Effects of N-hydroxyethyl-pyrrolidinium methiodide, a choline analogue, on passive avoidance behaviour in mice

doi:10.1016/0028-3908(75)90121-5

Neuropharmacology

Volume 14, Issue 8, August 1975, Pages 561-564

https://doi.org/10.1016/0028-3908(75)90121-5 Get rights and content

Abstract

N-Hydroxyethyl-pyrrolidinium methiodide (pyrrolcholine) administered intraventricularly impaired passive avoidance learning in mice. This effect of pyrrolcholine was antagonized by choline and hemicholinium-3, potentiated by scopolamine, and depending upon the time of injection, either potentiated or antagonized by physostigmine. The results are consistent with the hypothesis that pyrrolcholine disrupts central cholinergic pathways by a presynaptic mechanism. Based on metabolism studies, both in vitro and in vivo, it is postulated that the action of pyrrolcholine is mediated via acetylpyrrolcholine, a putative cholinergic false transmitter

References (10)

L.A. Barker et al.
Comparative studies on synaptosomes: high affinity uptake and acetylation of [N-Me-³H]-choline and [N-Me-³H]-N-methyl, N-hydroxyethylpyrroli-dinium by squid optic lobe synaptosomes
Brain Res.
(1975)
Z. Bohdanecky et al.
Impairment of one-trial passive avoidance learning in mice by scopolamine, scopolamine methylbromide and physostigmine
Int. J. Neuropharmac.
(1967)
C.Y. Chiou
Studies on action mechanisms of a possible false transmitter (2-hydroxyethyl) methyldieth-ylammonium
Life Sci.
(1974)
S.D. Glick et al.
Central cholinergic correlates of impaired learning
Neuropharmacology
(1973)
S. Greenstein et al.
A simple procedure for making stereotaxic lesions in the mouse
Physiol Behav.
(1972)

There are more references available in the full text version of this article.

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A microliter syringe was connected to a 26-gauge needle with polyethylene 20 tubing. The needle was inserted into the lateral ventricle through a stereotaxically drilled Plexiglas plate as described previously (Glick et al., 1975). Drug solutions (2 μl) were manually injected over a 1-min period, and the needle removed after an additional minute.
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Improgan, a cimetidine analog, induces morphine-like antinociception in opioid receptor-knockout mice
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Citation Excerpt :
A microliter syringe was connected to a 26-gauge needle with PE20 tubing. The needle was inserted into the lateral ventricle through a stereotaxically drilled Plexiglas plate as described previously in detail [4]. A total of 2 μl of drug solution was injected over a 1-min period.
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We have examined the progressive effects of replacement of dietary choline with NADe for a period of 120 days on a broad spectrum of behavioral and physiological functions known to involve cholinergic system. The magnitudes of these effects tended to increase with time on the NADe diet, but those related to learning and memory were largely confined to the 60–120-day period. Neurochemical effects were concomitant with the replacement of Ch by NADe, being consistent with a hypocholinergic state as found in such progressive degenerative dementias as Alzheimer's disease. As cholinergic functioning was progressively impaired, basic physiological (“vegetative”) processes appeared not to be affected. Apparently the rate at which the hypofunctional state developed was sufficiently slow for adjustments to occur, allowing the animal to adapt at a survival level to neurochemical changes. More complex behavioral functions were affected progressively, cognitive processes (e.g., learning and memory) being most sensitive and showing the least adaptability. We propose that the syndrome generated by NADe replacement of Ch represents an experimental model of progressive degenerative dementia.
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The purpose of this study was to determine whether a series of analogs of choline depress central cholinergic function in a manner consistent with the activity of their acetylated derivatives. Intracerebroventricular infusion of monoethylcholine (MECh), diethylcholine (DECh) and triethylcholine (TECh) inhibited the pressor response of unanesthetized rats to the subsequent intravenous injection of physostigmine (a well-characterized muscarinic response). The order of blocking potency was TECh > DECh > MECh > choline, directly opposite to the order of potency for elicitation of a central pressor response by their associated acetylated derivative (i.e. ACh > AMECh > ADECh = ATECh; Aronstam, Marshall and Buccafusco, 1988). In contrast, there was little selectivity between the analogs of choline in terms of their affinity for muscarinic receptors in the brainstem or cortex; the Ki's for inhibition of the binding of [³H]quinuclidinyl benzilate ranged from 0.33 to 0.95 mM). In terms of their affinity for nicotinic receptors (from the electric organ of Torpedo californica) the following order of potency was obtained: choline > MECh = DECh > TECh. Choline and MEC stimulated the binding of [³H]phencyclidine to the nicotinic ion channel (EC₅₀'s = 79 and 115 μM, respectively). At greater concentrations, all of the analogs inhibited ligand binding to the channel (Ki's from 0.2 to 10 mM), with the following order of potency: TECh > DECh > MECh > choline. These findings suggest that the inhibitory actions of these analogs of choline are related to their synthesis and release as false cholinergic neurotransmitters.
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^☆: This research was supported by NIMH grants MH24949, MH25644 and by Research Scientist Development Award DA70082.

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Effects of N-hydroxyethyl-pyrrolidinium methiodide, a choline analogue, on passive avoidance behaviour in mice☆

Abstract

Brain Res.

Int. J. Neuropharmac.

Life Sci.

Neuropharmacology

Physiol Behav.