Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention.

Of pertinence to this study on possible feedback mechanisms that the anticholinesterase DDVP may activate as an acute adaptive response to its toxic actions, is our ongoing work on elucidating the feedback loops in the striatum and hippocampus which regulate cholinergic activity. Understanding of feedback loops further would indicate other means of mitigating toxicity, perhaps by potentiating mechanisms that reduce acetylcholine release. Tests are being made on new-type inhibitors of choline acetyltransferase, the enzyme responsible for the synthesis of acetylcholine as a means of protecting against anticholinesterase poisoning. The effects are being studied of cholinergic muscarinic receptor agonists and antagonists specific for type I M1 or type II M2 muscarinic receptors, on brain regional acetylcholine and choline contents and acetylcholine turnover rate. Preliminary results from the study show that only the M2 type drugs affect acetylcholine content. Specific M2 type antagonists are not presently available but theoretically they would be the drugs of choice as antidote for anticholinesterase poisoning. The powerful muscarinic antagonist, atropine sulfate, blocks both M1 and M2 type receptors.