Nicotinic receptor inactivation after acute and repeated in vivo nicotine exposures in rats
14
Citation
28
Reference
10
Related Paper
Citation Trend
Keywords:
Methyllycaconitine
A bstract : Adrenal secretion and binding studies were performed using ring E analogues of methyllycaconitine to assess structural determinants affecting activity on bovine adrenal α3β4* nicotinic receptors. The most potent analogues are as potent as many inhibitors of adrenal secretion. Our data support the potential use of methyllycaconitine analogues to generate nicotinic receptor subtype‐specific compounds.
Methyllycaconitine
Cite
Citations (10)
Abstract Nicotine and other nicotinic acetylcholine receptor agonists have been shown to exert neuroprotective actions in vivo and in vitro by an as yet unknown mechanism. Even the identification of the subtype of nicotinic receptor(s) mediating this action has not been determined. In neural cell lines, the induction of cytoprotection often requires exposure to nicotine for up to 24 hr to produce a full protective effect. One phenomenon associated with chronic exposure of neural cells to nAChR agonists is the increased expression of nAChRs (upregulation), possibly as a response to desensitization. Because nicotinic receptors desensitize rapidly in the continuous presence of agonist, we investigated whether the neuroprotective actions produced by different nicotinic receptor agonists was related to their ability to induce nicotinic receptor upregulation. Differentiated PC12 cells were preincubated for 24 hr with various nAChR ligands, and the cells were subsequently deprived of both NGF and serum to induce cytotoxicity. Under control conditions cell viability was reduced to 66.5 ± 5.4% of control by trophic factor withdrawal. For those cells pretreated with nicotine (1 nM–100 μM) cell viability increased from 74.2 ± 1.5 to 97.3 ± 4%. The neuroprotective action of nicotine was blocked by co‐treatment with either 5 μM mecamylamine or 10 nM methyllycaconitine (MLA). The high potency blockade by MLA suggested that neuroprotection was mediated through the α7 nicotinic receptor subtype. For the seven agonists examined for neuroprotective activity, only nicotine was capable of evoking a near maximal (near 100% cell viability) neuroprotective action. The next most effective group included epibatidine, 4OHGTS‐21, methycarbamylcholine, and 1,1‐dimethyl‐4‐phenyl‐piperazinium iodide. These least effective group included cytisine and tetraethylammonium. Incubation of differentiated PC12 cells with 10 μM nicotine increased the number of [ 125 I]αbungarotoxin ([ 125 I]αBGTbinding sites by 41% from 82.6 ± 3.67 to 117 ± 10.3 fmol/mg protein). Under similar conditions of incubation, the nicotinic receptor agonist cytisine (that was least effective in terms of neuroprotection) failed to increase the number of [ 125 I]αBGT binding sites. Cells expressing increased levels of cell surface [ 125 I]αBGT binding sites received added neuroprotective benefit from nicotine. Thus the induced upregulation of the α7 subtype of nicotinic receptors during chronic exposure to nicotine may be responsible for the drug's neuroprotective action. J. Neurosci. Res. 66:565–572, 2001. © 2001 Wiley‐Liss, Inc.
Methyllycaconitine
Mecamylamine
Cytisine
Viability assay
Nicotinic Antagonist
Cite
Citations (120)
Methyllycaconitine
Nicotinic Antagonist
Bungarotoxin
Cite
Citations (20)
Methyllycaconitine
Nicotinic Antagonist
Mecamylamine
Cys-loop receptors
Cite
Citations (62)
Methyllycaconitine
Nicotinic Antagonist
Competitive antagonist
Cite
Citations (77)
Background This study was performed to elucidate and compare the effects of sevoflurane and of isoflurane on the nicotinic acetylcholine receptor of mouse myotubes. The experiments were done with special reference to anesthetic concentrations considerably less than those used for clinical anesthesia. Methods The patch-clamp technique was used to record acetylcholine-activated currents from the embryonic type of the nicotinic acetylcholine receptor in the outside-out mode. A piezo-driven liquid filament switch was used for the ultrafast application of acetylcholine alone or in combination with isoflurane or sevoflurane. In addition, the patches were preexposed to either anesthetic, preceding the activation with acetylcholine. Results The current elicited by acetylcholine was reduced reversibly and in a concentration-dependent manner by both anesthetics, which were equally effective. Preexposure of the patches to isoflurane or sevoflurane showed an additional inhibition that was present at micromolar concentrations. The time courses of current decay could be fitted by single exponentials for isoflurane. At higher concentrations of sevoflurane, the current decay became biexponential. In contrast to isoflurane, sevoflurane increased the time constants of desensitization when applied in low concentrations. Conclusions At the nicotinic acetylcholine receptor, isoflurane and sevoflurane act primarily through the same mechanisms: Both affect the open and the closed state of the channels in concentrations equal to and less than those encountered clinically. The kinetics of desensitization, however, are altered in a different manner. Thus there may be several different sites of interaction.
Cite
Citations (81)
Cys-loop receptors
Cite
Citations (59)
Knockout mouse
Cite
Citations (58)
Nicotinic Antagonist
Methyllycaconitine
Cite
Citations (28)
Although nicotinic agonists can modulate sensory transmission, particularly nociceptive signaling, remarkably little is known about the functional expression of nicotinic acetylcholine receptors (nAChRs) on primary sensory neurons. We have utilized molecular and electrophysiological techniques to characterize the functional diversity of nAChR expression on mammalian dorsal root ganglion (DRG) neurons. RT-PCR analysis of subunit mRNA in DRG tissue revealed the presence of nAChR subunits α2–7 and β2–β4. Using whole cell patch-clamp recording and rapid application of nicotinic agonists, four pharmacologically distinct categories of nicotinic responses were identified in cultured DRG neurons. Capacitance measurements were used to divide neurons into populations of large and small cells, and the prevalence of nicotinic responses was compared between groups. Category I (α7-like) responses were seen in 77% of large neurons and 32% of small neurons and were antagonized by 10 nM methyllycaconitine citrate (MLA) or or 50 nM α-bungarotoxin (α-BTX). Category II (α3β4-like) responses were seen in 16% of large neurons and 9% of small neurons and were antagonized by 20 μM mecamylamine but not 10 nM MLA or 1 μM DHβE. Category II responses had a higher sensitivity to cytisine than nicotine. Two other types of responses were identified in a much smaller percentage of neurons and were classified as either category III (α4β2-like) or category IV (subtype unknown) responses. Both the α7-like and α3β4-like responses could be desensitized by prolonged applications of the analgesic epibatidine.
Methyllycaconitine
Mecamylamine
Cytisine
Dorsal root ganglion
Nicotinic Antagonist
Epibatidine
Cite
Citations (161)