Stressful manipulations that elevate corticosterone reduce blood-brain barrier permeability to pyridostigmine in the rat

Pyridostigmine bromide (PB), a reversible inhibitor of acetylcholinesterase (AChE), is used for the treatment of myasthenia gravis. PB has also been p rovided to military personnel for preexposure protection against potential soman release. The entry of PB into the brain is typically minimal, but rec ently published data in mice suggest that a brief forced swim stress increa ses the permeability of the blood-brain barrier to PB. From these results, PB administered under stressful conditions was proposed to induce long-last ing central cholinergic deficits, potentially explaining the neurological a nd neuropsychological symptoms presented by some Gulf War veterans. In unde rtaking to replicate these results in the Long-Evans rat, no evidence of a stress-potentiated central effect of PB, administered at doses up 5.0 mg/kg ip, was found. Three stress protocols were used: restraint, forced swim, o r a combined restraint/forced swim. Wister rats were also tested in some of the protocols to ensure that the results were generalizable across rat str ains, and plasma corticosterone levels were measured to test the effectiven ess of the stressors employed. In contrast to the previously reported findi ngs in the mouse, stress significantly reduced the entry of PB into rat bra in, as measured by reduced inhibition of AChE activity: a 12.5% reduction i n whole brain AChE activity after treatment with 5.0 mg/kg PB under control conditions declined to 9% after stress exposure. It is apparent, therefore , that the interaction between stress and PB requires further study, and pr evious data should be reassessed before they are used as a basis for interp reting symptoms presented by veterans. (C) 2000 Academic Press.