The Experts below are selected from a list of 4749 Experts worldwide ranked by ideXlab platform
Edward D. Levin - One of the best experts on this subject based on the ideXlab platform.
-
effects of chronic sazetidine a a selective α4β2 neuronal Nicotinic acetylcholine receptors desensitizing agent on pharmacologically induced impaired attention in rats
Psychopharmacology, 2013Co-Authors: Amir H Rezvani, Yingxian Xiao, Marty Cauley, Kenneth J Kellar, Edward D. LevinAbstract:Rationale Nicotine and Nicotinic Agonists have been shown to improve attentional function. Nicotinic receptors are easily desensitized, and all Nicotinic Agonists are also desensitizing agents. Although both receptor activation and desensitization are components of the mechanism that mediates the overall effects of Nicotinic Agonists, it is not clear how each of the two opposed actions contributes to attentional improvements. Sazetidine-A has high binding affinity at α4β2 Nicotinic receptors and causes a relatively brief activation followed by a long-lasting desensitization of the receptors. Acute administration of sazetidine-A has been shown to significantly improve attention by reversing impairments caused by the muscarinic cholinergic antagonist scopolamine and the NMDA glutamate antagonist dizocilpine.
-
Effects of AZD3480, a neuronal Nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats
Psychopharmacology, 2012Co-Authors: Amir H Rezvani, Edwin C. Johnson, Gregory J. Gatto, Marty C. Cauley, Edward D. LevinAbstract:Background and rationale Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of Nicotinic Agonists improve attention, and Nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel Nicotinic receptor agonist at α4β2 Nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801). Methods Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control. Results Dizocilpine caused a significant ( p
-
Effects of AZD3480, a neuronal Nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats.
Psychopharmacology, 2012Co-Authors: Amir H Rezvani, Marty Cauley, Edwin C. Johnson, Gregory J. Gatto, Edward D. LevinAbstract:Background and rationale Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of Nicotinic Agonists improve attention, and Nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel Nicotinic receptor agonist at α4β2 Nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801).
-
Lobeline-induced learning improvement of rats in the radial-arm maze.
Pharmacology Biochemistry and Behavior, 2003Co-Authors: Edward D. Levin, Channelle N. ChristopherAbstract:Lobeline is a Nicotinic ligand with some nicotine-like effects, but with some atypical effects as well, including actions as a Nicotinic antagonist. Lobeline, like nicotine, has been found to significantly improve memory function as well as provide anxiolytic-like effects in the elevated plus maze. Lobeline effects on learning remain to be fully characterized. Nicotine has been found to improve learning of shock avoidance tasks. Other Nicotinic Agonists also have been shown to improve learning performance. However, this effect is limited. In some tasks, nicotine has been found to cause deficits. In the current study, effects of lobeline and nicotine injections were assessed in a repeated acquisition procedure in the radial-arm maze for 3 weeks of drug administration. Lobeline (0.3 and 0.9 mg/kg) improved learning on the radial-arm maze. Neither nicotine dose (0.1 and 0.3 mg/kg) improved learning. This nicotine dose range was previously found to improve post-acquisition working memory performance in the radial-arm maze. The atypical effects of lobeline may underlie its greater efficacy than nicotine for improving repeated acquisition. The effect of lobeline improving learning may be useful in the development of novel treatments for learning deficits.
-
Nicotinic and muscarinic interactions and choice accuracy in the radial arm maze
Brain Research Bulletin, 1991Co-Authors: Edward D. Levin, Jed E RoseAbstract:Muscarinic acetylcholine (ACh) systems have long been known to be necessary for accurate performance in cognitive tests. Nicotinic ACh systems have been shown to be involved as well. However, there is only a limited amount of information concerning the interactions of these two branches of the ACh transmitter system. The current study was conducted to investigate the improvement in choice accuracy caused by muscarinic and Nicotinic Agonists and how it is affected by antAgonists of these systems. Adult female Sprague-Dawley strain rats (N = 11) were trained on a working memory task in an 8-arm radial maze. Acute injections of the muscarinic and Nicotinic Agonists, pilocarpine (PILO, 1.0 mg/kg) and nicotine (NIC, 0.2 mg/kg), were made alone or in combination with the muscarinic and Nicotinic antAgonists, scopolamine (SCOP, 0.1 mg/kg) and mecamylamine (MEC, 10 mg/kg). NIC administration caused a significant improvement in choice accuracy compared with saline (p<0.01) and PILO caused a marginally significant improvement in choice accuracy (p<0.06). The combination of these Nicotinic and muscarinic Agonists did not cause an additive improvement. However, the improvement caused by either agonist was reversed by both Nicotinic or muscarinic antAgonists. This reversal was more complete for NIC than PILO despite the fact that NIC caused a greater improvement than PILO. These results suggest that muscarinic and Nicotinic components of the ACh system, which are both important for cognitive function, interact in important ways. These interactions may be critical to consider when devising treatments for cognitive dysfunction associated with cholinergic hypofunction such as with Alzheimer's disease.
Susan Wonnacott - One of the best experts on this subject based on the ideXlab platform.
-
subtype selective Nicotinic Agonists enhance olfactory working memory in normal rats a novel use of the odour span task
Neuroscience Letters, 2010Co-Authors: Samantha L Rushforth, Susan Wonnacott, Claire Allison, Mohammed ShoaibAbstract:Abstract Nicotinic Agonists have been shown to enhance performance in cognitive tasks based on attention and memory. The aim of this study was to use a test of olfactory working memory; the odour span task (OST) in rodents, to investigate the effects of subtype-specific Nicotinic Agonists on working memory in normal rats. Rats were trained in a non-matching to sample (NMTS) rule and then the full OST, which involved identifying a novel odour from an increasing number of presented odours. Male hooded Lister rats were treated with nicotine, selective Nicotinic Agonists or vehicle (saline). In order to validate the task, muscarinic and Nicotinic receptor antAgonists were also examined. Nicotine at both 0.05 and 0.1 mg/kg significantly increased mean span length in the OST. The selective α4β2 Nicotinic receptor agonist metanicotine (0.1 mg/kg s.c.) and the selective α7 Nicotinic receptor agonist (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A, 10 mg/kg i.p.) also improved performance. In contrast, mecamylamine and scopolamine significantly decreased mean span length. These findings suggest a role for the activation of both α4β2 and α7 subtypes of neuronal Nicotinic receptor in mediating enhancements of olfactory working memory capacity in normal, non-compromised rats. These Nicotinic receptor subtypes may therefore prove to be useful targets for the development of novel treatments for neuropsychiatric disorders that involve cognitive dysfunction.
-
attentional effects of Nicotinic Agonists in rats
Neuropharmacology, 2003Co-Authors: Britta Hahn, Christopher G V Sharples, Susan Wonnacott, Mohammed Shoaib, I P StolermanAbstract:Abstract Nicotine can increase stimulus detection, response rate and speed in the five-choice serial reaction time task, a rodent test of attention. In the present experiments, four other Nicotinic Agonists with different pharmacological profiles were compared in the same procedure. The response profile of epibatidine resembled that previously obtained with nicotine in that response accuracy was enhanced and omission errors and correct response latency decreased. ABT-418 transiently increased accuracy in the first 10 min of test sessions and reduced response latency. Isoarecolone caused a dose-related increase in accuracy, but had no effect on omissions or response latency. This absence of effects on response rate- or speed-related measures may be related to its previously reported reduced ability to release dopamine as compared with nicotine. The α7-agonist AR-R17779 was without effect on any measure, indicating that this receptor subtype may not mediate Nicotinic effects on attention. Affinity constants of compounds, determined in competition binding assays targeting the α4β2, α7, α3β4 and α3β2∗ nAChR subtypes, could not explain the differential behavioural effects observed. Differences in their functional efficacy at nAChR subtypes may instead be responsible. The finding that attentional performance and response rate and speed can be selectively modulated by Nicotinic Agonists is encouraging for the development of drugs with therapeutic properties similar to those of nicotine but with reduced unwanted effects.
-
differential effects of chronic drug treatment on α3 and α7 Nicotinic receptor binding sites in hippocampal neurones and sh sy5y cells
British Journal of Pharmacology, 2001Co-Authors: Diana L Ridley, Adrian T Rogers, Susan WonnacottAbstract:The aim of this study was to compare the effects of chronic treatment (for 4 or 7 days) with Nicotinic drugs and 20 mM KCl on numbers of surface α7 Nicotinic AChR, identified by [125I]-α bungarotoxin (α-Bgt) binding, in primary hippocampal cultures and SH-SY5Y cells. Numbers of α3* Nicotinic AChR were also examined in SH-SY5Y cells, using [3H]-epibatidine, which is predicted to label the total cellular population of predominantly α3β2* Nicotinic AChR under the conditions used. All the Nicotinic Agonists examined, the antAgonists d-tubocurarine and methyllycaconitine, and KCl, upregulated [125I]-α Bgt binding sites by 20–60% in hippocampal neurones and, where examined, SH-SY5Y cells. Upregulation of [125I]-α-Bgt binding sites by KCl was prevented by co-incubation with the L-type Ca2+ channel blocker verapamil or the Ca2+-calmodulin dependent kinase II (CaM-kinase II) inhibitor KN-62. Upregulation of [125I]-α-Bgt binding sites by nicotine or 3,[(4-dimethylamino) cinnamylidene] anabaseine maleate (DMAC) was insensitive to these agents. [3H]-Epibatidine binding sites in SH-SY5Y cells were not affected by KCl but were upregulated in a verapamil-insensitive manner by nicotine and DMAC. KN-62 itself provoked a 2 fold increase in [3H]-epibatidine binding. The inactive analogue KN-04 had no effect, suggesting that CaM-kinase II plays a role in regulating numbers of α3* Nicotinic AChR. These data indicate that numbers of α3* and α7 Nicotinic AChR are modulated differently. Nicotinic Agonists and KCl upregulate α7 Nicotinic AChR through distinct cellular mechanisms, the latter involving L-type Ca2+ channels and CaM-kinase II. In contrast, α3* Nicotinic AChR are not upregulated by KCl. This difference may reflect the distinct physiological roles proposed for α7 Nicotinic AChR. British Journal of Pharmacology (2001) 133, 1286–1295; doi:10.1038/sj.bjp.0704207
Sainik Kumar Mahata - One of the best experts on this subject based on the ideXlab platform.
-
Chromaffin cell catecholamine secretion: bisindolylmaleimide compounds exhibit novel and potent antagonist effects at the Nicotinic cholinergic receptor in pheochromocytoma cells.
Molecular Pharmacology, 2002Co-Authors: Manjula Mahata, Daniel T. O'connor, Nitish R Mahapatra, Sainik Kumar MahataAbstract:Activation of protein kinase C (PKC) stimulates nicotine-induced catecholamine secretion. PKC down-regulation by prolonged pretreatment with phorbol 12-myristate 13-acetate diminished nicotine-induced catecholamine secretion only slightly (∼16%), suggesting substantial PKC independence of Nicotinic receptor activation. However, we found that bisindolylmaleimide compounds (which are also putative PKC chemical inhibitors) dramatically inhibited nicotine-induced catecholamine secretion (IC 50 values of ∼24–37 nM). This inhibition was specific for the Nicotinic cholinergic receptor. Catecholamine secretion induced by other Nicotinic Agonists (such as epibatidine, anatoxin, or cytisine) was also powerfully antagonized by bisindolylmaleimide II (IC 50 values of ∼60–90 nM). Even high-dose Nicotinic Agonists failed to overcome the inhibition by bisindolylmaleimide II, suggesting noncompetitive Nicotinic antagonism by this class of compounds. Nicotinic inhibition by bisindolylmaleimide seemed not to be readily reversible. Structure-activity studies of bisindolylmaleimide compounds revealed that bisindolylmaleimides I through III are the most potent Nicotinic antAgonists at the Nicotinic cholinergic receptor in PC-12 cells (IC 50 ≤37 nM), whereas bisindolylmaleimide IV and V have far less Nicotinic antagonist activity (IC 50 >1 μM); the active compounds I through III have cationic tails at an indole nitrogen, whereas the least potent compounds IV and V do not. By contrast, a free NH within the maleimide ring is crucial for PKC inhibition by this class of compounds. We conclude that bisindolylmaleimides I through III are some of the most potent noncompetitive neuronal Nicotinic antAgonists, indeed the most potent such antAgonists we have observed in PC-12 cells. Nicotinic antagonism of these compounds seems to be independent of PKC inhibition.
-
THE NOVEL CATECHOLAMINE RELEASE-INHIBITORY PEPTIDE CATESTATIN (CHROMOGRANIN A344 -364) ACTS AT THE RECEPTOR TO PREVENT Nicotinic CHOLINERGIC TOLERANCE*
1999Co-Authors: Sainik Kumar Mahata, Manjula Mahata, Robert J ParmerAbstract:Nicotinic cholinergic receptors undergo desensitization upon repeated or prolonged exposure to agonist. We investigated the effects of a novel chromogranin A catecholamine release-inhibitory fragment, catestatin (chromogranin A344 ‐364), on agonist-induced desensitization of catecholamine release from pheochromocytoma cells. In a dose-dependent fashion, the Nicotinic antagonist catestatin blocked agonist desensitization of both catecholamine release (IC50 ; 0.24 mM) and 22 Na 1 uptake (IC50 ; 0.31 mM), the initial step in Nicotinic cationic signal transduction; both secretion inhibition and blockade of desensitization were noncompetitive with agonist. Desensitizing effects of the Nicotinic Agonists nicotine and epibatidine were blocked. This antagonist action was specific to desensitization by Nicotinic Agonists, since catestatin did not block desensitization of catecholamine release induced by agents which bypass the Nicotinic receptor. Hill plots with slopes near unity suggested noncooperativity for catestatin effects on both Nicotinic responses (secretory antagonism and blockade of desensitization). Human, bovine, and rat catestatins (as well as substance P) had similar potencies. IC50 values for secretion inhibition and blockade of desensitization paralleled each other (r 5 0.76, n 5 10 antAgonists, p 5 0.01) for several noncompetitive Nicotinic antAgonists. Peptide Nicotinic antAgonists (catestatins, substance P) were far more potent inhibitors of both secretion (p 5 0.019) and desensitization (p 5 0.005) than nonpeptide antAgonists (trimethaphan, hexamethonium, procaine, phencyclidine, cocaine, or clonidine), and the peptides displayed enhanced selectivity to block desensitization versus secretion (p 5 0.003). We conclude that catestatin is a highly potent, dose-dependent, noncompetitive, noncooperative, specific inhibitor of Nicotinic desensitization, an effect which may have implications for control of catecholamine release.
-
Desensitization of Catecholamine Release THE NOVEL CATECHOLAMINE RELEASE-INHIBITORY PEPTIDE CATESTATIN (CHROMOGRANIN A344–364) ACTS AT THE RECEPTOR TO PREVENT Nicotinic CHOLINERGIC TOLERANCE
Journal of Biological Chemistry, 1999Co-Authors: Sainik Kumar Mahata, Manjula Mahata, Robert J Parmer, Daniel T. O'connorAbstract:Abstract Nicotinic cholinergic receptors undergo desensitization upon repeated or prolonged exposure to agonist. We investigated the effects of a novel chromogranin A catecholamine release-inhibitory fragment, catestatin (chromogranin A344–364), on agonist-induced desensitization of catecholamine release from pheochromocytoma cells. In a dose-dependent fashion, the Nicotinic antagonist catestatin blocked agonist desensitization of both catecholamine release (IC50 ∼ 0.24 μm) and22Na+ uptake (IC50 ∼ 0.31 μm), the initial step in Nicotinic cationic signal transduction; both secretion inhibition and blockade of desensitization were noncompetitive with agonist. Desensitizing effects of the Nicotinic Agonists nicotine and epibatidine were blocked. This antagonist action was specific to desensitization by Nicotinic Agonists, since catestatin did not block desensitization of catecholamine release induced by agents which bypass the Nicotinic receptor. Hill plots with slopes near unity suggested noncooperativity for catestatin effects on both Nicotinic responses (secretory antagonism and blockade of desensitization). Human, bovine, and rat catestatins (as well as substance P) had similar potencies. IC50 values for secretion inhibition and blockade of desensitization paralleled each other (r = 0.76,n = 10 antAgonists, p = 0.01) for several noncompetitive Nicotinic antAgonists. Peptide Nicotinic antAgonists (catestatins, substance P) were far more potent inhibitors of both secretion (p = 0.019) and desensitization (p = 0.005) than nonpeptide antAgonists (trimethaphan, hexamethonium, procaine, phencyclidine, cocaine, or clonidine), and the peptides displayed enhanced selectivity to block desensitization versus secretion (p = 0.003). We conclude that catestatin is a highly potent, dose-dependent, noncompetitive, noncooperative, specific inhibitor of Nicotinic desensitization, an effect which may have implications for control of catecholamine release.
Channelle N. Christopher - One of the best experts on this subject based on the ideXlab platform.
-
Lobeline-induced learning improvement of rats in the radial-arm maze.
Pharmacology Biochemistry and Behavior, 2003Co-Authors: Edward D. Levin, Channelle N. ChristopherAbstract:Lobeline is a Nicotinic ligand with some nicotine-like effects, but with some atypical effects as well, including actions as a Nicotinic antagonist. Lobeline, like nicotine, has been found to significantly improve memory function as well as provide anxiolytic-like effects in the elevated plus maze. Lobeline effects on learning remain to be fully characterized. Nicotine has been found to improve learning of shock avoidance tasks. Other Nicotinic Agonists also have been shown to improve learning performance. However, this effect is limited. In some tasks, nicotine has been found to cause deficits. In the current study, effects of lobeline and nicotine injections were assessed in a repeated acquisition procedure in the radial-arm maze for 3 weeks of drug administration. Lobeline (0.3 and 0.9 mg/kg) improved learning on the radial-arm maze. Neither nicotine dose (0.1 and 0.3 mg/kg) improved learning. This nicotine dose range was previously found to improve post-acquisition working memory performance in the radial-arm maze. The atypical effects of lobeline may underlie its greater efficacy than nicotine for improving repeated acquisition. The effect of lobeline improving learning may be useful in the development of novel treatments for learning deficits.
Daniel T. O'connor - One of the best experts on this subject based on the ideXlab platform.
-
Chromaffin cell catecholamine secretion: bisindolylmaleimide compounds exhibit novel and potent antagonist effects at the Nicotinic cholinergic receptor in pheochromocytoma cells.
Molecular Pharmacology, 2002Co-Authors: Manjula Mahata, Daniel T. O'connor, Nitish R Mahapatra, Sainik Kumar MahataAbstract:Activation of protein kinase C (PKC) stimulates nicotine-induced catecholamine secretion. PKC down-regulation by prolonged pretreatment with phorbol 12-myristate 13-acetate diminished nicotine-induced catecholamine secretion only slightly (∼16%), suggesting substantial PKC independence of Nicotinic receptor activation. However, we found that bisindolylmaleimide compounds (which are also putative PKC chemical inhibitors) dramatically inhibited nicotine-induced catecholamine secretion (IC 50 values of ∼24–37 nM). This inhibition was specific for the Nicotinic cholinergic receptor. Catecholamine secretion induced by other Nicotinic Agonists (such as epibatidine, anatoxin, or cytisine) was also powerfully antagonized by bisindolylmaleimide II (IC 50 values of ∼60–90 nM). Even high-dose Nicotinic Agonists failed to overcome the inhibition by bisindolylmaleimide II, suggesting noncompetitive Nicotinic antagonism by this class of compounds. Nicotinic inhibition by bisindolylmaleimide seemed not to be readily reversible. Structure-activity studies of bisindolylmaleimide compounds revealed that bisindolylmaleimides I through III are the most potent Nicotinic antAgonists at the Nicotinic cholinergic receptor in PC-12 cells (IC 50 ≤37 nM), whereas bisindolylmaleimide IV and V have far less Nicotinic antagonist activity (IC 50 >1 μM); the active compounds I through III have cationic tails at an indole nitrogen, whereas the least potent compounds IV and V do not. By contrast, a free NH within the maleimide ring is crucial for PKC inhibition by this class of compounds. We conclude that bisindolylmaleimides I through III are some of the most potent noncompetitive neuronal Nicotinic antAgonists, indeed the most potent such antAgonists we have observed in PC-12 cells. Nicotinic antagonism of these compounds seems to be independent of PKC inhibition.
-
Desensitization of Catecholamine Release THE NOVEL CATECHOLAMINE RELEASE-INHIBITORY PEPTIDE CATESTATIN (CHROMOGRANIN A344–364) ACTS AT THE RECEPTOR TO PREVENT Nicotinic CHOLINERGIC TOLERANCE
Journal of Biological Chemistry, 1999Co-Authors: Sainik Kumar Mahata, Manjula Mahata, Robert J Parmer, Daniel T. O'connorAbstract:Abstract Nicotinic cholinergic receptors undergo desensitization upon repeated or prolonged exposure to agonist. We investigated the effects of a novel chromogranin A catecholamine release-inhibitory fragment, catestatin (chromogranin A344–364), on agonist-induced desensitization of catecholamine release from pheochromocytoma cells. In a dose-dependent fashion, the Nicotinic antagonist catestatin blocked agonist desensitization of both catecholamine release (IC50 ∼ 0.24 μm) and22Na+ uptake (IC50 ∼ 0.31 μm), the initial step in Nicotinic cationic signal transduction; both secretion inhibition and blockade of desensitization were noncompetitive with agonist. Desensitizing effects of the Nicotinic Agonists nicotine and epibatidine were blocked. This antagonist action was specific to desensitization by Nicotinic Agonists, since catestatin did not block desensitization of catecholamine release induced by agents which bypass the Nicotinic receptor. Hill plots with slopes near unity suggested noncooperativity for catestatin effects on both Nicotinic responses (secretory antagonism and blockade of desensitization). Human, bovine, and rat catestatins (as well as substance P) had similar potencies. IC50 values for secretion inhibition and blockade of desensitization paralleled each other (r = 0.76,n = 10 antAgonists, p = 0.01) for several noncompetitive Nicotinic antAgonists. Peptide Nicotinic antAgonists (catestatins, substance P) were far more potent inhibitors of both secretion (p = 0.019) and desensitization (p = 0.005) than nonpeptide antAgonists (trimethaphan, hexamethonium, procaine, phencyclidine, cocaine, or clonidine), and the peptides displayed enhanced selectivity to block desensitization versus secretion (p = 0.003). We conclude that catestatin is a highly potent, dose-dependent, noncompetitive, noncooperative, specific inhibitor of Nicotinic desensitization, an effect which may have implications for control of catecholamine release.