Posted by cumulative on April 4, 2008, at 2:13:04
In reply to Re: Memantine +glutamate ex.toxicty, dramatic recovery, posted by undopaminergic on April 2, 2008, at 5:28:39
This will be a little long. Pardon the disorganization; I am inattentive.
30 mg is quite a bit. Isn't it impairing during the day, with that long half-life?
NMDA antagonism provokes dopamine release and there's one good-looking small trial showing good benefits for memantine in ADHD. 10mg was the typical working dose, it looks like. I believe there has in fact been some work that noted excitotoxicity in ADHD-type states. Know also that dopaminergic transmission actually lowers glutamate release in many parts of the brain, and one might also examine the apparently sometimes-antagonistic relationship between AMPA activity and NMDA activity, reminiscent of the relationship between nicotinic and muscarinic acetylcholine.
Magnesium has also seen to be useful in ADHD in some studies.
So as far as memantine preventing psychostimulant tolerance. I just am not sure of the mechanism. Does excitotoxic glutamate transmission provoke a downregulation of the dopamine receptors in the limbic system, for instance? Intuitively (maybe it's just me, but spend all your time reading about this stuff and after a while you gain an intutition about it) I think there may be something here.
This entire issue hinges on and is complicated by the idea that, with the psychostimulants, the initial mood boost/euphoric-type reactions, as well as probably an increase in motivation, have been linked to a stimulation of mesolimbic dopamine, to which tolerance develops very rapidly. OTOH, the concentrative benefits can often last much longer (many people can attain a therapeutic effect from dopaminergic stimulants for many years) and may even show sensitization. I roughly link this latter, different effect (which may actually be accompanied by mood-flattening, the "zombification" problems) to potentiation of prefrontal structures.
This also brings to mind ideas I have been having with regards to differences between those with hyperactive problems, and those with inattention.
Recent research suggests that hyperactivity may resolve over time, even aided by the psychostimulants -- probably a process of plasticity -- as concentrative abilities are developed. The issue here may often be something like too great of a ratio of limbic excitatory transmission (and development) in comparison to prefrontal transmission. Whereas those with inattention (or sluggish cognitive tempo), problems that more closely resemble the negative symptoms of schizophrenia, or even the mental-behavioral consequences of Parkinson's, may have a more problematic condition, a more global deficit/impairment of dopaminergic function -- more problematic because maintaining a potentiation of limbic dopamine seems nigh-impossible.
You always run up against that accursed homeostatic wall.
With inattention and a unmedicated zombie-like state, I often feel that the initial mood boost of the first few weeks is much more useful for concentration/motivation, a feeling of life, a sort of expansion of my being, than the concentrative effects that linger, which can make it easier to direct myself and get things done but still leave me with the problem of being a zombie.
So, with memantine, is it this initial mood boost that is preserved?
Again, I'm sorry for the ramble and I hope it interests someone.
poster:cumulative
thread:820576
URL: http://www.dr-bob.org/babble/neuro/20080204/msgs/821495.html