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

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.