Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788

Lachowicz, Jean E.; Duffy, Ruth A.; Ruperto, Vilma; Kozlowski, Joseph A.; Zhou, Guowei; Clader, John W.; Billard, William; Binch, Herbert; Crosby, Gordon; Cohen-Williams, Mary; Strader, Catherine D.; Coffin, Victoria

doi:10.1016/s0024-3205(01)01056-6

Cited by 37 publications

(24 citation statements)

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“…Pharmacological studies stemming from this line of reasoning have shown that in aged animals that have impaired cognition and impaired cholinergic function, M 2 receptor-preferring antagonists increase ACh release and improve cognitive performance [36,37,46]. Similarly, M 2 receptor-preferring antagonists reverse scopolamine-induced cognitive deficits in young animals [7,28,36,46]. Based on these data, it appears that blockade of M 2 receptors offers a way of fine-tuning a disrupted cholinergic system by restoring cholinergic activity to some optimal level for cognitive function.…”

Section: Discussionmentioning

confidence: 99%

“…Based on these data, it appears that blockade of M 2 receptors offers a way of fine-tuning a disrupted cholinergic system by restoring cholinergic activity to some optimal level for cognitive function. Nevertheless, all of these pharmacological studies are limited by the fact that the available M 2 receptor antagonists have limited subtype selectivity [6,15,16,22,28,29,32].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, elevating ACh release through pharmacological antagonism of M 2 receptors is beneficial because it restores ACh release to this optimal level after cholinergic signaling has been decreased by aging [36,37,46], drugs (e.g. scopolamine) [7,28,36,46], or disease (e.g. AD).…”

Section: Discussionmentioning

confidence: 99%

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Learning and memory impairments in a congenic C57BL/6 strain of mice that lacks the M2 muscarinic acetylcholine receptor subtype

Bainbridge

Koselke

Jeon

et al. 2008

Behavioural Brain Research

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The neurotransmitter acetylcholine is an important modulator of cognitive functions including attention, learning, and memory. The actions of acetylcholine are mediated by five distinct muscarinic acetylcholine receptor subtypes (M 1 -M 5 ). The lack of drugs with a high degree of selectivity for these subtypes has impeded the determination of which subtypes mediate which components of cholinergic neurotransmission relevant to cognitive abilities. The present study examined the behavioral functions of the M 2 muscarinic receptor subtype by utilizing congenic C57BL/6 mice possessing a null-mutation in the M 2 muscarinic receptor gene (M 2 −/− mice). Comprehensive assessment of general health and neurological function found no major differences between M 2 −/− and wild-type (M 2 +/+ ) mice. In tests of learning and memory, M 2 −/− mice were impaired in the acquisition (trials to criterion), but not the retention (72 hr) of a passive avoidance task. In a novel open field, M 2 −/− mice were impaired in between-sessions, but not within-session habituation. In a holeboard test of spatial memory, M 2 −/− mice committed more errors in working memory than M 2 +/+ mice. Reference memory did not differ between the genotypes. M 2 −/− mice showed no impairments in either cued or contextual fear conditioning. These findings replicate and extend earlier findings in a hybrid strain and solidify the interpretation that the M 2 receptor plays a critical role in specific components of cognitive abilities.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Learning and memory impairments in a congenic C57BL/6 strain of mice that lacks the M2 muscarinic acetylcholine receptor subtype

Bainbridge

Koselke

Jeon

et al. 2008

Behavioural Brain Research

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“…Next, we studied the antiinflammatory efficacy of an independent pharmacological pathway of central cholinergic activation. The release of acetylcholine in the cholinergic synapse is negatively regulated by the presynaptic M2 autoreceptor, and inhibition of this receptor by methoctramine and other specific antagonists enhances central cholinergic transmission (13,14). We injected methoctramine (0.5, 5, and 500 ng͞kg, i.c.v.)…”

Section: Central Administration Of Methoctramine Decreases Systemic Tmentioning

confidence: 99%

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Pavlov

Ochani

Gallowitsch-Puerta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

300

215

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TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this ''cholinergic antiinflammatory pathway'' inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents. muscarinic receptors ͉ systemic inflammation ͉ TNF ͉ vagus nerve T he overproduction of cytokines, including TNF, mediates tissue damage during the response to injury or pathogenic invasion (1). Physiological and molecular mechanisms that control TNF production maintain cytokine homeostasis and minimize or prevent damage during the host response to infection, injury, arthritis, and other disorders (1-3). Recently, we found (4-6) that electrical or pharmacological activation of the efferent vagus nerve inhibits the release of TNF and attenuates the development of endotoxin-induced shock in rodents. Stimulation of the efferent vagus nerve activates the release of acetylcholine. Although the vagus nerve is a ''classical'' cholinergic regulator of visceral functions in which peripheral muscarinic acetylcholine receptors have a major mediating role, the vagusnerve cytokine-inhibiting activity (which is termed ''the cholinergic antiinflammatory pathway'') requires signaling through nicotinic ␣ 7 subunit-containing receptors (4, 5).Studies have implicated muscarinic receptor-dependent mechanisms in the central modulation and integration of vagal regulation of visceral functions. For example, vagus nerve control of glycogen synthesis in the liver, the Bezold-Jarish cardiovascular reflex and the regulation of exocrine pancreatic secretion are modulated centrally by brain muscarinic receptor mechanisms (7-10). Thus, we reasoned that brain muscarinic receptors could be involved in the central regulation of the vagus-nerve immunomodulatory function. Our results indicate that central cholinergic activation by selective muscarinic receptor ligands significantly inhibits systemic TNF in endotoxemic rats and activates th...

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“…The current treatment of AD utilizes acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft [1,2]. The use of SCH 211803 is an alternative strategy, which increases intrasynaptic acetylcholine levels by inhibiting presynaptic M 2 autoreceptors [3][4][5]. Animal studies have shown that SCH 211803 improved both learning and consolidation memory in rats.…”

Section: -(2-amino-3-methylbenzoyl)-4-[[[mentioning

confidence: 99%

Validation and application of a liquid chromatography–tandem mass spectrometric method for the determination of SCH 211803 in rat and monkey plasma using automated 96-well protein precipitation

Wu¹,

Clement²,

Rudewicz³

2004

Journal of Chromatography B

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Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788

Cited by 37 publications

References 0 publications

Learning and memory impairments in a congenic C57BL/6 strain of mice that lacks the M2 muscarinic acetylcholine receptor subtype

Learning and memory impairments in a congenic C57BL/6 strain of mice that lacks the M2 muscarinic acetylcholine receptor subtype

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Validation and application of a liquid chromatography–tandem mass spectrometric method for the determination of SCH 211803 in rat and monkey plasma using automated 96-well protein precipitation

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