Posted by Larry Hoover on January 13, 2005, at 10:26:03
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 11, 2005, at 16:10:33
> Larry, thanks for the reply.
>
> But that doesn't explain why NAC reduceses the effects of MAP (in this case, acute hyperlocomotion)
> Hyperlocomotion couldn't possibly be a result of oxidative stress could it??
>
> The abstract also doesnt explain behaverial sensitzation other then that NAC attenuates MAP induced dopmaine deficits.I'm going to have to emphasize the opening sentence in each of the quoted abstracts. The researchers were trying to discover the role of oxidative stress in the development of persistent behavioural changes following acute exposure to methamphetamine. Earlier work by this same team had shown that blockade of excitatory NMDA receptors would also abolish this effect.
There are three redox-sensitive cysteine residues (sulfhydryl functional group) on this NMDA-receptor complex. Glutathione is basically a sulfhydryl sacrificial molecule. It takes the oxidative heat, and quenches it, before the receptor sulfhydryls can be affected. At least, that's the way it's supposed to work.
One of the mechanisms by which methamphetamine does its damage is by inhibiting MAO. When combined with dopamine efflux induced by this drug, the inhibition of MAO leaves dopamine open to a multitude of auto-oxidative and enzyme catalyzed oxidative transformations. The products of these reactions can still have dopamine-like affinities for receptors and transporters, but their chemistry has changed. They can undergo reactions with the receptor sites, taking them out of action. So, I think the persistent effects are mediated by a host of factors, but all of them can be attenuated by antioxidants. The fact that N-acetyl-cysteine works in this role (and selenium, in other references) points to glutathione as a key molecule. The seleno form of glutathione is even more effective than is the sulfur version.
Now, as to the conclusion that NAC might be a post-exposure treatment for methamphetamine toxicity, I respectfully have to disagree. It may encourage a faster rate of recovery, by preventing new avenues of oxidative stress from exerting additive damage in these synapses, but I can't see that it will directly reverse these adverse effects. You need the enhanced NAC concentration to be present with the methamphetamine exposure.
That's how I read it, anyway.
Lar
poster:Larry Hoover
thread:439943
URL: http://www.dr-bob.org/babble/20050113/msgs/441562.html