![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 16 of 16. This is the beginning of the thread.
Posted by Shawn. T. on July 10, 2002, at 17:16:30
There is a theory stating that increased levels of cortisol is a possible cause of depressive symptoms. "Cortisol ... decreased body weight, food intake, plasma norepinephrine (NE), and epinephrine (E) levels." (1st link below)Also, "These data indicate that chronic exposure to high glucocorticoid levels alters 5-HT1 receptor-mediated functions and provides additional evidence relevant to the contribution of glucocorticoid elevation to the symptoms of depression." So increased stress leads to altered serotonin receptor function, which leads to increased release of cortisol and probably other stress related substances into the bloodstream. I have consistently seen scientifically derived notions correspond to real life experiences. Recent advances in neuroscience have lead me to believe that a more ideal antidepressant may have the following properties: serotonin reuptake inhibition, 5HT-2 antagonism, and 5HT-3 antagonism. Or possibly a drug like Remeron, just with increased activation of 5-HT1a receptors and reduced antihistamine function. Organon does own some 5-HT1 agonist drugs by the way. This is confirmed by the many reports of people with treatment resistant depression responding to combinations of SSRI's and Remeron. The role of norepinephrine in depression is also explained by my reasoning. I would guess that SSRI monotherapy may reduce norepenephrine levels, which may explain why the stronger SSRI's like Paxil are much more sedating than the weaker, especially Prozac which is activating."
5-HT1a activation is one possible action in the brain thought to contribute to cortisol release. My belief is that many depressed patients have increased sensitivity in their 5-HT1a receptors, thus facilitating cortisol release. Stress related migraines are thought to be caused by 5-HT1a hypersensitivity.
With regards to serotonin (5-HT), I'll give you a quick rundown. I have found that 5-HT1a activation is an important antidepressant mechanism. 5-HT1b may also be important in depression. 5-HT1b agonists have anti-agressive properties and probable anxiolytic (anti-anxiety) properties. 5HT-1a reduces 5HT levels, and the reduced sensitivity of these receptors due to tonic activation may be the cause of the delay in the onset of antidepressant action. Pindolol, a partial 5HT-1a agonist, decreases the delay in onset of SSRI's, thus contributing to this theory. 5-HT1b, on the other hand, contributes to the release of 5-HT (serotonin).
Cortisol secretion has been said to be caused by activation of 5-HT2 receptors (likely 5-HT2a and 5-HT2c) and 5-HT1a. An alternate explanation is that cortisol release is increased by 5-HT2 activation and 5-HT1c receptor activation. I am currently more convinced by the first explanation.
I would argue that tonic 5-HT1a receptor activation to reduce sensitivity helps to increase 5-HT release from neurons, which increases the amount of 5-HT available in the brain. Increased 5-HT transmission without a 5-HT2 antagonist is the best explanation for most SSRI side effects. 5-HT3 antagonism is said to reduce nausea.
Another idea is an eventual lack in the sensitity of 5HT-1b autoreceptors due to tonic activation, which would counteract the reduction in sensitivity of 5-HT1a receptors. This is a possible explanation for poopout, but it's my own theory and not proven, so take it with a grain of salt.
With regards to Remeron, I would guess that its faster onset is a result of a faster reduction in 5HT-1a sensitivity due to increased amounts of available 5-HT owing to the lack of 5-HT's ability to attach to 5-HT2 and 5-HT3 receptors. Another possible explanation is its actions on noradrenergic function simply allow for greater 5-HT release.
Remeron is particularly effective for depression based on its effects as a 5-HT2 antagonist and indirect 5-HT1 agonist. I believe its ability to fight depressive symptoms is partly because of effects on cortisol. Based on this, I hypothosized that a test for abnormally low cholesterol may be an indicator of depression, based on the fact that cholesterol is a precursor to the precursors of cortisol (cholesterol breaks down into cortisol). I found some confirmation of this idea in the second link provided below. "[There are] reported increases in depression, suicide and violence in individuals with low or lowered cholesterol." That is certainly intriguing.http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=20628415
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=16420132
Please feel free to disagree! I would very much like to improve all of this.
Posted by katekite on July 10, 2002, at 21:32:23
In reply to Some antidepressant theory, posted by Shawn. T. on July 10, 2002, at 17:16:30
I like it -- nice someone is thinking about it. I followed as far as 5HT1a activation.
Now I'm confused or need clarification: so are you saying chronic 5HT1a activation/agonist therapy causes or could cause eventual down-regulation of 5HT1a receptors or decreased sensitivity or decreased induced cortisol release?
Thanks,
Kate
Posted by LostBoyinNC1 on July 11, 2002, at 1:32:18
In reply to Some antidepressant theory, posted by Shawn. T. on July 10, 2002, at 17:16:30
I personally think Remeron is a fine antidepressant...one of the best actually particularly for agitated depression. It has a good side effect profile for severe depression accompanied by severe insomnia and agitation, which is a very dangerous form of depression BTW. However, overall I dont believe Remeron is any better of an antidepressant than plain old Prozac. Pretty much all antidepressants are equally effective, with the exception of the MAOIs and high dose Effexor, which are stronger.
Remeron does have a good side effect profile though. Because it antagonizes the 5HT2A receptor, its great for anxiety, agitation and possibly even mild psychosis. Its also a good drug for someone suffering from anti-psychotic drug induced EPS. Remeron doesnt cause the initial akathisia that the SSRIs often cause, again due to the fact it antagonizes 5HT2A receptor.
In my opinion, Organon took the good things about atypical anti-psychotic drugs (antagonism of the serotonin 2A receptor) and applied it to an antidepressant. But left out the bad thing about atypical anti-psychotics...dopamine receptor blockade. Very few depressives need any dopamine receptor blockade. For the few who do have real psychotic symptoms to their depression, bilateral ECT would be safer better choice than taking atypical anti-psychotics.
Thus, Remeron is the perfect antidepressant for the agitated depressive with severe insomnia. It has some of the properties of the atypical anti-psychotics, but without the potential dangers of the atypical anti-psychotics. Remeron reduces agitation, but without creating any dangerous dopamine receptor blockade.
Also, Remeron doesnt cause sexual dysfunction like the SSRIs cause.
But I disagree with you that Remeron is a "wonder drug" its not any better than the SSRIs in the end. Maybe more tolerable for some, but more effective? Nope. Remeron is definitely not any kind of CRF-Antagonist antidepressant either. I wouldnt try to make it look like one.
Currently, the only drugs on the market I know of that might work directly on cortisol to improve depression is that abortion drug pill RU-486. There was a drug in development for AIDS called "Anti-Cort" which was supposedly going to be used for depression as well. I dont know if this drug has been FDA approved or whether its been rejected or the company gave up on it or what. Drugs which improve depression and anxiety by cortisol are still ten years away, if they are ever actually marketed at all. Im personally skeptical we will ever see cortisol blocking antidepressants.
Improvements run extremely slowly in psychiatry.
Posted by cybercafe on July 11, 2002, at 1:49:39
In reply to Some antidepressant theory, posted by Shawn. T. on July 10, 2002, at 17:16:30
>life experiences. Recent advances in neuroscience have lead me to believe that a more ideal antidepressant may have the following properties: serotonin reuptake inhibition, 5HT-2 antagonism, and 5HT-3 antagonism. Or possibly a
okay 5HT2 antagonism i think is a really good idea... not just because of
a. 5HT2 is responsible for anxiety, agitation, sexual side effets, weight gain
but also because
b. by antagonizing "bad" receptors, were there not be more available for "good" receptors?
and even more importantly
c. it may be that the nucleus accumbens, possibly globus pallidus, are responsible for feelings of joy, happiness, pleasure, everything good (except sexual pleasure which i believe occurs in the septal nuclei) ... i believe that firing of 5HT 2B and 2C reduce firing of dopamine neurons in the VTA (which leads to the nucleus accumbens)... also 5HT 2A inhibits striatal firing ...
now as for 5HT3... yes i hate constipation... but i believe 5HT3 actually increases dopamine function in the nucleus accumbens (a good thing)... so i'll keep that :) ...
>would guess that SSRI monotherapy may reduce norepenephrine levels, which may explain why the stronger SSRI's like Paxil are much more sedating than the weaker, especially Prozac which is activating."hmm... maybe... since there are feedback inhibitory pathways from the raphe nucleus (serotonin) to the locus ceruleus (norepenephrine)....
> 5-HT1a activation is one possible action in the brain thought to contribute to cortisol release.
yes... and cortisol is related to steroid diabetes and accelerated aging... these are bad things :)
>a quick rundown. I have found that 5-HT1a activation is an important antidepressant
are there 5ht1a postsynaptic receptors, or are they all autoreceptors?
> I would argue that tonic 5-HT1a receptor activation to reduce sensitivity helps to increase 5-HT release from neurons, which... well i don't think it necessarily increases release from neurons... but i think that there is greater release than when there is more sensitivity...
... i would imagine that reuptake inhibitors don't necessarily allow more neurotransmitter to be in the synaptic gap, .. but simply that they allow it to be there for longer...
>HT2 antagonist is the best explanation for most SSRI side effects. 5-HT3 antagonism is said to reduce nausea.
... yeah the 5ht2 family certaihly doesn't seem very nice...
5ht3 is responsible for nausea, emesis, and possibly IBS but i don't remember exactly
>Another possible explanation is its actions on noradrenergic function simply allow for greater 5-HT release.
i believe reading somewhere that it is because of ations on certain NE receptors... see above
> Remeron is particularly effective for depression based on its effects as a 5-HT2 antagonist and indirect 5-HT1 agonist. I believe its ability to fight depressive symptoms is partly because of effects on cortisol. Based on this, I hypothosized that a test for abnormally low cholesterol may be an indicator of depression, based on the fact that cholesterol is a precursor to the precursors of cortisol... i'm not sure remeron is one of the more powerful antidepressants...
... although i suspect it is quite useful in augmentation therapy...
Posted by Shawn. T. on July 11, 2002, at 3:08:54
In reply to Re: Some antidepressant theory, posted by katekite on July 10, 2002, at 21:32:23
You asked a good question, and I'm going to have to delve into this more; I've only been reading about all of this since my Remeron kicked in two weeks ago. I started slowly, but I am definitely picking up the pace. I'll have to get back to you on the issue of up/down regulation; I'm tired and I need to go to bed :) I also would like to find out more on 5-HT4; I believe SSRI's exert their antidepressanton action by acting on it as well. I'm also doing research on drugs and peptides that act to increase or decrease cortisol levels. I hope to be able to combine all this knowledge to suggest a better antidepressant than the one I described. I apologize for my lack of clarity; I wish to be able to explain all of this in a more accessible manner. Comments like yours contribute to my ability to do this.
My newfound understanding of sensitization, based on Eric Kandel's studies on the sea snail Aplysia californica, is as follows. (He used a sea snail because they have few and very large neurons, allowing for easy study.) Repeatedly stimulating sensory neurons axons from the head or tail causes an increase in serotonin. Increases in serotonin in the snail's brain activate receptors in neuron terminal membranes that are linked by a G-Protein to adenylate cyclase, which activates the second messenger cAMP, which activates protein kinase A, which phosphorylates (adds a phosphate group to) potassium ion channels in the terminal membrane. As a result of the last step mentioned, the terminal stays positive (potassium ions have a positive charge) for a longer period of time after an action potential comes down a sensory neuron axon (basically a terminal in the serotonin neuron is caused to stay opened longer). This allows more calcium ions (with a +2 positive charge) to enter the terminal and promote neurotransmitter release. Thus, you have just learned about short term learning (a little bit).
Taking the above into consideration, I will try to explain the best I can. 5-HT1a is very complicated. Activation of presynaptic 5-HT1a receptors induces both hyperphagia (increased appetite) and anxiolytic-like (anxiety relieving) effects in rats. This potentially explains Remeron's quick onset.
Ok, onto another type of 5-HT1a receptor. 5-HT1a receptors in the raphe nuclei act as somatodendritic autoreceptors which inhibit neuronal cell firing and 5-HT release onto postsynaptic sites. These are the receptors that may help explain the antidepressant actions of SSRI's and their sensitisation leads to increased levels of 5-HT in the synapses. I would propose that changes in mRNA are the meaning of sensitisation when referring to it in the long term sense. Tonic activation of these 5-HT1a receptors may affect gene expression in other words.
Moving along, stimulation of postsynaptic 5-HT1a receptors may cause anxiogenic-like (anxiety producing) responses. I would propose that these receptors are the ones that combine with 5-HT2a and 5-HT2c to increase the release of cortisol. This may help explain why drugs like Paxil can initially cause anxiety.
> I like it -- nice someone is thinking about it. I followed as far as 5HT1a activation.
>
> Now I'm confused or need clarification: so are you saying chronic 5HT1a activation/agonist therapy causes or could cause eventual down-regulation of 5HT1a receptors or decreased sensitivity or decreased induced cortisol release?
>
> Thanks,
>
> Kate
Posted by Shawn. T. on July 11, 2002, at 4:35:22
In reply to Re: Some antidepressant theory, posted by cybercafe on July 11, 2002, at 1:49:39
I wouldn't think that there would be a down regulation of say 5-HT1a receptors because of 5-HT2 blockade, but I will research this for you tomorrow. Thank you for bringing that up. As for 5-HT2a, I can't find the studies that you are referring to (I'm not looking hard enough). Could you please point me to them?
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=7364595
This study suggests that 5-HT2 antagonists block dopamaine release in the medial prefrontal cortex:
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=16329960
This one suggests that 5-HT2 and 5-HT2a antagonists attenuate the stimulus effects of cocaine:
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=16404130
More on M,100,907 which is a potent 5-HT2 receptor antagonist
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=1986311
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=8171765
I think that this study will interest you:
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=24790086
5-HT3 does modulate the firing of mesolimbic dopaminergic cell bodies; thank you for pointing that out. Rats cannot discriminate substances that activate 5-HT3, however. Its antagonisation can help block pain, enhance cognitive functions, and may have anxiolytic actions in some, but not all rodent and primate models of anxiety. With regards to constipation, I've personally found that Wellbutrin and Remeron offset each other when it comes to that, although YMMV. 5-HT4 activation has been shown to increase striatal dopamine release by the way; we both win there.http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=25023352
And finally, here's my new favorite study, which could further help explain 5-HT2's effects on anxiety. http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=11719015
As for Remeron, it has been shown to decrease stress induced increase of extracellular release of cortical dopamine and norepinephrine output. I believe the 5-HT2 receptors are involved in this, and it also implies a cortisol reducing effect of the drug I believe. Furthermore, Remeron increases dopamine transmission in the frontocortical region and norepinephrine transmission in the corticolimbic region. I believe that 5-HT2 actually modulates dopamine and norepinephrine activity. It seems to not only increase them but to also prevent stress induced spikes in their levels. I'm still convinced that 5-HT2 antagonists are good. I shall have to compile a list of evidence for this.
You are correct in stating that Remeron is not a wonderdrug. I do believe that either Remeron or Wellbutrin is the most effective drug currently available for antidepressant treatment. Call me biased, but I have previously denied psychiatrist's attempts to put me on Zoloft, Neurontin, and Trazadone. I also did not suggest the Remeron augmentation to Wellbutrin, my current pdoc did.
Posted by Shawn. T. on July 11, 2002, at 7:04:01
In reply to Re: Some antidepressant theory, posted by LostBoyinNC1 on July 11, 2002, at 1:32:18
With regards to CRF-Antagonist antidepressants, they may be closer than you think. I have some information that such drugs may already exist but have not been exploited as antidepressants. Until a drug acting on CRF's is released, I have an idea for a drug cocktail that could beat Remeron hands down. Mix an SSRI with the new potent 5-HT2 antagonist M,100,907. During initial treatment, augment the SSRI with pindolol to decrease the amount of time necessary for the SSRI to kick in. This avoids 5-HT3 antagonism and antihistamine problems. I think that is a wonderful idea. Maybe the improvements in psychiatry are running so slowly because I haven't been around to speed them up.
Posted by Shawn. T. on July 11, 2002, at 7:56:35
In reply to Some antidepressant theory, posted by Shawn. T. on July 10, 2002, at 17:16:30
http://www.biopsychiatry.com/depression/evolution.html
and
http://www.huxley.net/rankmood/index.html
and
http://www.huxley.net/rankmood/adapt.htm
and
http://www.biopsychiatry.com/depression/index.html
and
http://www-np.unimaas.nl/PsyPharm/postersBAP/posterwim.html
and
last but not least...
http://members.aol.com/jefferiesw/research/cortisone.html
I believe that these links help further my theory. I also believe that this shows a clear link between antidepressants that work on serotonin, cortisol, and natural selection. Might antidepressants improve fertility? Might they prevent miscarriage? This information also has powerful clues to possible causes of depression (heriditary, childhood abuse or neglect, starvation, high levels of stress, basically anything that causes increased levels of cortisol secretion). I believe this also furthers my claim that 5-HT2 antagonism is an important antidepressant mechanism and could possibly save lives."Meanwhile I also began to work in an infertility clinic associated with Western Reserve University and found that many of its women patients had evidence of mild disorders of adrenal function that improved when they were given small, subreplacement dosages of cortisone or cortisol (3). During the next twenty years over 200 babies were born to women with mild disorders of ovarian function who took safe, physiologic dosages of cortisone or cortisol not only in order to get pregnant but also throughout their pregnancies to protect against miscarriages, without any evidence or harm to either mothers or babies (4). These dosages therefore appeared to be restoring normal function rather than impairing it."
I believe that of all currently available antidepressants, Remeron is clearly the most effective because of its effects as an 5-HT2 antagonist. That doesn't mean it can't be improved upon, just that it's the best thing around right now.
Posted by johnj on July 11, 2002, at 9:16:37
In reply to Re: Some antidepressant theory, posted by LostBoyinNC1 on July 11, 2002, at 1:32:18
It is a myth that remeron does not cause sexual dysfunction. Sure it calmed me down, helped me sleep, but it NUMBED everything for me too. I had severe "sponge brain" with it and it screwed up my short term memory. I just couldn't think straight and was zoned out most of the time. I know of several other people who have had the same problem with remeron. It was easy to get off of though and I felt great for a week after getting off of it.
johnj
Posted by cybercafe on July 11, 2002, at 9:24:11
In reply to Re: Some antidepressant theory, posted by Shawn. T. on July 11, 2002, at 7:04:01
> With regards to CRF-Antagonist antidepressants, they may be closer than you think. I have some information that such drugs may already exist but have not been exploited as antidepressants. Until a drug acting on CRF's is released, I have an idea for a drug cocktail that could beat Remeron hands down. Mix an SSRI with the new potent 5-HT2 antagonist M,100,907. During initial treatment, augment the SSRI with pindolol to decrease the amount of time necessary for the SSRI to kick in. This avoids 5-HT3 antagonism and antihistamine problems. I think that is a wonderful idea. Maybe the improvements in psychiatry are running so slowly because I haven't been around to speed them up.
Why not use something like..... nefazodone (serzone) as a 5TH2 antagonist? ... and if Serzone acts like a SSRI + 5HT2 antagonist, why do people not report it as being very effective?
... yes pindolol seems like a good idea to me....
... hell why not throw in a stimulant while we're at it? ...
Posted by cybercafe on July 11, 2002, at 9:27:21
In reply to Natural selection, cortisol, and antidepressants, posted by Shawn. T. on July 11, 2002, at 7:56:35
>basically anything that causes increased levels of cortisol secretion). I believe this also furthers my claim that 5-HT2 antagonism is an important antidepressant mechanism and could possibly save lives.
I feel very strongly about that as well.....
... in fact i believe it was stated that suicide risk was strongly correlated to an increase of 5HT2A neuroreceptors in the neocortex....
... keep in mind also that 5HT2A is responsible for "agitation", and agitation is considered a strong risk factor in suicide....
... anyways.. you should see if you can get $50k off the gov't, and do some research into it...
Posted by cybercafe on July 12, 2002, at 1:13:13
In reply to Re: Some antidepressant theory, posted by Shawn. T. on July 11, 2002, at 4:35:22
Hey this is interesting stuff, thanks dude :)
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=7364595
>
> This study suggests that 5-HT2 antagonists block dopamaine release in the medial prefrontal cortex:Yes fascinating, 5HT2A agonists stimulate release in the thinking centers, but decrease release in the pleasure centers... which would explain why happy people are so dumb ;)
What else is fascinating is that D2 dopamine receptors actually decrease the firing of dopaminergic neurons -- possibly because of it's decreasing the activity of adenylate cyclase? .. i dunno know if the two are connected...
>that activate 5-HT3, however. Its antagonisation can help block pain, enhance cognitive functions, and may have anxiolytic actions in some, but not all rodent and primate models of anxiety. With
.... yeah who knows... the good and bad actions of 5HT3 can all be accomplished by other means...
>regards to constipation, I've personally found that Wellbutrin and Remeron offset each other when it comes to that, although YMMV. 5-HT4
... yeah i've found gabapentin offsets antidepressants... but i also found a few vitamin supplements that help as well (help is a weak word -- complete 100% remission is more accurate)...
... any ideas on 5HT5 and 5HT6 for depression or anxiety?
Posted by Shawn. T. on July 12, 2002, at 21:59:24
In reply to Re: Some antidepressant theory, posted by cybercafe on July 12, 2002, at 1:13:13
Awesome, thanks for your help. I haven't had time to do any reading on dopamine; what you told me is really fascinating. I can really put that information to good use! You really clued me in on 5-HT4 action as well. My interest in moving beyond 5-HT2 receptors (yes, that is my primary interest because of Remeron) has brought me away from serotonin and dopamine receptor research. I've been really into hormones recently if you haven't notice. There is definitely much more to depression than serotonin, despite what SSRI producing companies would like you to believe. You should see how many IE windows I have open at once all the time (I try to keep it under 18).
I am really blown away by evidence linking intelligence to depressive symptoms and lack of it to euphoria. I have an IQ of 135 or higher (not bragging, just illustrating a point) and am
not the happiest guy in the world when not on drugs by any means. You may be intrigued by the fact that Remeron+Wellbutrin has entirely curtailed my drug abuse.As for 5-HT3, I believe there are definitely lots of pro's and con's to blocking this receptor. This is a complicated receptor, and I don't know whether or not I'm glad mine is being antagonised or not.
5-HT5 receptors interact negatively with adenylyl cyclase. So their activation decreases adenylyl cyclase activity. That would seem to signal a decrease in cortisol. Another anti-depressant mechanism of serotonergic agents, perhaps? Also, a possible explanation of seasonal affective disorder?
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=25950478Based on five minutes of reading, antagonists of 5-HT6 receptors appear to increase glutamate (excititory neurotransmitter) levels. That means cognitive enhancement without a doubt. I'll update you on more about this later.
You might be interested in my theory of SSRI related male sexual dysfunction. 5-HT1a activation in combination with 5-HT2a and 5-HT2c leads to increased prolactin excretion. Increased levels of prolactin lead to hypogonadism, with decreased sex drive, decreased sperm production and possible impotence. It also makes your breasts larger. I can't wait for M,100,907 (the 5-HT2 selective antagonist) to be released.
I believe 5-HT1f may be linked to migraine headaches. 5-HT1f controls contraction in vascular, urinary, gastrointestinal, and uterine functions. Migraines cause vascular dilation (not sure if that's the word I want) I believe.
Check this out on aggression too:
http://www.biopsychiatry.com/aggression.htmAlso 5-HT1a agonists seem to cause up-regulation by the way. This makes me think that taking an SSRI after consuming MDMA really is a good idea.
The increase in serotonin caused by an SSRI would prevent serotonin receptor up regulation in response to a massive serotonin decrease after taking MDMA.
http://mdma.net/mdmaeff.htm
Makes me wish that I hadn't done ecstacy (I've done it all, and I'm now going about undoing what damage I may have done hahaha).Something tells me this might spark your interest.
http://www.tocris.com/cat/5ht567.html
Posted by cybercafe on July 13, 2002, at 0:20:54
In reply to More more more antidepressant theory, posted by Shawn. T. on July 12, 2002, at 21:59:24
> Awesome, thanks for your help. I haven't had time to do any reading on dopamine; what you told me is really fascinating. I can really put that information to good use! You really clued me in
maybe we are both being somewhat close-minded or tunnel-visioned... but personally i tend to judge serotonin neuroreceptors by their effects on dopamine release... since i know dopamine is responsible for cognitive functioning and the pleasure centers of the brain...
... i also find it interesting that dopamine increases arousal, libido, weight loss, decreases appetite, (eg wellbutrin) whereas 5HT2 blocks dopamine and causes sedation, decreased libido, weight gain, increased appetite etc ... (5HT2 may cause inhibition of orgasm by spinal motor neuron inhibition)... so i really wonder how many effects might be secondary rather than primary.....
>on 5-HT4 action as well. My interest in moving beyond 5-HT2 receptors (yes, that is my primary interest because of Remeron) has brought me away from serotonin and dopamine receptor research. I've been really into hormones recently if you haven't notice. There is definitely much more to
hmm.. is cortisol in the extracellular areas of the brain? .... and how does it cause depression? does it decrease cell firing in the pleasure centers of the brain?
>depression than serotonin, despite what SSRI producing companies would like you to believe. You should see how many IE windows I have open at once all the time (I try to keep it under 18).
... perhaps if you gave someone a drug that worked really well they wouldn't be able to stop themselves from taking more and more ?
> I am really blown away by evidence linking intelligence to depressive symptoms and lack of it to euphoria. I have an IQ of 135 or higher... where have you seen evidence to this effect? ...
>drugs by any means. You may be intrigued by the fact that Remeron+Wellbutrin has entirely curtailed my drug abuse.
... hows that?
> 5-HT5 receptors interact negatively with adenylyl cyclase. So their activation decreases adenylyl cyclase activity. That would seem to signal a decrease in cortisol. Another anti-depressant mechanism of serotonergic agents, perhaps? Also, a possible explanation of seasonal affective disorder?... i wonder if decreasing a secondary messenger might mean inhibiting the firing of a neuron which would be synonymous with depression... although some neurons will cause others to fire, some will inhibit the firing of other neurons so it's not that simple...
> Based on five minutes of reading, antagonists of 5-HT6 receptors appear to increase glutamate (excititory neurotransmitter) levels. That means cognitive enhancement without a doubt. I'll update you on more about this later.
... well it depends where... glutamate might excite a neuron that produces GABA and inhibits 1000 other neurons...
> You might be interested in my theory of SSRI related male sexual dysfunction. 5-HT1a activation in combination with 5-HT2a and 5-HT2c leads to increased prolactin excretion.i believe 5HT2A and 5HT2C decreases dopamine release, ... and D2 dopamine receptors in the pituitary release testosterone and increase libido
>makes your breasts larger. I can't wait for M,100,907 (the 5-HT2 selective antagonist) to be released.
what's wrong with ritanserin?> Also 5-HT1a agonists seem to cause up-regulation by the way. This makes me think that taking an SSRI after consuming MDMA really is a good idea.
up regulation means... compensating by increasing the number of neuroreceptors? ... but if you use an agonist.. and cause the neuron to fire more than usual.. wouldn't it adapt .. compensate.. by decreasing the number of neuroreceptors?> The increase in serotonin caused by an SSRI would prevent serotonin receptor up regulation in response to a massive serotonin decrease after taking MDMA.
... but then if you're wrong, you could die from serotonin syndrome or the opposite :)
> Something tells me this might spark your interest.
> http://www.tocris.com/cat/5ht567.htmlhmmm... was hoping for an explanation of what they actually do :)
Posted by wcfrench on July 13, 2002, at 0:55:26
In reply to More more more antidepressant theory, posted by Shawn. T. on July 12, 2002, at 21:59:24
Great article about 5HT receptors and their functions.
http://www.clusterheadaches.org/library/serotonin/serotonin_receptors.htm
Posted by Shawn. T. on July 13, 2002, at 16:39:52
In reply to Re: More more more antidepressant theory, posted by cybercafe on July 13, 2002, at 0:20:54
Those are some challenging questions.
With regards to linking intelligence to depressive symptoms; I actually thought that you told me that! I will definitely look into this more. Especially noteworthy is the high rates of depressive symptoms in child prodigies. That may just be because of social reasons. I don't know how I came up with that, strange. I would argue that it is to everyone's benefit that we research different topics; you are certainly not a close minded person.The adrenal gland is responsible for cortisol production. It also produces aldosterone and testosterone.
"Corticosteroids may affect brain function through two general mechanisms, interaction with the genome and interaction with cell membranes (9, 10). Corticosteroids freely cross neuronal cell membranes and, in neurons containing specific cytoplasmic steroid receptors, translocate as a steroid-receptor complex to the cell nucleus (9, 35). There, the complex binds to chromatin and regulates transcription of specific genes."
See the following for the best information you'll find on cortisol on the net
http://www.psychosomaticmedicine.org/cgi/content/full/61/5/698So 5-HT2 actions are related to every neurotransmitter implicated in depression!
I suggest that Wellbutrin was the first step in curtailing my drug abuse. I used it to quit smoking. You'd probably be able to explain that better than I could. Next, the addition of Remeron effectively reduced my opiate cravings. As for why I don't crave marijuana, I'll get back to you. I can figure it out. Also, I now believe that hallucinogens will be ineffective on me (see my discussion on schizophrenia).
As for the opiate cravings, see
http://opioids.com/naloxone/depcrf.html
and
http://www4.infotrieve.com/newmedline/detail.asp?NameID=11931344&loggedusing=M&Session=98474&SearchQuery=mirtazapine+AND+dopamine&count=12For more on adenylyl cyclase and some good knowledge on caffeine (I quit consuming it after reading this), see
http://www.madsci.org/posts/archives/feb2000/950223638.Cb.r.html
"Up regulation means... compensating by increasing the number of neuroreceptors? ... but if you use an agonist.. and cause the neuron to fire more than usual.. wouldn't it adapt .. compensate.. by decreasing the number of neuroreceptors?"
-Yes, I believe you are probably correct. A possible poopout theory? I'll do some more reading on this.
"but then if you're wrong, you could die from serotonin syndrome or the opposite :)"
-Please don't take them at the same time! Take the SSRI say an hour or two after you have completely come down (that would signal a decrease in serotonin transmission).I'll get back to you on the glutamate with relation to 5-HT6. Increasing glutamate levels is the single most effective means of improving cognition in my opinion (neurotransmission is sped up). I'll have to read about dopamine's effects on glutamate levels.
I described why I don't like ritanserin elsewhere in this forum.
This is the end of the thread.
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