Effects of Acetylethylcholine Mustard on [3H]Quinuclidinyl Benzilate Binding and Acetylcholine Release in Rat Brain Synaptosomes

doi:10.1111/j.1471-4159.1987.tb04117.x

Paper

Effects of Acetylethylcholine Mustard on [3H]Quinuclidinyl Benzilate Binding and Acetylcholine Release in Rat Brain Synaptosomes

Published Feb 1, 1987 · Edwin M. Meyer, D. H. Otero, E. Morgan

Journal of Neurochemistry

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Abstract

Abstract: The effects of acetylethylcholine mustard and its aziridinium derivative (AMMA) on acetylcholine (ACh) release and [3H]quinuclidinyl benzilate (QNB) binding were studied in rat cortical synaptosomes. After incubation for 5 min at 37°C, AMMA reduced [3H]QNB binding with an IC50 of 9 μM. Following incubation for 5 min with 50 μM AMMA and washing, there was a 62% reduction in the [3H]QNB binding capacity with no change in the KD value for the remaining receptors, a result indicating the irrevers‐ibility of the AMMA binding. AMMA and oxotremorine both reduced the basal and 30 mM K+‐induced release of newly synthesized [3H]ACh in dose‐dependent manners over a 2.5‐min period. At identical 50 μM concentrations, AMMA produced a much longer inhibition of basal [3H]ACh release than oxotremorine did. The inhibition of basal and 30 mM K+‐induced [3H]ACh release by AMMA (10–250 μM) was blocked by 2 μM atropine during a 2.5‐min release incubation, but not during a 30‐min release in cubation. After synaptosomes were treated with 50 μM AMMA for 5 min and the unbound drug was washed out from the tissue, [3H]ACh release (basal and K+‐induced) was reduced. AMMA (50 μM) reduced high‐affinity choline uptake and ACh synthesis by >90% in this tissue, but these effects did not account for the [3H]ACh release inhibition, because (a) they were not atropine sensitive and (b) hemi‐cholinium‐3 had no effect on [3H]ACh release under the conditions used in these studies, i.e., after extracellular [3H]choline was washed out. Taken together, these results suggest that AMMA may be an irreversible agonist at pre‐synaptic muscarinic autoreceptors.

In Vitro Study

Study Snapshot

Acetylethylcholine mustard (AMMA) is an irreversible agonist at pre-synaptic muscarinic autoreceptors, reducing acetylcholine release and binding in rat brain synaptosomes.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Effects of Acetylethylcholine Mustard on [3H]Quinuclidinyl Benzilate Binding and Acetylcholine Release in Rat Brain Synaptosomes

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References

Pharmacological and ionic characterizations of the muscarinic receptors modulating [3H]acetylcholine release from rat cortical synaptosomes

The muscarinic receptors that modulate acetylcholine release from rat cortical synaptosomes are of the M2 type, with high affinity and potential for receptor regulation through depolarization and ionic strength changes.

The conversion of 2-chloroalkylamine analogues of oxotremorine to aziridinium ions and their interactions with muscarinic receptors in the guinea pig ileum.

BM 123 and BM 130 are potent and specific muscarinic agonists that bind irreversibly to muscarinic receptors in the guinea pig ileum.

Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo.

AF64A is a presynaptic neurotoxin that causes a persistent deficiency in central cholinergic transmission in mice, leading to neurological motor disturbances and weight loss.

Cholinergic Modulation of the Release of [3H]Acetylcholine from Synaptosomes of the Myenteric Plexus

The release of acetylcholine from synaptosomes is presynaptically modulated, with muscarinic agonists negatively affecting it and nicotinic agonists positively affecting it.

Correlations Between Na+‐K+ ATPase Activity and Acetylcholine Release in Rat Cortical Synaptosomes

Acetylcholine release in rat cortical synaptosomes is partially due to inhibition of Na+-K+ ATPase, with varying effects depending on external calcium concentration.

Citations

Characteristics of a presynaptic plasma membrane Ca2(+)-ATPase activity from electric organ.

The Ca2+-ATPase activity in electric organ synaptosomal homogenates shows characteristics similar to the enzyme that catalyzes outward transport of Ca2+ in nerve terminals, but is not coupled to muscarinic binding sites.

The release of endogenous acetylcholine from the medial septum/diagonal band of rat brain

Acetylcholine release from cholinergic neurons in the medial septum/diagonal band of the rat brain is calcium-dependent and atropine-sensitive.

Structural Determinants of Muscarinic Agonist Activity

In vitro assays are more accurate for studying structure-activity relationships among muscarinic agonists than in vivo studies, as they avoid distributional and pharmacokinetic factors.