Acetylcholine, atropine and their ups and downs in epilepsy theory and treatment

Neurology Division, Children's Hospital, Los Angeles, California

Acetylcholine, atropine, muscarine and nicotine were all known (in crude form) in the 19th century, but chemical neurotransmission was a 20th century idea. Sir Henry Dale proposed acetylcholine as a cellular regulator in 1907; its neurotransmitter role was proven by Otto Loewi in 1921, who showed that "vagusstoff" released by nerve stimulation was acetylcholine. Dale and Loewi shared the 1936 Nobel Prize. Sakel's use of insulin coma for schizophrenia, starting in 1927, is well known. Some know that Meduna replaced insulin with metrazol, but how many realize that acetylcho-line was injected intracisternally to produce convulsions for the treatment of general paresis?

The famous British neurologist S.A. K. Wilson listed four primary anticonvulsant drugs in 1933. They were phenobarbital, potassium bromide, belladonna and borax. Atropine is the active principle of belladonna. Acetylcholine was used as a convul-sant in clinical medicine and laboratory investigation. Frank Forster noted in 1945 that acetylcholine (Ach) was the only convulsant found in the mammalian brain, and therefore likely to be of special importance in epilepsy. However, by 1955, the use of atropine and atropine-like drugs for epilepsy had greatly declined. There were no controlled trials, but good results obtained with hydantoins and succinimides after World War II seemed to sweep borax and belladonna from the field, and the discov-ery of GABA in 1953 was followed by the realization that many convulsants were GABA antagonists.

Acetylcholine is not dead. The lithium-pilocarpine epilepsy model, introduced by Olney and coworkers, has been fruitful in epilepsy research. The 1990s saw the de-lineation of autosomal dominant nocturnal frontal lobe epilepsy as an epilepsy syndrome usually due to mutations in nicotinic cholinergic receptors. This syndrome is uncommon and genetically heterogeneous, but one form is associated with mutated nicotinic Ach receptors, shown to be especially sensitive to carbamazepine. Atropine was not a good antagonist of most ACh convulsant effects studied in the 1930s and 1940s. Cholinergic receptors are important in learning and brain excitability. Today we know many neurotransmitters, and don't expect any one to "explain epilepsy". We see that nicotinic receptors are as important as muscarinic receptors for human epilepsy.

Session IV -- Epilepsy
Monday, 3 June 2002, 9:30 am

Seventh Annual Meeting of the International Society for the History of the Neurosciences (ISHN)

Los Angeles, California, USA