摘要:

AbstractChlorisondamine, a nicotinic cholinergic receptor antagonist, can block many of the in vivo effects of nicotine for weeks after a single icv injection. The time course of this effect was examined in a single group of rats by assessing the effects of nicotine on locomotor activity at 1, 3, and 6 weeks after the icv administration of 23 nmol of chlorisondamine. The effects of nicotine on locomotor activity were biphasic as has been previously reported, with decreases in activity early in the session and increases in activity later in the session. These effects of nicotine were blocked in chlorisondamine‐treated rats at 1 or 3 weeks but not 6 weeks after administration of chlorisondamine. Nicotinic receptor binding in the brains of chlorisondamine‐treated rats revealed no change in Bmaxbut a significant increase in affinity (47–59% decrease in Kd) 1, 3, 6, or 7 weeks after treatment. In contrast to its effects on affinity when administered icv, chlorisondamine did not alter binding affinity when added directly to the incubation buffer in vitro. Thus, although chlorisondamine significantly alters neuronal nicotinic cholinergic receptor binding affinity, this effect of chlorisondamine on binding affinity does not appear to be a direct effect of chlorisondamine on the receptor or to match the time course of chlorisondamine blockade of nicotine‐induced changes in locomotor activity. © 1994 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430310202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractChronic twice daily systemic administration of nicotine (1 mg [2 μmol]/kg, sc) over 10 days to rats produced a significant increase in the apparent Bmaxfor cortical nicotinic receptors. Similar results were obtained whether the labeled ligand employed was [3H]methylcarbamylcholine ([3H]MCC) or [3H]cytisine: Rats were treated twice daily for 10 days with the cholinesterase inhibitor physostigmine (25 μg [64 nmol]/kg, sc) to indirectly activate nicotinic receptors. This regimen inhibited cortical cholinesterase activity by about 51%. Binding analysis of physostigmine‐treated rat cortical tissue indicated that while the Bmaxfor muscarinic receptors was significantly reduced, there was no change in the binding parameters for neuronal nicotinic receptors. In the next series of experiments, chronic twice daily intracerebroventricular (icv) injection of 30 μg [108 nmol] of MCC, like nicotine, also produced a significant increase in the Bmaxfor cortical nicotinic receptors. MCC treatment also produced a small but significant increase in the apparent Kd. Twice daily icv injection of 6 μg [23 nmol] of the competitive nicotinic antagonist dihydro‐β‐erythroidine hydrobromide (DHBE) for 10 days did not itself alter the apparent Bmaxfor cortical nicotinic receptors. In a separate group of rats 6 μg [23 nmol] icv of DHBE preceded by 15 min the icv injection of 30 μg [108 nmol]of MCC. This regimen was administered twice daily for 10 days. Under these conditions the DHBE produced a significant 44% inhibition of the MCC‐induced increase in Bmax. Antagonist pretreatment also blocked the small MCC‐induced increase in Kd. Thus, direct activation of the agonist binding site of the neuronal nicotinic receptor following chronic administration of nicotine or the acetycholine‐like MCC leads to receptor up‐regulation. Indirect activation through cholinesterase inhibition was not effective in this regard. ©

ISSN:0272-4391    

DOI:10.1002/ddr.430310203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

Abstract[3H]nicotine bound to rat cortical membranes in a biphasic manner consistent with previous models of receptor function. The kinetics of binding were characterized by a rapid component with a rate constant of 0.007 min−1nM−1and a slower component with an apparent rate constant of 0.024 min−1. Dissociation was monophasic with a rate constant of 0.046 min−1. Addition of 3 mM propofol caused the abolition of the slow component of association and increased the rate constants for the rapid component to 0.012 min−1and for dissociation to 0.086 min−1. Under non‐equilibrium conditions propofol caused a dose‐dependent increase in the binding of [3]Hnicotine, which reached 147% of the control value at 3 mM propofol. The equilibrium binding of [3H]nicotine was unaffected by the drug. These results are consistent with propofol causing enhanced desensitization at the cortical nicotinic acetylcholine receptor, suggesting an alternative to receptor agonists which bind to active sites as a method of modulating receptor function. © 1994

ISSN:0272-4391    

DOI:10.1002/ddr.430310204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractTranscortical dialysis was employed to investigate the effects of systemic nicotine (3.6 μmol/kg, sc) administration on cortical extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA), and serotonin (5‐HT). Systemic administration of [–]‐nicotine produced a 106% increase of cortical ACh release over basal levels that persisted for approximately 2 h. Concurrently, NE levels were increased 86% over basal values for 60 min. The effects appear to be stereoselective, as systemic injections of [+]‐nicotine significantly increased cortical ACh levels only 48% over basal levels for 30 min, and NE levels in the dialysate only 43% over control levels for 60 min. No significant changes of basal dopamine (DA) or serotonin (5‐HT) levels were observed, although DA did appear to increase in response to systemic nicotine. In addition, striatal total endogenous ACh increased significantly over control levels 15 min after [–]‐nicotine administration (3.6 μmol/kg, sc), and then significantly declined after 3 h, suggesting that nicotine may influence synthesis as well as release. Analysis of total ACh levels in cortical tissue revealed a similar trend. At the dose utilized in this study, no changes in the cortical electroencephalogram (EEG) were observed. © 1994

ISSN:0272-4391    

DOI:10.1002/ddr.430310205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractIn contrast with the now well‐recognized effects of nicotine in promoting learning and memory, little is known about the functional and pharmacological properties of putative nicotinic acetylcholine receptors located in neocortical areas involved in cognitive functions. Recent electrophysiological experiments using intracellular recordings in the rat prefrontal cortex in vitro have revealed that nicotine selectively enhances the amplitude of excitatory postsynaptic potentials mediated by glutamate in pyramidal cells. The effect was blocked by the specific nicotinic antagonists neuronal bungarotoxin and dihydro‐β‐erythroidine. Several arguments suggest that the potentiation of excitatory potentials by nicotine is due to the activation of presynaptic nicotinic receptors located on glutamatergic afferent terminals. Thus the control by nicotinic receptors of the effectiveness of excitatory inputs to the prefrontal cortex might influence significantly the processing of information in this area. The possibility of a functional cooperation between nicotinic and glutamatergic systems in the neocortex provides an integrative mechanism for the involvement of both neurotransmitter systems in synaptic plasticity underlying memory processes. © 1994 Wiley‐

ISSN:0272-4391    

DOI:10.1002/ddr.430310206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractSeveral novel anabaseine‐derived compounds were investigated with respect to their ability to displace high affinity [3H]cytisine binding in rat brain membranes, as well as their ability to improve passive and active avoidance behaviors in nucleus basalis‐lesioned rats. The relative potencies for displacement of 1 nM [3H]cytisine binding IC50 in parentheses: anabaseine (70 nM)>DMAB (140 nM) = DMXB (150 nM)>anabasine (270 nM)>DMAC (420 nM). Passive avoidance behavior in bilaterally nucleus basalis‐lesioned rats was improved by each of these drugs to an extent comparable to that observed with (–)‐nicotine. The relative potencies of these compounds for improving this behavior exhibited a pattern very similar to their affinities for displacing [3H]cytisine binding (nicotine>anabaseine>DMXB>DMAB = DMAC>anabasine). Acquisition of active avoidance behavior was slower in unilaterally and bilaterally nucleus basalis‐lesioned rats than unlesioned controls; (−)‐nicotine improved acquisition behavior only in the former group. At doses that improved passive avoidance behavior, DMXB also improved acquisition of active avoidance behavior in unilaterally lesioned rats, while DMAB and DMAC did not. (−)Nicotine and DMXB had no effect on escape behavior in the active avoidance task at doses that improved retention of avoidance behavior itself. These results suggest that anabaseine and several of its analogs bind to brain α4β2 nicotinic receptors and mimic non‐spatial, memory‐related behaviors in a nicotine‐like manne

ISSN:0272-4391    

DOI:10.1002/ddr.430310207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe potential cytoprotective actions of a novel nicotinic agent 2,4‐dimethoxybenzilidene anabaseine (DMXB) were investigated in differentiated PC12 cells and transected rat septal cholinergic neurons in vivo. In NGF‐differentiated PC12 cells, removal of both NGF and serum led to cell loss, a reduced % of cells expressing neurites, the release of lactate dehydrogenase, and a decrease in total cellular protein. Cell loss was apparent within 24 h, and remained constant between 4–8 days post‐NGF removal. NGF alone (100 ng/ml), DMXB (10 μM), but not nicotine (10 μM), prevented these cell and neurite losses. DMXB‐induced cytoprotection was blocked by 1 μM mecamylamine. DMXB (1 mg/kg, ip) injected twice but not once per day protected cholinesterase‐staining septal neurons from retrograde degeneration following unilateral fimbrial transections. The twice per day DMXB injection‐protocol also decreased cell roundness among cholinesterase‐staining cells in the lesioned septal hemisphere compared to saline‐injected animals. These studies suggest that DMXB may exert cytoprotective activity in NGF‐sensitive neuronal populations.

ISSN:0272-4391    

DOI:10.1002/ddr.430310208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractStructure‐activity studies were performed on a series of newly synthesized N‐sub‐stituted carbamate esters of choline and dimethylethanolamine which exhibited either or both nicotinic and muscarinic cholinergic properties. Substitutions on the carbamyl N consisted of varying lengths of dialkyls, diphenyl, and various heterocycles. The compounds were evaluated for their nicotinic and muscarinic receptor binding properties in rat brain membranes, their effect on muscarinic receptor‐activated phosphoinositide (PI) turnover in rat cortical slices, and for muscarinic receptor‐mediated intracelluar Ca release in a mouse adrenal carcinoma cell line transfected with an m1 muscarinic cholinergic receptor gene. N,N‐diethylcarbamylcholine had the highest affinity for nicotinic cholinergic receptors; the Kivalue of 1 × 10−9M approached that of nicotine and being 1/5 that for the dimethyl analogue. With increasing chain length of the dialkyl substituents the nicotinic affinity progressively decreased, while muscarinic affinity increased. N,N‐diphenylcarbamylcholine had a Kivalue of 1 × 10−7M for nicotinic receptors and exhibited nicotinic antagonist activity. Contrary to the results with [3H]‐N‐methylcarbamylcholine binding, the tertiary derivatives exhibited higher Kivalues for [3H]‐3‐quinuclidinyl benzilate binding than the quarternaries; the tertiary dibutyl and diphenyl had the highest affinities with Kivalues of 4 × 10−7M. The inhibition of muscarinic receptor‐mediated PI turnover and release of intracellular calcium were related to the muscarinic antagonist potency of the c

ISSN:0272-4391    

DOI:10.1002/ddr.430310209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe potent nicotinic agonist anatoxin‐a has a semi‐rigid structure amenable to chemical synthesis and modification, making it an attractive candidate for exploring the structure‐activity relationships of ligands at nicotinic acetylcholine receptors. Racemic anatoxin‐a and a series of three analogues with one or more methine or methylene units added to the acetyl sidechain were synthesised and designated homoanatoxin, propylanatoxin, and isopropylanatoxin. In competition binding assays on two neuronal nicotinic receptors in rat brain membranes, labelled with [3H]nicotine and [125I]αbungarotoxin, the analogues retained or exceeded the potency of the parent structure. Kivalues for anatoxin‐a, homoanatoxin, propylanatoxin, and isopropylanatoxin were 19, 5.5, 24 and 7.5 nM, respectively, at the [3H]nicotine site and 900, 340, 40, and 120 nM, respectively, at the [125I]αbungarotoxin site. Thus propylanatoxin appears to show a preference for the latter receptor site. Functional potencies of homoanatoxin and isopropylanatoxin were determined at neuronal α7 nicotinic receptors reconstituted inXenopusoocytes, by two electrode voltage clamp recording. EC50values of 0.72 μM and 0.66 μM were determined, similar to that previously published for (+)anatoxin‐a. Molecular modelling of anatoxin‐a and its alkyl‐modified analogues shows them to have very similar energy profiles, consistent with their similar potencies. In the preferred (low energy) conformation, the enone moiety adopts an s‐trans arrangement, although this configuration does not fit the classical pharmacophore model for nicotinic ligands. This series of alkyl‐modified analogues based on anatoxin‐a provides some novel potent nicotinic agonists and with propylanatoxin, receptor subtype selectivity may be emerging. This rational approach to ligand design also enables us to explore further the requirements for ligand recognition through the application of computational chemist

ISSN:0272-4391    

DOI:10.1002/ddr.430310210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430310201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY