Cholinesterase inhibitors and stress: Effects on brain muscarinic receptor density in mice

Exposure to the reversible cholinesterase inhibitor, pyridostigmine bromide (PB), in conjunction with stress, has been suggested as a possible cause of Gulf War Syndrome. This work explores the hypothesis that PB exposure coupled with stress will alter cholinergic receptor density based on the rationale that prolonged exposure to PB and stress will lead to increased stimulation of cholinergic receptors due to the reduced capacity to degrade acetylcholine, leading to changes in receptor levels. Male C57Bl6 mice were exposed to PB (3 or 10 mg/kg/day) or physostigmine (2.88 mg/kg/day) for 7 days via ALZET mini-osmotic pumps implanted subcutaneously. The mice were stressed by shaking at random intervals (avg of 2 min/30 min) for 1 week, which was sufficient to increase blood cortisol levels. Brain tissue for autoradiographic analysis was collected on day 7 of treatment. While we examined many brain regions, analysis revealed that most of the significant changes (p < 0.05) were seen in cholinergic nuclei. Stress typically increased muscarinic receptor density, while PB and PHY generally decreased muscarinic receptor density.