Cerebral Acetylcholine and Choline Contents and Turnover Following Low- Dose Acetylcholinesterase Inhibitor Treatment in Rats

摘要

Rats were treated for three weeks with regular drinking water plus subcutaneous (sc) saline (0.5 ml/kg) injections three times/week; pyridostigmine bromide (PB) in drinking water (80 mg/L) plus sc saline injections three times/week; regular drinking water plus sc sarin (0.5 x LD50) injections three times/week; or PB in drinking water plus sc sarin injections three times/week. Repeated doses of sarin, with or without PB, were devoid of acute toxicity during the three-week treatment period. Two, 4, and 16 weeks post-treatment, animals were given an intravenous pulse injection of choline labeled with 4 deuterium atoms (D4Ch) followed, 1 min later, by microwave fixation of the brain in vivo. Tissue levels of endogenous acetylcholine (D0ACh), endogenous choline (D0Ch), D4Ch, and ACh synthesized from D4Ch (D4ACh) were measured by GC-MS in hippocampus, infundibulum, mesencephalon, neocortex, piriform cortex, and striatum. Ch uptake from blood and ACh turnover were estimated from D4Ch and D4ACh concentrations in brain tissue, respectively. Statistically significant differences among brain regions were found for D0Ch, D4Ch, D0ACh and D4ACh at 2, 4 and 16 weeks post-treatment. Differences in these parameters between control and drug treatments were found only for D0ACh and D0Ch at 2 and 4 weeks. The results from these experiments do not support a delayed or persistent alteration in cholinergic function after exposure to low doses of PB and/or sarin.