Posted by JohnX on October 21, 2001, at 10:30:25
Scott (SLS) had an earlier question regarding the
difference between competitive and non-competetive
nmda receptor antagonists.There is some good information on memantine,
a non-competitive NMDA receptor antagonist
and its mode of action compared to mk-801
(dizocilipine), a competitive NMDA receptor
antagonists at a www.memantine.com website.Anonther non-competitive nmda antoginst I am
aware of is dextromethorphan which is an antitussive
found in cough syrups. It is a bit more competitive than memantine and can be toxic at higher doses (but
not nearly as bad as things like pcp or mk-801).According the information I read, under normal
conditions the nmda receptor is blocked by magnesium
ions in a voltage dependant fashion. During
physiological learning and memory processes, high
concentrations of glutamate are quickly released
when the cell is fired (depolarization).
Magnesium has a strong voltage dependancy mode of action at its receptor site and it leaves the
receptor during a voltage spike. Under resting state
magnesium maintains its action at its recognition
site.Memantine, a non-competitive nmda antagonist, is also
strongly linked to voltage-dependancy, and it leaves
its recognition site (which i believe is the pcp
binding site, but it may be the glutamate site, don't
quote me), when an action potential is maintained. This
keeps it from being neurotoxic and inhibiting the norma
uses of glutamate important to actions such as learning
and memory. The medicine (memantine) remains active
at its site and prevents pathological "leakage" of
glutamate when the cell is not depolarized. Hence its
neuroprotective therapeutic effect prevents excessive
calcium conductance that would damage cells.There is also an indirect correlation that I am trying
to understand between 5ht-2a and alpha-1 receptors
linked to depolarization of NMDA receptors. I believe
the 5ht-2a is coupled to glutamate receptors and activation of the 5ht-2a receptor leads may lead to
depolarization of the NMDA receptor. I'm not sure
exactly how this works, but I think it is important
in understanding atypicaly antipsyhotics, depression,
my pain, etc.I was specifically looking into the VTA (ventral tegmental) area of the brain. It has been found in
*many* studies that the nmda receptors in the VTA
are responsible for "pace-maker or burst firing" like of dopamine up the mesocortical tract to the prefrontal
cortex. This is of interest to me because I believe it
relates to my bruxism and head pain.There is one part of the brain where there are dopamine
neurons that *do not* contain auto-receptors and these
are the mesoprefrontal dopamine neurons in the
prefrontal cortex. These dopamine neurons disinhibit
muscles that control bruxism. Their
action is at the mercy of junctions with 5ht-1,and 2a
neurons and dopaminergic projections from the vta (where we also have junctions with 5ht neurons).
The extensions into the frontal cortex in a hypo
dopaminergic state are thought to be related to
negative symptoms of schizophrenia (emotional
blunting, etc).I have found a consistent trend of medicines that
releive this chronic pain in my face:- 5ht-2a antagonists, alpha-1 antagonists
(Serzone, Zyprexa)
- nmda electolyte mediation
(lower doses of lomotrigine for me)
- nmda-antagonists
(dextromethorphan)
- adderall (when I am not tolerant)
(sympathomimetic release of dopamine in the
pfc, i.e. byasss everything else and
release dopamine).I think this is consistent with my information regarding dopaminergic projections along the
mesocortical tract.Regarding a few topics I have studied, I found
interesting information in a few articles, I'm
tying this quickly off the top of my head, do
a search on medline for exact (I can post more
specifics later, or If you search for my
back posts, you will also find information):- "Buspirone as an anti-dote to SSRI induced bruxism"
quiky summary:
5ht-2a inversely related to dopamine
firing in the vta and activation at the
mesoprefrontal dopamine neurons. Post-synaptic
5ht-1a directly related to firing of the vta and
activation of mesoprefrontal dopamine neurons.
Suggested using buspar or 5ht-2a antagonists
to alleviate SSRI induced bruxism, specifically
covered Zoloft induced bruxism (which coincidentally
was worst to me). The same action of the 5ht1a and
2a receptors was found at juction at the
mesoprefrontal dopamine neurons themselves.- "Amphetamine Depresses Excitatory Synaptic
Transmission via Serotonin Receptors in the Ventral
Tegmental Area" Journal of Neuroscience , nov 15
1999 19(22):9780-9787Summary: This was interesting. The conclusion was
that amphetamine produced sensitization via its
sympathomimetic release of serotonin not dopamine!.
They tried a challenge with ketanserin or ritanserin,
but it did not inhibit the sensitization. (However,
I believe ketanserin/ritanserin to be rather dirty).
The sympathomimetic release of serotonin activates
glutamate on NMDA receptors producing probably
what I believe is a noise level background
pathological nmda activation leading to some sort
of sensitization of the nmda receptor itself/and
or downstream sensitization of other neurons.
The paper couldn't concluded the next step. I think
this clearly could show how nmda-antagonists which
maintain pace-maker firing in the vta and prevent
sensitization by inhibiting this low level
pathological glutamate efflux stimulation of NMDA.I had another paper discussing how clonazapam
inhibits amphetamine sensitization. They couldn't
come to a conclusion as to why it worked, but I think
it may be due partially due to how clonazepam potently
inhibits firing in the raphe serotonergic projections.
Also found a lot of references of 5ht-2a antgonists
for the treatment of tension headache.Anyways, I'll post more details if anyone is interested.
Also there are a couple interesting patents
discussing Olney's lesion, and how to prevent
neurotoxic nmda hypofunction:- u.s patent 5,034,400 (patent by Olney, the
discoverer of Olney's lesion which is caused
by damage of nmda hypoactivity due to its lack
of stimulation of gaba receptors causing "vacoules"
or death of cingluate/retropsinenial cerebrocortical
neurons).
He suggests using anti-cholinergics.
Funny, high-doses of dyphenhydramine relieve my
chronic pain, uh ho.- u.s. patent 5,605,911
Discusses using alpa-1 agonists to prevent nmda
hypofuction toxicity. This relates to a balance
between the noradrenergic/acetylcholine axis.I have the patents in a compressed cpc format
available from www.getthepatent.com. I may be able
to mail the patents which have all the interesting diagrams if anyone is interested (you need to
get the cpc viewer on your computer).I'm still wondering about the utility of NMDA
antagonists to prevent medication poop out.Sorry for my quick typing, misspelling, lack of
references etc. My ususally rambling. Cam is so
much better at documentingm, she even uses "tm". ;)-john
poster:JohnX
thread:81859
URL: http://www.dr-bob.org/babble/20011015/msgs/81859.html