The muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brain

doi:10.1016/0922-4106(94)90158-9

European Journal of Pharmacology: Molecular Pharmacology

Volume 267, Issue 3, 17 May 1994, Pages 329-334

https://doi.org/10.1016/0922-4106(94)90158-9 Get rights and content

Abstract

In the present study we examined the effects of lithium chloride and the muscarinic receptor agonists pilocarpine hydrochloride and L-658,903 (3-(3-methyl-1,2,4-oxadiazol-5-yl) quinuclidine hydrochloride) upon the accumulation of inositol monophosphates in mouse brain using a radiometric technique. Lithium was able to stimulate dose dependently the accumulation of inositol monophosphates with a minimal effective dose (MED) of 3 mEq/kg s.c. and maximal effect seen at 20 mEq/kg. This corresponded to an increase in the radioactivity in the inositol monophosphate fraction from 1.4 ± 0.06% to 4.6 ± 0.60%. The response was time-dependent, with a peak effect observed at 4 h post administration and returning to basal levels by 48 h. The muscarinic receptor agonist pilocarpine (MED 10 mg/kg i.p.) was able to enhance dose dependently the response to 10 mEq/kg lithium, with a maximum response seen at 30 mg/kg (9.3% of the total brain radioactivity present in the inositol monophosphate fraction). The efficacious oxadiazole muscarinic receptor agonist L-658,903 also enhanced the response to lithium, producing a maximal effect of 10.4% of the total brain radioactivity present in the inositol monophosphate fraction at 1 mg/kg i.p. This stimulation was blocked by 1 mg/kg scopolamine i.p. but not by 1 mg/kg N-methylscopolamine. These results demonstrate the linkage of muscarinic receptors to the accumulation of inositol monophosphates in vivo, and confirm that following peripheral administration L-658,903 is a potent efficacious agonist at muscarinic receptors within the central nervous system.

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Cited by (11)

Receptor reserve of phosphoinositide-coupled muscarinic receptors in mouse hippocampus in vivo
2001, Brain Research
Citation Excerpt :
Thus, a key issue in the use of partial agonists for activation of central PI coupled receptors is in vivo determination of the receptor reserve for PI hydrolysis. Recently, a technique for determination of in vivo PI hydrolysis has been developed [26,6,34]. Using this method, we have shown that the weak partial agonists pilocarpine and xanomeline produce robust responses on in vivo PI hydrolysis in mice and rats [6].
The ability of the partial muscarinic agonist pilocarpine to increase in vivo phosphoinositide (PI) hydrolysis in mouse brain was compared to two full agonists. Pilocarpine increased in vivo phosphoinositide (PI) hydrolysis in cortex, striatum, and to the greatest extent in the hippocampus. Pilocarpine injected either subcutaneously or intracerebroventricularly robustly increased in vivo PI hydrolysis in hippocampus up to 500% of control levels and the increases were blocked by the muscarinic antagonist scopolamine. The increases in vivo PI hydrolysis induced by pilocarpine were 60–75% of the magnitude of the full muscarinic agonists oxotremorine-M and cis-dioxolane. The muscarinic M₁ preferring antagonist pirenzepine potently blocked pilocarpine-induced increases in in vivo PI hydrolysis, consistent with the increase being mediated by M₁ receptors. Since pilocarpine is a relatively weak partial agonist, these data suggest a substantial level of receptor reserve for the PI response in mouse hippocampus.
Blockade of pilocarpine-induced cerebellar phosphoinositide hydrolysis with metabotropic glutamate antagonists: Evidence for an indirect control of granule cell glutamate release by muscarinic agonists
2000, Neuroscience Letters
The ability in vivo of the muscarinic agonist, pilocarpine, to increase phosphoinositol (PI) hydrolysis in lithium pretreated rats was investigated by measuring the accumulation of [³H]inositol phosphates (IP). As expected, 20 mg/kg s.c. pilocarpine, a muscarinic agonist, increased PI hydrolysis in the striatum, frontal cortex and hippocampus. Somewhat surprisingly, an increase in IP was also found in the cerebellar homogenates. In all four tissues the pilocarpine-induced effect could be completely inhibited by pretreatment with the muscarinic antagonist scopolamine (1.2 mg/kg i.p.). It was also found that the cerebellar but not the hippocampal pilocarpine-induced rise in PI hydrolysis could be blocked by the metabotropic glutamate (mGlu) receptor antagonist, LY341495 (100 nmol, i.c.v.). The same dose of LY341495 was found to also block both the cerebellar and hippocampal increase in IP formed by stimulation with the group I mGlu receptor agonist 3,5-dihydroxyphenylglycine (1 μmol, i.c.v.). Given this data and the current information on the distribution of muscarinic and mGlu receptors in the cerebellum, it is suggested that these results may be a reflection of pilocarpine acting at M₂ receptors to indirectly increase glutamate release from parallel fibers by inhibition of γ-aminobutyric acid-releasing Golgi cells.
Phosphoinositide hydrolysis in vivo with group I metabotropic glutamate receptor agonists
1999, Brain Research
The present report describes the effect of mGluR agonists and antagonists administration on phospholipase C activation by measuring accumulation of [³H] inositol monophosphates (IP) in rats pre-labeled with [³H]myo-inositol (i.c.v. 24 h pre-treatment). The levels of accumulated [³H]IP were then determined from clarified tissue homogenates using ion-exchange chromotography. Following lithium chloride treatment (10 mg/kg, s.c.), (R/S)-3,5-dihydroxyphenylglycine (DHPG), a selective group I mGluR agonist was found to dose-dependently cause a maximal increase in the levels of [³H]IP at 0.3 to 3 μmol/8 μl i.c.v. with lower doses resulting in less efficacious or no responses. This effect was temporal-dependent reaching a plateau at 2 h. The DHPG-induced increases in [³H]IP were most pronounced in the hippocampus where a 3- to 5-fold increase above vehicle was consistently found, but significant approximately 2-fold increases were also seen in the cerebellum, striatum and frontal cortex. The mixed group I and II agonist, (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (1S,3R-t-ACPD), similarly resulted in dose-dependent increases in [³H]IP levels with doses of 1 to 3 μmol i.c.v. Furthermore, this effect was enantiomer specific since the less active 1R,3S-t-ACPD failed to alter phosphoinositol hydrolysis. Administration of the selective mGluR5 agonist (R/S)-2-chloro-5-hydroxyphenyl-glycine (CHPG) resulted in a dose-dependent increase in hippocampal but not cerebellar levels of [³H]IP, consistent with the receptor distribution of the two group I mGluRs. The Group II agonist LY354740 (1S,2S,5R,6S-2-aminobicycl[3.1.0]hexane-2,6-dicarboxylate monohydrate) and the group III agonist L-AP₄ (L-(+)-2-amino-4-phosphonobutyric acid) failed to alter the levels of [³H]IP. LY341495 (2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid) is a nM potent Group II antagonist. However, LY341495 has also been found to have μM potency in inhibiting mGluR1 and 5. The stimulation of [³H]PI hydrolysis by 1 μmol DHPG was dose-dependently blocked by co-administration of the mGluR antagonists, LY341495 at doses that are constant with an interaction at Group I mGluR's. Taken together these results suggest that stimulation of group I mGluRs results in measurable increases in PI hydrolysis in vivo. This method could be quite useful in determining the doses and routes of administration of agonists and antagonists that are required to interact with group I mGluRs.
Xanomeline compared to other muscarinic agents on stimulation of phosphoinositide hydrolysis in vivo and other cholinomimetic effects
1998, Brain Research
Activation of muscarinic m1 receptors which are coupled to the phosphoinositide (PI) second messenger transduction system is the initial objective of cholinergic replacement therapy in Alzheimer's disease. Thus, we evaluated the ability of the selective muscarinic receptor agonist (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydrolysis and compared it to a number of direct acting muscarinic agonists, two cholinesterase inhibitors and a putative m1 agonist/muscarinic m2 antagonist. Using a radiometric technique, it was determined that administration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating mediation by muscarinic receptors. The non-selective muscarinic agonists pilocarpine, oxotremorine, RS-86, S-aceclidine, but not the less active isomer R-aceclidine, also effectively stimulated PI hydrolysis in mice. Amongst the putative m1 agonists, thiopilocarpine, hexylthio-TZTP as well as xanomeline effectively stimulated PI hydrolysis, but milameline, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-induced PI stimulation, suggesting that they act as antagonists at PI-coupled receptors in vivo. The cholinesterase inhibitors, tacrine and physostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vivo PI hydrolysis. Xanomeline, hexylthio-TZTP and thiopilocarpine were relatively free of cholinergic side effects, whereas milameline, WAL 2014 and SKB 202026 produced non-selective effects. Therefore, these data demonstrate that xanomeline selectively activates in vivo PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomeline's beneficial clinical effects on cognition in Alzheimers patients.
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Regular paperThe muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brain

Abstract

Biochem. Biophys. Res. Commun.

Neuron

Eur. J. Pharmacol.

J. Biol. Chem.

Eur. J. Pharmacol.

Reduced brain inositol in lithium treated rats

Nature

Measurement of lithium-induced changes in mouse inositol 1 phosphate levels in vivo

J. Neurochem.

Identification of a family of muscarinic receptor genes

Science

Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction

Biochem. Pharmacol.

Antagonism of aceclidine-induced tremor, analgesia, hypothermia, salivation and lacrimation by some pharmacologic agents

Arch. Int. Pharmacodyn.

Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves

Am. J. Physiol.

Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/ oxo-M ratio as an index of efficacy at cortical muscarinic receptors

Br. J. Pharmacol.

A novel series of non-quaternary oxadiazoles acting as full agonists at muscarinic receptors

Br. J. Pharmacol.

Regular paper
The muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brain

Relationship between the inhibition constant (K_i) and the concentration of inhibitor which causes 50 percent inhibition (I₅₀) of an enzymatic reaction