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Measurement of lithium-induced changes in mouse inositol(1)phosphate levels in vivo
J R Atack1, S M Cook, A P Watt
1Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, England, U.K.
Insights
Lithium treatment significantly increases inositol(1)phosphate [Ins(1)P] levels in mouse brain, particularly under stimulated conditions, supporting its role in modulating the phosphatidylinositol (PI) cycle.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Inositol phosphates are key signaling molecules in cellular pathways.
- Lithium is a mood-stabilizing drug with a known but incompletely understood mechanism of action.
- The phosphatidylinositol (PI) cycle is implicated in various cellular functions and drug responses.
Purpose of the Study:
- To characterize inositol(1)phosphate [Ins(1)P] levels in mouse brain and peripheral tissues.
- To investigate the effect of lithium on Ins(1)P levels in vivo.
- To explore the role of cholinergic systems in basal and lithium-modulated PI cycle activity.
Main Methods:
- Anion-exchange High-Performance Liquid Chromatography (HPLC) mass assay was employed.
- Swiss-Webster mouse brain and peripheral tissues were analyzed.
- Lithium and pilocarpine (cholinergic agonist) were administered to assess dose-dependent effects and stimulation.
Main Results:
- Ins(1)P was detected in all studied tissues; Ins(4)P was only identified in brain with limitations.
- Lithium administration (10 mmol/kg) caused a 35-fold increase in stimulated and 20-fold increase in unstimulated brain Ins(1)P levels.
- Cholinergic systems account for 40% of basal PI cycle activity, and lithium's effects are dose-dependent with significant accumulation in brain, kidney, heart, and liver.
Conclusions:
- Lithium significantly elevates brain Ins(1)P levels, supporting its hypothesis of modulating the PI cycle in vivo.
- The brain exhibits higher PI cycle turnover compared to peripheral tissues under basal and stimulated conditions.
- Cholinergic pathways play a substantial role in regulating basal PI cycle activity, which is further modulated by lithium.
Abstract:
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)