Subchronic effects following a single sarin exposure on blood-brain and blood-testes barrier permeability, acetylcholinesterase, and acetylcholine receptors in the central nervous system of rat: A dose-response study

Subchronic neurotoxic effects of sarin (O- isopropyl methylphosphonofluorid ate) treatment at various doses in male Sprague Dawley rats were studied. T he animals were treated with a single intramuscular ( im) injection of 0.01 , 0.1, 0.5, or 1 x LD50 ( 100 mug/kg). The animals were maintained for 90 d thereafter. [H-3] Hexamethonium iodide was used to monitor the changes in blood-brain barrier ( BBB) permeability in cortex, brainstem, midbrain, and cerebellum. Brainstem exhibited a significant decrease (similar to 58% of control) in uptake of [H-3] hexamethonium iodide at 1 x LD50 dose. No signi ficant changes were observed in BBB permeability in cortex, midbrain, and c erebellum at any dose. Plasma butyrylcholinesterase (BChE) activity remaine d unchanged, reflecting recovery of the enzyme activity from the initial in hibition following single exposure of 1 x LD50 sarin. Acetylcholinesterase (AChE) activity in the cortex remained inhibited (similar to 29%), whereas in the brainstem there was an increase (similar to 20%) at 1 x LD50 dose of sarin. The m2-selective muscarinic acetylcholine receptor (m2-mAChR) ligan d binding was inhibited significantly at 1 x LD50 in the cortex, whereas br ainstem showed significantly increased (similar to 45%) ligand binding at 1 x LD50 dose. Nicotinic acetylcholine receptor (nAChR), on the other hand, showed a biphasic response in ligand binding in the cortex with a decrease (similar to 30%) at 0.01 x LD50 but an increase (similar to 40%) at 1 x LD5 0. Brainstem did not show any significant change in nAChR ligand binding. T hese results suggest that single exposure of sarin could lead to changes th at may play an important role in neuropathological abnormalities in the cen tral nervous system.