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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by turalizz on July 23, 2002, at 10:18:30
Is it a fact that increasing intercellular concentrations of a neurotransmitter results in downregulation of its receptors, or is it just a speculation on how the AD's loose their effectiveness in time?
Can someone refer me to studies about AD (especially MAOI'S) induced downregulation, how to reverse it etc.?
...and a second question: What does "receptor sensitivity" mean?
thanks,
cem
Posted by Shawn. T. on July 24, 2002, at 18:24:28
In reply to downregulation??, posted by turalizz on July 23, 2002, at 10:18:30
Everything that I've read about this issue so far has been less than satisfying. I finally found a good explanation, however. I posted something earlier about up/down regulation that was incorrect based on this knowledge by the way. I was misled by some studies that seemed to agree with what I was saying. I know that this page is hard to understand, so feel free to ask me questions if you don't understand something. It pretty much makes everything about fifty times more complicated, but it also means that we now know how to make some incredibly selective drugs (I don't use selective as in the context of selective serotonin reuptake inhibitors, SSRI is pretty much a contradiction of terms). It's going to take me a while to sift through all of their research.
http://www.camh.net/research/research_ar2000/molecular_pharmacology.html
Posted by cybercafe on July 24, 2002, at 21:56:31
In reply to Re: downregulation??, posted by Shawn. T. on July 24, 2002, at 18:24:28
hey Shawn, what is a dimer? dictionary.com tells me it is a molecule made up of two identical molecules, but i'm thinking X + X = X --> X = 0
Posted by Shawn. T. on July 25, 2002, at 18:40:39
In reply to Re: downregulation??, posted by cybercafe on July 24, 2002, at 21:56:31
I believe it is a combination of two molecules which can fit another molecule into it.
Here's a picture:
http://www.chem.sci.osaka-u.ac.jp/lab/nakasuji/qqh.html
Here's some interesting info about mad cow disease involving dimers:
http://www.lerner.ccf.org/news/20010926.phpOK the following may or may not be a good example of how dimers affect neuronal processes, but I think it should clue you in on what is generally happening. My belief is that certain hormones can lock into dimers which are located in G-proteins, and this may cause certain pairs of receptors to manipulate their coupling function. I believe that the coupling function is often manipulation of calcium or potassium channels. Lets consider a certain action of estrogen for example. If estrogen attaches into a dimer linked to a mu opioid receptor and a GABAb receptor, the two receptors decrease their functional coupling to an inward rectifying K+ channel. Rectifying would seem to be used in the electrical context here, so I believe it means to convert alternating current into direct current.
So estrogen causes a cell to become less positive than its surroundings. So it would inhibit an action potential, therefore making neurotransmitter release less likely (the neuron is resistant to weak stimuli). Note that GABAb receptors can also inhibit N type voltage operated calcium channels. Mu opioid receptors can inhibit various other types of calcium channels which may be types N, P, and Q (and they may also possibly activate L type calcium channels). The two receptors share the ability to activate k+ channels. If the neuron that I am describing is on your finger tip, I think that the effect of estrogen on it would be somewhat numbing.
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=23673622There was a thread earlier about GHB; I'll try to apply what I've said to it. There have been arguments made that GHB may actually be a neurotransmitter, but I don't agree. I believe that it probably serves a role similar to estrogen as described above, but it is not as widely utilized as estrogen. I believe that it interacts with both presynaptic and postsynaptic GABAb receptors. GHB increases dopamine release, and I believe that it may accomplish this via G proteins. It may fit into the dimer (tetramer?) connected to both GABAb and dopamine receptor D2 (the presynaptic autoreceptor). This would effectively reverse the action of the GABA receptor and allow the release of dopamine. It's postsynaptic effects are probably responsible for sedation. Opioids and THC can accomplish the same process in the ventral tegmental area. Note how all three substances can relieve pain, cause euphoria, and put you to sleep.
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=24177273
The difference between GABAa receptors and GABAb receptors seems to be that the a receptors are linked to Cl- channels, and the b receptors are linked to K+ channels. I would suggest that a GABAb agonist like Baclofen may be the successor to the benzodiazepines. It has been shown to be very useful in withdrawal from opiates and other substances. It would be similar to using clonodine for such a purpose, but would lack the negative mental effects. Clonidine is an alpha-2-adrenergic agonist, and I believe that alpha-2-adrenergic receptors are linked via G protein to postsynaptic dopamine D2 receptors, which decrease adenylyl cyclase levels. One school of opiate withdrawal thought points to a rebound increase in adenylyl cyclase to be the cause of withdrawal.http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=29859723
What I am doing right now is trying to figure some of the combinations that the monoamines can make with other receptors. The thing that I find interesting is how many of them are involved in pain regulation. For instance, 5-HT3 may be negatively coupled with GABAb. GABAb may be able to inhibit substance P release. So when 5-HT3 is activated, substance P is released. A 5-HT3 antagonist like Remeron should therefore inhibit substance P release, which it has been shown to do. Extrapolating data is very useful in my opinion. I can really cover some ground in figuring out side effects based on this new methodology.
http://nootropics.com/5-ht3/index.html
>
> hey Shawn, what is a dimer? dictionary.com tells me it is a molecule made up of two identical molecules, but i'm thinking X + X = X --> X = 0
Posted by Shawn. T. on July 25, 2002, at 20:02:36
In reply to Re: downregulation??, posted by Shawn. T. on July 25, 2002, at 18:40:39
Here's an interesting study on panic disorders:
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=29148518Note that the mysterious reticular activating substance referred to is probably arachidonic acid; I don't know why they don't just call it that. Because Remeron has effects on GABA receptors as well as other anxiety relieving receptors, I believe it is a better choice than benzodiazepines, which are very addictive.
Here's a study that helps me understand why I experienced panic attacks on Paxil:
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=29834771
With drugs like Paxil and Zoloft, the 5-HT2A/2C receptors experience an increase in activation due to the increase of serotonin in the synapse.
My sister was taking 100mg/day of Zoloft, and she had several seizures. She was fired from her job because of this (in a clear violation of the ADA). Drugs like Remeron, which block 5-HT2A/2C receptors, are much safer. I do not understand why the American public tolerates the terrible quality inherent in many of the drugs on the market. Remeron may make you sleepy initially, but if you only take 7.5mg/day for the first two weeks, you will not have to deal with the sleepiness for long. I really see no need for anyone to start off taking more (especially not 30mg, that is just not clear thinking), but I am not their doctor and cannot tell them what to do. Sure, if you start off with a high dose, you are going to feel horrible. I had a much easier time adjusting to Remeron than Paxil. SSRI's are dirty, unselective drugs, and they often cause just as much harm as good. I don't know how many times I am going to have to post this message on this board before people realize the problems inherent in SSRI's. What is it going to take?More about the GABAb antagonist Baclofen: it isn't very effective for panic disorder. It is, however, useful in Tourette's syndrome:
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=16088143It also appears to be very useful in treating withdrawal symptoms.
Posted by johnj on July 25, 2002, at 21:02:43
In reply to SSRI's are horrible drugs, posted by Shawn. T. on July 25, 2002, at 20:02:36
Remeron at 7.5 mg made me a zombie and made the depression worse. The higher I went the "better" I felt, but became "sponge-brained" and it NEVER went away. It was great for sleep, and helped anxiety, but made me less alert and mistake prone at work. It was strange how it helped concentration, but ruined short term memory. I felt the best in years for a week or so after stopping remeron. Maybe it had some residual effect on seretonin after the zoned out feeling wore off, but remeron is not for everyone.
Posted by MarkCSF on July 25, 2002, at 22:27:07
In reply to Remeron, not great for all, posted by johnj on July 25, 2002, at 21:02:43
> Remeron at 7.5 mg made me a zombie and made the depression worse. The higher I went the "better" I felt, but became "sponge-brained" and it NEVER went away. It was great for sleep, and helped anxiety, but made me less alert and mistake prone at work. It was strange how it helped concentration, but ruined short term memory. I felt the best in years for a week or so after stopping remeron. Maybe it had some residual effect on seretonin after the zoned out feeling wore off, but remeron is not for everyone.
Yes, I too did not have a good experience with Remeron though my doc may have done it wrong according to Shawn T. I started Wellbutrin 150 mg and Remeron 30 mg at the same time. The first couple days I felt decent, anxiety was wiped away for the most part immediately. The pits of my shirt were actually dry! But by the end of the week, I was feeling more miserable than I had in a long time and the anxiety was basically back. Shawn T., any thoughts?
Posted by cybercafe on July 26, 2002, at 0:53:18
In reply to Re: downregulation??, posted by Shawn. T. on July 25, 2002, at 18:40:39
okay i'm really sleepy so i'm going to have to fly through this
> I believe it is a combination of two molecules which can fit another molecule into it.
hmmm... okay, may i ask where you arrived at that conclusion from
>functional coupling to an inward rectifying K+ channel. Rectifying would seem to be used in the electrical context here, so I believe it means to convert alternating current into direct current.
rectifying means current is only allowed in one direction... inward rectifying means, K+ ions are only allowed to travel inward ... probably due to some active transport mechanism (as diffusion would cause it to flow outward)
... there are some excellent discussions on this and much more in Kaplan and Sadock's Comprehensive Textbook of Psychiatry (Not Synopsis of Psychiatry)> There was a thread earlier about GHB; I'll try to apply what I've said to it. There have been arguments made that GHB may actually be a
if i could actually get my hands on GHB, i do have some guinea pigs awaiting
>pain regulation. For instance, 5-HT3 may be negatively coupled with GABAb. GABAb may be able to inhibit substance P release. So when 5-HT3 is activated, substance P is released. A 5-HT3 antagonist like Remeron should therefore inhibit substance P release, which it has been shown to
it probably depends on what brain circuit you are talking about...
for example, i have been concerned with the nucleus accumbens, and i know that 5HT3 has positive effects on the release of dopamine, and substance P may have negative effects.... therefore i wonder if a 5HT3 agonist may display substance P antagonism .... but that would be a jump in logic.. and i see no reason to make jumps in logic when there is solid information out there ... or at least until i have run out of solid information to go on :)
cybercafe
Posted by cybercafe on July 26, 2002, at 0:57:29
In reply to SSRI's are horrible drugs, posted by Shawn. T. on July 25, 2002, at 20:02:36
>receptors, are much safer. I do not understand why the American public tolerates the terrible quality inherent in many of the drugs on the market. Remeron may make you sleepy initially, but if you only take 7.5mg/day for the first two weeks, you will not have to deal with the just as much harm as good. I don't know how many times I am going to have to post this message on this board before people realize the problems inherent in SSRI's. What is it going to take?
Dude... if you feel that strongly about things why don't you try discussing matters with the local college of psychiatry professors and see if they cannot give you a decent answer or direct you to a source that can....
... or you could consider doing a trial on these drugs (5HT2 antagonists?), win the nobel peace prize, become famous, get a lucrative drug company contract and so fourth...
Posted by Shawn. T. on July 26, 2002, at 3:17:56
In reply to Re: downregulation??, posted by cybercafe on July 26, 2002, at 0:53:18
> okay i'm really sleepy so i'm going to have to fly through this
>
> > I believe it is a combination of two molecules which can fit another molecule into it.
>
> hmmm... okay, may i ask where you arrived at that conclusion from
>
I suppose that I jumped at that conclusion. The definition of dimer is "A molecule which consists of two similar (but not necessarily identical) subunits."
Here's an image of what I was imagining:
http://hsc.virginia.edu/medicine/basic-sci/pharm/garrisonresimage.gif
and
http://www.nature.com/nrn/journal/v2/n4/slideshow/nrn0401_274a_F3.html
http://home.uchicago.edu/~yuanzhou/note2.htm
> >functional coupling to an inward rectifying K+ channel. Rectifying would seem to be used in the electrical context here, so I believe it means to convert alternating current into direct current.
>
> rectifying means current is only allowed in one direction... inward rectifying means, K+ ions are only allowed to travel inward ... probably due to some active transport mechanism (as diffusion would cause it to flow outward)
correct> ... there are some excellent discussions on this and much more in Kaplan and Sadock's Comprehensive Textbook of Psychiatry (Not Synopsis of Psychiatry)
>> > There was a thread earlier about GHB; I'll try to apply what I've said to it. There have been arguments made that GHB may actually be a
>
> if i could actually get my hands on GHB, i do have some guinea pigs awaiting
>I wouldn't doubt that.
> >pain regulation. For instance, 5-HT3 may be negatively coupled with GABAb. GABAb may be able to inhibit substance P release. So when 5-HT3 is activated, substance P is released. A 5-HT3 antagonist like Remeron should therefore inhibit substance P release, which it has been shown to
>
> it probably depends on what brain circuit you are talking about...
>
true. I'm thinking about the autonomic nervous system, so perhaps this would take place in the hypothalamus (a guess; I'll try to find out more about this later). It would definitely have to be a region that has access to descending inhibitory pathways (e.g. the spinal cord).> for example, i have been concerned with the nucleus accumbens, and i know that 5HT3 has positive effects on the release of dopamine, and substance P may have negative effects....
I immediately thought schizophrenia when I read that. I think that Remeron might be a great choice for the treatment of schizophrenia.
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=23334753
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=22939439
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=20603959The 5-HT3 <-> dopamine connection really has me interested now. I'll throw some more links at you later.
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=25665543
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=25337852
therefore i wonder if a 5HT3 agonist may display substance P antagonism .... but that would be a jump in logic.. and i see no reason to make jumps in logic when there is solid information out there ... or at least until i have run out of solid information to go on :)
>
> cybercafeI don't always trust the solid information out there; I usually try to look at things from several different angles before coming to a conclusion (actually I consider everything that I know to be tentative; if I didn't, I wouldn't be very interested in learning more). I don't have time to read absolutely everything, so I often use logic to fill in smaller gaps in the information that I come across. I'm an INTP by the way; perhaps I use logic too much, but it doesn't fail me as often as taking some information at face value does. I have been taught to be ever critical of everything that I read; everyone is prone to make mistakes, myself included. The solid information out there seems to indicate that a 5-HT3 agonist would induce the release of substance P.
http://www.cfs.inform.dk/Tropisetron/iv.tropisetron01.txt
Shawn
This is the end of the thread.
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