Posted by JohnX2 on March 24, 2002, at 4:06:43
In reply to Re: ltp in the hippocampus » SLS, posted by JohnX2 on March 24, 2002, at 2:20:06
This always seemed curious to me, how an NMDA antagonist which generally may inhibit long term potentiation (and hence sensitization) may also enhance learning and cognition. This is what memantine is market for in regards to neurodegenerative diseases (alzheimers dementia, etc).Here is one explanation (naturally funded by the pharmaceutical maker):
Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP.
Zajaczkowski W, Frankiewicz T, Parsons CG, Danysz W.
Department of Pharmacology, Merz and Co., Frankfurt/M, Germany. wdanysz@t-online.de
In general, N-methyl-D-aspartate (NMDA) receptor antagonists inhibit learning and long term potentiation (LTP). However, it has been suggested that direct tonic, i.e. non-temporal, activation of NMDA receptors, in contrast to learning, may lead to an increase in synaptic "noise" and, in turn, to a loss of association detection. In the present study, a two-choice passive avoidance task and LTP in vitro (CA1 hippocampal region) were used to address this issue. Dark avoidance learning was impaired by systemic NMDA administration (starting at 25 mg/kg) that was not related to either toxic effects or state-dependent learning. NMDA-induced amnesia was antagonized by ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801) and 1-amino-3,5-dimethyladamantane (memantine), starting at low doses of 0.05 and 2.5 mg/kg, respectively, in a bell-shaped dose-response relationship. A competitive NMDA receptor antagonist CGP-39551 failed to reverse NMDA-induced amnesia. In hippocampal slices, NMDA (10 microM) depressed (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor-mediated field potentials in CA1 and also caused a moderate reduction of LTP induction/expression. It was this latter effect that was antagonized by memantine (1 microM). Thus, under conditions of tonic activation of NMDA receptors, uncompetitive NMDA receptor antagonists can paradoxically reverse deficits in learning and synaptic plasticity.
PMID: 9257940 [PubMed - indexed for MEDLINE]
John
> > Hi John.
> >
> > Glad you interjected...
> >
>
> >
> > What is "ltp"?
> >
>
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> ltp = long term potentiation. For learning, etc.
>
>
> > I have been keeping an eye on research involving lithium and its ability to change the neuronal output of nerve growth factors and to increase the volume of certain brain regions. Much of this work has been done by Husseini Manji, MD. From what I remember, valproate has also demonstrated some these properties, but not to as great a degree as lithium.
> >
> > Here a few summary articles from the NDMDA website. Note the damnable observation that there is indeed a neurodegenerative process involved in mood-disorders, particularly with bipolar disorder and conditions involving a chronic overproduction of cortisol. An optimistic perspective lies in the fact that the brain remains plastic and perhaps capable of a significant arresting and reversal of atrophy along with the sprouting of new neurons and neural connections.
> >
> >
> >
> > LITHIUM: THE ULTIMATE BRAIN FOOD?
> >
> > http://www.ndmda.org/McManamy.html
> >
>
> Thats a pretty cool read.
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> >
> > Antidepressants have also been shown to restore the size of the hippocampus. However, I wonder if this phenomenon is actually a consequence of an extended remission rather than being intrinsic to the drug itself.
> >
> >
> > ANTIDEPRESSANTS AND BRAIN CELL GROWTH
> >
> > http://www.ndmda.org/ResearchUpdate2-6.html
> >
> >
> > In another post, you mentioned something regarding 5-HT2 receptors being somehow linked to NMDA function. Can you elaborate?
> >
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> I need to check my notes, my memory is failing. Maybe i need some lithium. ;)
>
> > Thanks.
> >
> > What's going on with you, by the way? It seems that you have had a few "false starts" recently. What gives?
> >
>
> Actually I'm not doing too bad. I dropped Zyprexa and added Serzone (which is the ONLY AD for me that works and doesn't poopout). The Serzone induced a chronic mild agitated hypomania. I quit it for a few days and became a bit depressed. I restarted it with some Zyprexa and now I feel good. Rats. The zyprexa may be giving me a dystonia, so I may be adding Li instead.
>
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> > I'm still playing with nortriptyline. There might be something I can glean from it in the absence of Effexor. It seems that Effexor may have interfered with my responding to both nortriptyline and imipramine. Although tricyclics don't do the job, they seem to be of some help when combined with Lamictal.
> >
> >
> > - Scott
>
> Good luck on your medicines Scott.
>
> I did a little research on the hippocampus thing.
> I think you can get an MRI to see if you have actually been nailed, right?
>
> Anyways, I found 1 really good paper describing the degenerative process and possible treatments.
> It goes into how many different disorders can more or less have the same cascade of neurodegeneration (stress,aging,depression).
>
> This is a really good read:
>
> http://www.utdallas.edu/~tres/aging_seminar2001/mcewen.pdf
>
> This paper suggests the old stand-by hypothesis of excess glucocorticoids hyperstimulating neurons to death. The paper suggests treatment with possibly phenytoin, nmda antagonist, or by facilitating serotonin reuptake with something like tianeptine.
>
> I would think Lithium may be useful as it modulates glutamate release. Do you recall the hypothesis set forth by the articles you read on Lithium and neurotrophic factor expression?
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> The nmda antagonists look interesting too. I found an abstract implying that memantine induces brain-derived neurotrophic factor expression.
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> Both Li and memantine look like interesting medicines to help with poop out and brain shrinkage and possibly cognition.
>
> What do you think?
>
> Best Regards,
> John
>
> ----------------------------------------------
>
> The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain.
> Mol Cell Neurosci 2001 Sep;18(3):247-58 (ISSN: 1044-7431)
> Marvanova M; Lakso M; Pirhonen J; Nawa H; Wong G; Castren E
> A. I. Virtanen Institute, University of Kuopio, Kuopio, 70211, Finland.
> Memantine is a medium-affinity uncompetitive N-methyl-d-aspartate receptor antagonist and has been clinically used as a neuroprotective agent to treat Alzheimer's and Parkinson's diseases. We have examined the effect of memantine (ip 5-50 mg/kg; 4 h) on the expression of brain-derived neurotrophic factor (BDNF) and trkB receptor mRNAs in rat brain by in situ hybridization. Memantine at a clinically relevant dose markedly increased BDNF mRNA levels in the limbic cortex, and this effect was more widespread and pronounced at higher doses. Effects of memantine on BDNF mRNA were also reflected in changes in BDNF protein levels. Moreover, memantine induced isoforms of the BDNF receptor trkB. Taken together, these data suggest that the neuroprotective properties of memantine could be mediated by the increased endogenous production of BDNF in the brain. These findings may open up new possibilities of pharmacologically regulating the expression of neurotrophic factors in the brain. [Copyright 2001 Academic Press.].
poster:JohnX2
thread:98310
URL: http://www.dr-bob.org/babble/20020322/msgs/99808.html