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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 5 of 5. This is the beginning of the thread.
Posted by Shawn. T. on July 29, 2002, at 2:32:09
If you think that someone at Eli Lilly hasn't heard of 5-ht-moduline, you are kidding yourself. The lack of information on this neuropeptide is disheartening; I have tried to add a bit of my own.
"The results support the hypothesis that 5-HT(1B) receptors within the VTA can function as heteroreceptors to inhibit GABA release(1).""5-HT-moduline, an endogenous tetrapeptide, regulates the efficacy of these 5-HT1B receptors, hence, is able to control the serotonergic activity in a synchronous manner for the various varicosities from a single neuron and thus may favour the differential effect of that neuron on distinct cerebral functions. Accordingly, the peptide allows the 'fine tuning' of the cerebral activity by the serotonergic system to elaborate the response given by the brain to a particular stimulus, that is, stress situations."
5-HT-moduline acts as an antagonist at 5-HT1b receptors. A logical conclusion would be that 5-HT-moduline causes the release of GABA (an inhibitory neurotransmitter) in the ventral tegmental area (VTA) of the brain.
"Overall, the results of this study suggest that terminal DA release in the ACB is under tonic GABA inhibition mediated by GABAA (and possibly GABAB) receptors, and tonic cholinergic excitation mediated by both muscarinic and nicotinic receptors. Activation of GABAA (and possibly GABAB) receptors within the ACB may be involved in the feedback inhibition of VTA DA neurons.(3)"
So 5-HT-moduline, via 5-HT1b antagonism, causes the release of GABA in the VTA. This results in an increase of the GABAergic inhibition of terminal dopamine (DA) release in the nucleus accumbens (ACB). Likewise, dopamine release in the ventral tegmental area is diminished by 5-HT-moduline (4). The VTA - nucleus accumbens pathway undoubtedly plays a major role in the brain's reward mechanisms (5).
"... Local application of 5-HT1B antagonists decreased the rate of clearance of the serotonin signal comparably to the selective 5-HT uptake inhibitor (SSRI), fluvoxamine. (6)"
For the first few weeks of SSRI treatment, a very common side effect is increased anxiety. I contend that these drugs exert their effects by essentially "dulling" the brain's reaction to stress.
Note the decrease in emotional range that often results from selective serotonin reuptake inhibitors. An effective antidepressant need not have this characteristic."Repetition of the restraint stress daily for 3 weeks totally abolished the effect of the stress on variations of 5-HT-moduline tissue content in all the studied brain regions. These results show that an acute restraint stress induces a rapid and significant increase in the amount of 5-HT-moduline contained in various brain areas. This phenomenon is likely to be related to the stress-induced 5-HT1B receptor desensitization which was previously demonstrated. (7)"
The brain responds to a consistently stressful environment by reducing the effects of 5-HT-moduline, or in the case of some antidepressant treatments, the SSRI. When someone taking a selective serotonin reuptake inhibitor ceases to take the drug, the 5-HT1b receptor regains its sensitivity, which would serve to enhance the effects of 5-HT-moduline. The withdrawal symptoms of SSRI's have been largely ignored by the drug companies producing them; they are in fact very real. Thus, SSRI's take advantage of a natural stress adaptation system in the brain. The ethical issues raised by this new understanding are extremely important in my opinion. The antibody for 5-HT-moduline seems to be the real cure that millions of people are seeking for anxiety related depression.
(1)
http://www4.infotrieve.com/newmedline/detail.asp?NameID=11723184&loggedusing=M&Session=102188&SearchQuery=%22SB+216641%22&count=9
(2)
http://www4.infotrieve.com/newmedline/detail.asp?NameID=10622374&loggedusing=M&Session=102188&SearchQuery=%225%2Dht%2Dmoduline%22&count=25
(3)
http://www4.infotrieve.com/newmedline/detail.asp?NameID=11841572&loggedusing=M&Session=102188&SearchQuery=gaba+and+VTA+and+dopamine+and+accumbens&count=41
(4)
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=29019305
(5)
http://www4.infotrieve.com/newmedline/detail.asp?NameID=10372570&loggedusing=M&Session=&SearchQuery=%22Localization+of+brain+reinforcement+mechanisms%22&count=10
(6)
http://www4.infotrieve.com/newmedline/detail.asp?NameID=10465699&loggedusing=M&Session=102188&SearchQuery=%225%2Dht%2Dmoduline%22&count=25
(7)
http://www4.infotrieve.com/newmedline/detail.asp?NameID=10216182&loggedusing=M&Session=102188&SearchQuery=%225%2Dht%2Dmoduline%22&count=25
Posted by bubblegumchewer on July 29, 2002, at 13:53:56
In reply to Anxiety neuropeptide; SSRI mechanisms, posted by Shawn. T. on July 29, 2002, at 2:32:09
The subject matter sounds fascinating, but some of us don't understand the terminology, as I was commenting in "I feel so stupid in here," down the line.
Could you please tell me how this information might apply to me and what kind of ray of hope I might have? I am just so sick of living with a cloud of anxiety over me. I wish I didn't have to take meds because none of them seem exactly "on target" (lots of unwanted mental or physical effects, like you mentioned) but I'll take what I have to in order to live. My anxiety at times makes me wish I didn't have to live through it anymore, which is I guess why I get the "depression" diagnosis. I outlined my particular problem in "let's play pick-a-med." I'm not asking for comment on the constipation side effect here... I'm asking for how your post above might relate to me and how I might get some relief now or in the future with better medications.
Posted by Shawn. T. on July 29, 2002, at 18:19:27
In reply to Shawn, please help., posted by bubblegumchewer on July 29, 2002, at 13:53:56
I apologize about that; I may try to write something more accessible on that topic. There are definitely much better medications already available, but the FDA has to approve them before they can be marketed in the US. You can buy some of these drugs, although they are wildly expensive (for lab use only). The one that I would most like to see is a drug that destroys 5-HT-moduline neuropeptides (although I cannot say whether or not it would be safe in humans; it has only been given to rats to my knowledge).
There is also a drug called SB-236057-A that is a 5-HT1b inverse agonist. My understanding of inverse agonists is that they maintain an equilibrium between the inactive state of a receptor and the active state. Agonist binding of a receptor results in a switch to the active state. Antagonists have will cause a receptor to be both in the active and inactive state; equilibrium is maintained, but agonists and antagonists cannot affect the receptor. Don't worry about understanding that, just know that such a drug will likely be an effective antidepressant with very few side effects.
http://www.biopsychiatry.com/sb-236057.htm
also check out the following, which is about a similar drug:
http://nootropics.com/5ht1bmem.html
There is another drug called GW353162 that is a noradrenaline/dopamine reuptake inhibitor that may be interesting (this one is in stage 1 clinical trials). Substance P antagonists (actually called NK1 antagonist) have been shown to be about 50% effective in treating depression, but they have very few side effects (5-HT3 antagonists are similar, although not as powerful for blocking the actions of substance P). There are some in stage 1 clinical trials, and I believe that they will be very effective for certain types of pain management. There is a corticotropin release factor antagonist (CRF-R1) called SB723620 (also in stage 1 clinical trials). CRF basically signals the body to release stress related hormones such as cortisol.
Drugs called Ampakines made by Cortex Pharmaceuticals are looking interesting (moreso for schizophrenia and Alzheimer's disease, however).
http://www.cortexpharm.com/html/research/ampakines.htmlBy refusing to take SSRI's, you can help the drug companies to understand that these drugs are unacceptable and that they should spend their millions of dollars on improving their products rather than marketing them. You should certainly not feel a loss of hope. The days of relying on snake oils are over; we are beginning to truly understand the actions of psychiatric drugs on the brain. Our understanding of the brain is advancing at a faster rate every year, so you should rest assured that a cure is on the way. I haven't read your other post, so I'll not comment on currently available meds.
Shawn
Posted by cybercafe on July 29, 2002, at 22:41:29
In reply to Re: Shawn, please help. » bubblegumchewer, posted by Shawn. T. on July 29, 2002, at 18:19:27
... i wonder if taking a Substance P antagonist would greatly decrease your ability to feel pain... and... for example.... you might not notice that your hand has just melted away from being placed on a hot stove...
Posted by Shawn. T. on July 30, 2002, at 23:26:33
In reply to Re: Shawn, please help., posted by cybercafe on July 29, 2002, at 22:41:29
There are actually neuropeptides for hot and cold, so unless you blocked those, I doubt that burning off your hand would be a hoot. I believe that a substance P antagonist would be best for inflammation and reducing the pain of cuts and whatnot. I'd certainly like to try it out someday; it would be interesting to find out what the sensation is like.
Shawn
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