Toxicological Sciences 57, 112-120 (2000)
Copyright © 2000 by the Society of Toxicology
Neurotoxicology |
Acute Sarin Exposure Causes Differential Regulation of Choline Acetyltransferase, Acetylcholinesterase, and Acetylcholine Receptors in the Central Nervous System of the Rat
Department of Pharmacology and Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, North Carolina 27710
Acute neurotoxic effects of sarin (O-isopropylmethylphosphonoflouridate) in male Sprague-Dawley rats were studied. The animals were treated with intramuscular (im) injections of either 1 x LD50 (100 µg/kg), and sacrificed at 0.5, 1, 3, 6, 15, or 20 h after treatment, or with im injections of either 0.01, 0.1, 0.5, or 1 x LD50 and sacrificed 15 h after treatment. Plasma butyrylcholinesterase (BChE) and brain regional acetylcholinesterase (AChE) were inhibited (45–55%) by 30 min after the LD50 dose. BChE in the plasma and AChE in cortex, brainstem, midbrain, and cerebellum remained inhibited for up to 20 h following a single LD50 treatment. No inhibition in plasma BChE activity was observed 20 h after treatment with doses lower than the LD50 dose. Midbrain and brainstem seem to be most responsive to sarin treatment at lower doses, as these regions exhibited inhibition (
49% and 10%, respectively) in AChE activity following 0.1 x LD50 treatment, after 20 h. Choline acetyltransferase (ChAT) activity was increased in cortex, brainstem, and midbrain 6 h after LD50 treatment, and the elevated enzyme activity persisted up to 20 h after treatment. Cortex ChAT activity was significantly increased following a 0.1 x LD50 dose, whereas brainstem and midbrain did not show any effect at lower doses. Treatment with an LD50 dose caused a biphasic response in cortical nicotinic acetylcholine receptor (nAChR) and muscarinic acetylcholine receptor (m2-mAChR) ligand binding, using [3H]cytisine and [3H]AFDX-384 as ligands for nAChR and mAChR, respectively. Decreases at 1 and 3 h and consistent increases at 6, 15, and 20 h in nAChR and m2-mAChR were observed following a single LD50 dose. The increase in nAChR ligand binding densities was much more pronounced than in mAChR. These results suggest that a single exposure of sarin, ranging from 0.1 to 1 x LD50, modulates the cholinergic pathways differently and thereby causes dysregulation in excitatory neurotransmission.
Key Words: sarin; choline acetyltransferase; acetylcholinesterase; muscarinic acetylcholine receptor; nicotinic acetylcholine receptor; neurotoxicity; Gulf War.
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