title: The muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brain.
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 at muscarinic receptors within the central nervous system.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D051379:Mice; D019832:N-Methylscopolamine; D010069:Oxadiazoles / Q000494:pharmacology*; D010095:Oxotremorine / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012601:Scopolamine / Q000494:pharmacology; D012602:Scopolamine Derivatives / Q000494:pharmacology
chemical_list: D007295:Inositol Phosphates; C089483:L 658903; D010069:Oxadiazoles; D010276:Parasympatholytics; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D010862:Pilocarpine; D010095:Oxotremorine; D012601:Scopolamine; D018021:Lithium Chloride; D019832:N-Methylscopolamine