger Tiron, as well as by the pharmacological inhibitors of eNOS, NADPH oxidases, flavin-containing enzymes and superoxide dismutase (SOD). Intracellular ROS-formation was most prominent in mitochondria, less pronounced in cytosol and undetectable in endoplasmic reticulum. Importantly, Tiron completely prevented the LPC 18:1-induced decrease in NO bioavailability in EA.hy926 cells. The importance of the discovered findings for more in vivo like situations was analyzed by organ bath experiments in mouse aortic rings. LPC 18:1 attenuated the acetylcholine-induced, endothelium dependent vasorelaxation and massively decreased NO bioavailability. We conclude that LPC 18:1 induces eNOS uncoupling and unspecific superoxide production. This results in NO scavenging by ROS, a limited endothelial NO bioavailability and impaired vascular function.
- Expression of choline and acetylcholine transporters in synovial tissue and cartilage of patients with rheumatoid arthritis and osteoarthritis. [JOURNAL ARTICLE]
- Cell Tissue Res 2014 Nov 25.
Increasing evidence is showing that the non-neuronal cholinergic system plays an important role in the pathology of rheumatoid arthritis (RA). Choline transport into the cell is the rate-limiting step for the synthesis of acetylcholine (ACh), which can be released directly or in vesicles from the cell. However, in the human joint little is known about choline import or the release of ACh from the cell. Thus, we analyze the expression of members of the organic cation transporter (OCT), of the newly discovered choline transporter-like (CTL) family and of classical neuronal components such as the high-affinity choline transporter (CHT1) and the vesicular ACh transporter (VAChT) in the synovium and cartilage of the human hip joint from patients with osteoarthritis (OA) and RA. OCT1, OCT3 and OCTN1 and all members of the CTL family were expressed in synovial and cartilage samples. The expression of CTL1 and CTL2 was localized in synovial macrophages and fibroblasts. CHT1 mRNA expression was detectable only in the synovium, whereas VAChT was completely absent in all samples. Therefore, in the human joint, choline transport into the cell and the release of ACh seems to be mediated mainly by members of the OCT and CTL family. Expression of transporters appears not to be influenced by the pathological state, as no differences have been detected between joints from OA or RA patients. Importantly, however, all necessary components for choline import and the release of non-neuronal ACh are present in the human joint.