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 provided to military personnel for preexposure protection against potential soman release. The entry of PB into the brain is typically minimal, but recently published data in mice suggest that a brief forced swim stress increases the permeability of the blood-brain barrier to PB. From these results, PB administered under stressful conditions was proposed to induce long-lasting central cholinergic deficits, potentially explaining the neurological and neuropsychological symptoms presented by some Gulf War veterans. In undertaking 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, or a combined restraint/forced swim. Wistar rats were also tested in some of the protocols to ensure that the results were generalizable across rat strains, and plasma corticosterone levels were measured to test the effectiveness of the stressors employed. In contrast to the previously reported findings in the mouse, stress significantly reduced the entry of PB into rat brain, as measured by reduced inhibition of AChE activity: a 12.5% reduction in 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 previous data should be reassessed before they are used as a basis for interpreting symptoms presented by veterans.
Sinton
C M
CM
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390-9070, USA.
Fitch
T E
TE
Petty
F
F
Haley
R W
RW
D000110:Acetylcholinesterase / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics; D003345:Corticosterone / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D006221:Halothane / Q000494:pharmacology; D008297:Male; D051379:Mice; D010539:Permeability; D010830:Physostigmine / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000493:pharmacokinetics*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000097:blood / Q000378:metabolism*
D018685:Anesthetics, Inhalation; D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; D010830:Physostigmine; D000110:Acetylcholinesterase; D011729:Pyridostigmine Bromide; D006221:Halothane; D003345:Corticosterone