The toxic effects of anticholinesterases on muscle

It has been shown that acute administration of ecothiopate iodine in vivo caused an approximate 80% depression of acetylcholinesterase activity in the diaphragms of mice. Inhibition of acetylcholinesterase was accompanied by an influx of calcium at the junctional region of the diaphragm, which continued during subsequent progressive development of a severe myopathy located in the same region. Myopathy was accompanied by loss of creatine kinase from the muscle and was represented, at the light microscope level, by hypercontraction, Procion Yellow staining and loss of cross striations within the muscle fibres. It appeared to reach a point of maximum severity approximately 3-6 hours after ecothiopate administration and then, by means of some repair/regeneration process, regained an apparently normal morphology within 72 hours of the intoxication. At the ultrastructural level, ecothiopate-induced myopathy was recognised by loss of Z-lines, swelling and vacuolation of mitochondria and sarcoplasmic reticulum, dissarray of myofilaments, crystal formation, and sometimes, by the complete obliteration of sarcomeric structure. The development of myopathy in vitro was shown to be nerve-mediated and to require a functional acetylcholine receptor for its development It was successfully treated therapeutically in vivo by pyridine-2-aldoxime methiodide and prophylactically by pyridostigmine bromide. However, the use of a range of membrane-on channel blockers, and of leupeptin, an inhibitor of calcium-activated-neutral-protease, have been unsuccessful in the prevention of ecothiopate-induced myopathy.

The effects of persistent articholinesterase action at the neuromuscular junction

The effects of organophosphorus compounds which form a rapidly-ageing complex with acetylcholinesterase (AChE) (e.g. pinacolyl S-(2- trimethylaminoethyl)methylphosphonothioate (BOS)) and hence exert a persistent anticholinesterase (anti-ChE) action have been compared with other compounds with a shorter time course of inhibition (e.g. ecothiopate iodide (ECO)). Although the inhibition of AChE produced by BOS lasted longer than that seen with ECO, the time course of the myopathy appeared very similar. BOS also possessed a number of properties which have been seen with other anti-ChEs. BOS and ECO produced significant increases in neuromuscular "jitter" 5 days after injection, not only in the diaphragm but also in the soleus and extensor digitorum longus muscles. Increases in "jitter" produced by ECO could be prevented by pyridostigmine prophylaxis or rapid treatment with pyridine-2- aldoxime methiodide. Some protection from the BOS-induced increases in "jitter" could be gained by repeated treatment with pyridine-2-aldoxime methiodide, an effect which could not be accounted for simply by enzyme reactivation. From experiments performed in Rej 129 mice it was determined that increases in "jitter", although demonstrated in some dystrophic muscles, could not be used as an early diagnostic tool. Because sequalae of inhibition were present some time after intoxication, by which time AChE appeared biochemically normal, experiments were performed to investigate inactivation of physiologically important AChE. The time course of extracellular MEPPs was utilised as an indicator of physiologically important AChE and compared with the AChE activity measured by the technique of Ellman et al. (1961). It was concluded that the degree of persistence of anti-ChE action was unimportant for the induction of myopathy with a time course of 3-24 hours, but had some importance in events of longer duration.

Reconstructing alcohol-induced memory blackouts

Many people who drink alcohol have experienced a blackout; whereby they are unable to recall events that occurred during a period of intoxication. Following these blackout episodes individuals may attempt to reconstruct what happened to them. Blackouts therefore afford an excellent opportunity to study the strategies people use to reconstruct forgotten experiences. We conducted a survey of university students to explore how people choose to reconstruct blackouts, and the likely accuracy of these reconstructions. Our findings add to the growing research literature on people's strategies for validating their past experiences, and highlight the important role of external sources in the reconstruction process. The data show that people's desire to "fill in the blanks" can lead them to rely on rather unreliable sources, and may also encourage them to adopt weaker source-monitoring criteria. Indeed, in at least some cases reconstructing blackouts appears to lead to the development of false beliefs or memories. © 2011 Psychology Press.