schonek@caen.engin.umich.edu (Anthony J Schonek) (01/14/88)
I was curious about "Acetylcholine." Supposedly it is a chemical in the brain that stimulates memory response. (I'm not a biologis/doctor so please excuse the ignorance) Anyway, does this actually stimulate memory response; and in what forms could this chemical be purchased in order to perform the desired effects. I heard fish and liver contain this chemical, but is there a drug that would be more efficient? -- Thanks in advance.
dyer@spdcc.COM (Steve Dyer) (01/15/88)
In article <506@dl901b.engin.umich.edu>, schonek@caen.engin.umich.edu (Anthony J Schonek) writes: > I was curious about "Acetylcholine." Supposedly it is a chemical in the > brain that stimulates memory response. (I'm not a biologis/doctor so please > excuse the ignorance) Anyway, does this actually stimulate memory response; > and in what forms could this chemical be purchased in order to perform the > desired effects. I heard fish and liver contain this chemical, but is > there a drug that would be more efficient? Acetylcholine (ACh) is a neurotransmitter found both in the central and peripheral nervous systems and at the neuromuscular junction. Its effects vary depending on the particular subsystem you are studying; this is to be expected. In a sense, having too much ACh is as bad as having too little. For example, the so-called nerve gases and most of the very poisonous insecticides in common use today act by inhibiting cholinesterase, the enzyme that deactivates ACh. ACh is released at the neuromuscular junction in response to a nerve pulse and is quickly destroyed. If the enzyme is deactivated, ACh accumulates, and a single nerve "pulse" becomes a prolonged depolarization, resulting in paralysis. It's a little misleading to simply say that ACh stimulates memory response, although there have been inconsistently successful attempts to increase levels of acetylcholine activity in the brain to improve functioning in people with dementia stemming from Alzheimer's Disease and Huntington's Chorea. This is postulated from the neurochemical and histological evidence found in such diseases. Raising ACh levels might help to eke out whatever activity is remaining in nerve pathways destroyed in disease, thus helping the person's condition, but to say that this helps "learning" is like saying that treating scurvy with Vitamin C helps "walking". Undoubtedly cholinergic systems are involved with memory and learning, but one usually has just the right amount of ACh without any outside help. There are drugs which increase ACh in the brain. These are cholinesterase inhibitors which can pass the blood-brain barrier and have very limited uses; physostigmine as an antidote to certain anticholinergic drugs, another, 5-aminotetrahydroacridine, is being tested for use in Alzheimer's Disease. Other approaches in the treatment of HD, AlzD and other nervous disorders involve the diet, "loading" the person with the precusor of acetylcholine, choline. (Note that circulating cholinesterases would inactivate Ach immediately if it were administered as itself. It would also not cross the blood-brain barrier, and would improperly stimulate whatever nerves and musculature it happened to touch before being hydrolyzed.) Choline is a quaternary ammonium base; it has the disagreeable side-effect of being attacked by bacteria in the gut to various methylamines, an extremely fishy-smelling class of substances. Choline is also a component of the phospholipid lecithin. This is supposed to avoid the cosmetic problem produced by choline, while still providing choline for conversion to ACh. Exactly how "bioavailable" the choline is in lecithin varies a good deal. None of these dietary treatments have been a smashing success, although certain persons with Alzheimers Disease and Huntington's Chorea have shown some improvement. Needless to say, if you're studying for an exam, I doubt any of these would be better than a cup of coffee. -- Steve Dyer dyer@harvard.harvard.edu dyer@spdcc.COM aka {ihnp4,harvard,husc6,linus,ima,bbn,m2c}!spdcc!dyer
werner@aecom.YU.EDU (Craig Werner) (01/16/88)
> In article <506@dl901b.engin.umich.edu>, schonek@caen.engin.umich.edu (Anthony J Schonek) writes: > > I was curious about "Acetylcholine." Supposedly it is a chemical in the > > brain that stimulates memory response. (I'm not a biologis/doctor so please > > excuse the ignorance) Anyway, does this actually stimulate memory response; > > and in what forms could this chemical be purchased in order to perform the > > desired effects. I heard fish and liver contain this chemical, but is > > there a drug that would be more efficient? Unfortunately, fish, liver, and whatever else, contain Choline, not acetylcholine. Acetylcholine is made in the nerve terminals, released on demand, and destroyed milliseconds later. Since the active metabolite is made to order (and Choline can be made by the human being), eating more in the form of Lethicin (which is primarily DPPC, dipalmityl phosphatidyl- choline) doesn't do much. Of course, there are drugs that increase acetylcholine in the nerve terminals: Edrophonium, Neostigmine, and other Acetylcholinesterase inhibitors. However, since acetylcholine is also used in autonomic ganglia and muscle-nerve endplates, the effect will bring on uncontrolled sweating and muscle spasms rather than memory enhancement. Two other "drugs" that increase acetylcholine in the nervous system are Malathion and Parathion, which are not used as drugs, but rather as industrial insecticides. However, as far as increasing Acetylcholine levels, they are quite "efficient," probably the most efficient in general use. Would that memory enhancement were as easy as a pill... -- Craig Werner (future MD/PhD, 3 years down, 4 to go) werner@aecom.YU.EDU -- Albert Einstein College of Medicine (1935-14E Eastchester Rd., Bronx NY 10461, 212-931-2517) "Doonesbury is more important than self-respect."
dyer@spdcc.COM (Steve Dyer) (01/18/88)
In article <1559@aecom.YU.EDU>, werner@aecom.YU.EDU (Craig Werner) writes: > Two other "drugs" that increase acetylcholine in the nervous > system are Malathion and Parathion, which are not used as drugs, but > rather as industrial insecticides. However, as far as increasing > Acetylcholine levels, they are quite "efficient," probably the most > efficient in general use. Actually, malathion is a relatively "inefficient" cholinesterase inhibitor for most birds and mammals, including humans. One of its sulfur atoms must be enzymatically replaced by an oxygen atom to "activate" it. Before this happens, mammalian decarboxylases detoxify the compound into an inactive metabolite which has no effect on cholinesterase. Insects also "activate" the compound, but they have no detoxification pathway, hence malathion's relative selectivity for insects over mammals and birds. It is possible to overwhelm the detoxification pathway, but it takes a LOT of malathion. Malathion is also poorly (10%) absorbed through the skin. This is why you will find malathion in use as a topical ectoparasiticide and advertised as a common garden insecticide, whereas parathion is limited to agricultural use, necessitates impermeable clothing and a respirator, and has been implicated in more poisonings and deaths than any other insecticide. -- Steve Dyer dyer@harvard.harvard.edu dyer@spdcc.COM aka {ihnp4,harvard,husc6,linus,ima,bbn,m2c}!spdcc!dyer
abc@brl-adm.ARPA (Brint Cooper) (01/18/88)
In article <1559@aecom.YU.EDU> werner@aecom.YU.EDU (Craig Werner) writes: > Of course, there are drugs that increase acetylcholine in the >nerve terminals: Edrophonium, Neostigmine, and other Acetylcholinesterase >inhibitors. However, since acetylcholine is also used in autonomic >ganglia and muscle-nerve endplates, the effect will bring on uncontrolled >sweating and muscle spasms rather than memory enhancement. > Two other "drugs" that increase acetylcholine in the nervous >system are Malathion and Parathion, which are not used as drugs, but >rather as industrial insecticides. However, as far as increasing >Acetylcholine levels, they are quite "efficient," probably the most >efficient in general use. Another drug that increases the quantity of acetylcholine released by a motor neuron at the neurymusclar synapse (did I get that right?) is Ephedrine Sulfate. Ephedrine is used primarilyas a bronchodilator for asthmatics. It is sold over-the-counter. Many people feel "jumpy" and experience increased heartrate from using it. For those people, the popular pseudo-ephedrine, sold as Sudafed and as other trade names, is available. Neurologists apparently were clued onto the acetylcholine-increasing properties of ephedrine by these side effects. Ephedrine is used as an adjunct therapy in the treatment of myasthenia gravis. It helps. -- Brint Cooper
dyer@spdcc.COM (Steve Dyer) (01/19/88)
In article <1559@aecom.YU.EDU>, werner@aecom.YU.EDU (Craig Werner) writes: > Of course, there are drugs that increase acetylcholine in the > nerve terminals: Edrophonium, Neostigmine, and other Acetylcholinesterase > inhibitors. However, since acetylcholine is also used in autonomic > ganglia and muscle-nerve endplates, the effect will bring on uncontrolled > sweating and muscle spasms rather than memory enhancement. Also, the drugs you mentioned are quaternary ammonium salts, deliberately designed to be impermeable to the blood-brain barrier so that a sufficient dose can exert its effect at the endplate in myasthenic patients without undue central nervous system effects. Physostigmine, a tertiary amine, (from whence is derived the name of the drug "neostigmine") penetrates the CNS, and is used in cases of overdoses of antimuscarinic drugs affecting both the CNS and periphery (e.g, atropine, scopolamine, antihistamines, tricyclic anti- depressants). The side-effects you mention along with a variety of central effects, e.g., delirium, drowsiness, or excitement, would occur before you could see any clear effect on memory. -- Steve Dyer dyer@harvard.harvard.edu dyer@spdcc.COM aka {ihnp4,harvard,husc6,linus,ima,bbn,m2c}!spdcc!dyer
daved@physiol.su.oz (Dave Davey) (01/20/88)
In article <1559@aecom.YU.EDU>, werner@aecom.YU.EDU (Craig Werner) writes: > Of course, there are drugs that increase acetylcholine in the > nerve terminals: Edrophonium, Neostigmine, and other Acetylcholinesterase > inhibitors. These inhibitors act on acetylcholinesterase, an enzyme which breaks down acetylcholine, the chemical transmitter released by some nerve terminals, notably those activating skeletal muscle cells, into its constituent choline and acetate, neither of which have appreciable affects on the receptor molecules. At the neuromuscular junction, the enzyme is present in the gaps between each nerve terminal and muscle cell in very significant amounts. This appears paradoxical, but makes it possible for a large amount of acetylcholine to be released, ensuring rapid and complete activation of the muscle cell involved, without lengthy activation that would otherwise occur. The result is that normal neuromuscular junctions can both transmit impulses very reliably, and achieve much higher frequencies than would otherwise be possible. The overall mechanism consumes more acetylcholine than would be required if the enzyme were absent but the added advantage of speed and reliability must have conferred a sufficient advantage in a world of predators and prey to have been genetically advantageous. Blocking the cholinesterase can augment the amount of acetylcholine which reaches the receptors, and greatly lengthen the time over which it may do so. At a normal neuromuscular junction, this can be very detrimental. At low doses, muscle responses will be accentuated and prolonged, but at higher doses a property of the receptor known as "desensitisation" comes into play. The prolonged presence of the transmitter causes the receptor response to fail, and the neuromuscular junction is "blocked"; the muscle cells are "paralysed". The low dose effect is useful in the treatment of conditions in which an abnormally small amount of acetylcholine is released (and is probably responsible for the uncontrolled wing motion in insects poisoned with anticholinesterases.) The paralytic effect is at the heart of the action of the class of "depolarising blocking agents" used in surgery, but that's another story... It is unlikely that blocking the destructive action of the enzyme would cause an increased amount of acetylcholine in the nerve terminal. A feedback mechanism would probably cause the reverse; the terminal can (and must) transport choline from the intercellular gap mentioned above into the terminal, but probably does not transport acetylcholine itself.