Measurement of lithium-induced changes in mouse inositol(1)phosphate levels in vivo.
An anion-exchange HPLC mass assay was used to characterize Swiss-Webster mouse brain and peripheral tissue inositol(1)phosphate [Ins(1)P]levels. Ins(1)P was identified in all tissues studied but Ins(4)P could be identified only in brain, and then only as a part of a peak containing an additional, unidentified component. As a result, it was not possible to quantify Ins(4)P levels. Following a single subcutaneous dose of lithium (10 mmol/kg), brain Ins(1)P levels were maximally elevated after 6 h (corresponding to peak brain lithium concentrations) and were increased to levels 35- and 20-fold higher than in saline-treated animals in cholinergic agonist (pilocarpine)-stimulated and unstimulated animals, respectively. The ED50 for the lithium-induced accumulation of brain Ins(1)P 6 h after administration was 4-6 mmol/kg. The pilocarpine stimulation of lithium-induced brain Ins(1)P accumulation had an ED50 of 22 mg/kg, with maximal accumulation occurring 120 min after pilocarpine administration. Atropine reduced Ins(1)P levels, in both the absence and the presence of lithium, by 40%, indicating that cholinergic systems contribute a large (40%) component of basal brain phosphatidylinositol (PI) cycle activity. In peripheral tissues, there were lithium-induced accumulations of Ins(1)P in kidney, heart, and liver (but not testes) but these were less than that seen in the brain, suggesting that under basal (and pilocarpine-stimulated) conditions, the brain has a higher turnover of the PI cycle than the various peripheral tissues studied. These data support the hypothesis that lithium exerts its effects in vivo via modulation of the PI cycle.(ABSTRACT TRUNCATED AT 250 WORDS)
Atack
J R
JR
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, England, U.K.
Cook
S M
SM
Watt
A P
AP
Ragan
C I
CI
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002712:Chlorides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007295:Inositol Phosphates / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008094:Lithium / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018021:Lithium Chloride; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D013997:Time Factors
D002712:Chlorides; D007295:Inositol Phosphates; D001285:Atropine; D008094:Lithium; D015720:5'-Nucleotidase; D018021:Lithium Chloride