5-HT1A/Gene Coding related research - singlecell OP

[Moloch]

forexworld12 on Mon Dec 29, 2014 12:50 pm

anacleta wrote:
Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.
Perlis RH1, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ. 2009

http://www.ncbi.nlm.nih.gov/pubmed/19295509


i know it isn't about 5-ht1a but is interesting... glutamate system

Its all 5HTIA but other things are interconnected , treating gultamte is more of a secondary option like an aid on.. because the 5HTIA is what is causing inhibition of dopamine,NMDA, glutamate, acetylcholine, oxytocin etc
so naturally Everything is dysfunctional

[Moloch]

catalunya on Mon Dec 29, 2014 1:50 pm

forexworld12 wrote:
anacleta wrote:
Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.
Perlis RH1, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ. 2009

http://www.ncbi.nlm.nih.gov/pubmed/19295509


i know it isn't about 5-ht1a but is interesting... glutamate system

Its all 5HTIA but other things are interconnected , treating gultamte is more of a secondary option like an aid on.. because the 5HTIA is what is causing inhibition of dopamine,NMDA, glutamate, acetylcholine, oxytocin etc
so naturally Everything is dysfunctional

5ht2c is also heavily implicated and to a lesser extent 5ht2a.

[Moloch]

forexworld12 on Mon Dec 29, 2014 2:34 pm

catalunya wrote:
forexworld12 wrote:
anacleta wrote:
Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.
Perlis RH1, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ. 2009

http://www.ncbi.nlm.nih.gov/pubmed/19295509


i know it isn't about 5-ht1a but is interesting... glutamate system

Its all 5HTIA but other things are interconnected , treating gultamte is more of a secondary option like an aid on.. because the 5HTIA is what is causing inhibition of dopamine,NMDA, glutamate, acetylcholine, oxytocin etc
so naturally Everything is dysfunctional

5ht2c is also heavily implicated and to a lesser extent 5ht2a.

yes right !

[Moloch]

Ghost on Mon Dec 29, 2014 5:09 pm

catalunya wrote:
forexworld12 wrote:
anacleta wrote:
Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.
Perlis RH1, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ. 2009

http://www.ncbi.nlm.nih.gov/pubmed/19295509


i know it isn't about 5-ht1a but is interesting... glutamate system

Its all 5HTIA but other things are interconnected , treating gultamte is more of a secondary option like an aid on.. because the 5HTIA is what is causing inhibition of dopamine,NMDA, glutamate, acetylcholine, oxytocin etc
so naturally Everything is dysfunctional

5ht2c is also heavily implicated and to a lesser extent 5ht2a.

Another thing I've been a bit confused on is that there are many more auto-receptors than the 5-HT1A. There's 5-HT1B, 5-HT1D, 5-HT5A, and 5-HT7. That's 5/14 5-HT receptors. If they haven't been damaged, why can't they notice the increased synaptic 5-HT levels and subsequently lower their serotonin release to readjust to this change in 5-HT levels induced by SSRI's?

[Moloch]

Ghost on Wed Jan 07, 2015 2:51 pm

Ghost wrote:
catalunya wrote:
forexworld12 wrote:
anacleta wrote:
Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.
Perlis RH1, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ. 2009

http://www.ncbi.nlm.nih.gov/pubmed/19295509


i know it isn't about 5-ht1a but is interesting... glutamate system

Its all 5HTIA but other things are interconnected , treating gultamte is more of a secondary option like an aid on.. because the 5HTIA is what is causing inhibition of dopamine,NMDA, glutamate, acetylcholine, oxytocin etc
so naturally Everything is dysfunctional

5ht2c is also heavily implicated and to a lesser extent 5ht2a.

Another thing I've been a bit confused on is that there are many more auto-receptors than the 5-HT1A. There's 5-HT1B, 5-HT1D, 5-HT5A, and 5-HT7. That's 5/14 5-HT receptors. If they haven't been damaged, why can't they notice the increased synaptic 5-HT levels and subsequently lower their serotonin release to readjust to this change in 5-HT levels induced by SSRI's?

I answered my own questions on this by asking around/ researching more.

5-HT1A receptors are clumped heavily in the raphe nucleus, a portion of the brain, which modulates sexual activity to a great degree. It's the serotonin bombardment here that destroys sexual functioning, and inhibits dopamine.

5-HT1A receptors are also concentrated in the cerebral cortex, hippocampus, septum, and in the amygdala.

I found:

5-HT1B= Not high concentrations in the raphe nucleus

5-HT1D= Couldn't find info for concentrations in the raphe nucleus

5-HT5A= Couldn't find info for concentrations in the raphe nucleus

5-HT7= High levels in the hypothalamus. This area controls body temp, appetite, sleep cycles, thirst, fatigue...

So I crossed off 1B for more research for now.

I will look into 1D, 5A, and 7 a bit more closely. Not that I think this will turn into anything (I think most/all desensitization is in 5-HT1A) but it's good to explore these options, and I would like to get more info on these receptors anyways.

I will find better sources for my information once I dive deeper.

[Moloch]

Twister on Thu Jan 08, 2015 1:58 pm

Ghost wrote:
Ghost wrote:
catalunya wrote:
forexworld12 wrote:
anacleta wrote:
Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.
Perlis RH1, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ. 2009

http://www.ncbi.nlm.nih.gov/pubmed/19295509


i know it isn't about 5-ht1a but is interesting... glutamate system

Its all 5HTIA but other things are interconnected , treating gultamte is more of a secondary option like an aid on.. because the 5HTIA is what is causing inhibition of dopamine,NMDA, glutamate, acetylcholine, oxytocin etc
so naturally Everything is dysfunctional

5ht2c is also heavily implicated and to a lesser extent 5ht2a.

Another thing I've been a bit confused on is that there are many more auto-receptors than the 5-HT1A. There's 5-HT1B, 5-HT1D, 5-HT5A, and 5-HT7. That's 5/14 5-HT receptors. If they haven't been damaged, why can't they notice the increased synaptic 5-HT levels and subsequently lower their serotonin release to readjust to this change in 5-HT levels induced by SSRI's?

I answered my own questions on this by asking around/ researching more.

5-HT1A receptors are clumped heavily in the raphe nucleus, a portion of the brain, which modulates sexual activity to a great degree. It's the serotonin bombardment here that destroys sexual functioning, and inhibits dopamine.

5-HT1A receptors are also concentrated in the cerebral cortex, hippocampus, septum, and in the amygdala.

I found:

5-HT1B= Not high concentrations in the raphe nucleus

5-HT1D= Couldn't find info for concentrations in the raphe nucleus

5-HT5A= Couldn't find info for concentrations in the raphe nucleus

5-HT7= High levels in the hypothalamus. This area controls body temp, appetite, sleep cycles, thirst, fatigue...

So I crossed off 1B for more research for now.

I will look into 1D, 5A, and 7 a bit more closely. Not that I think this will turn into anything (I think most/all desensitization is in 5-HT1A) but it's good to explore these options, and I would like to get more info on these receptors anyways.

I will find better sources for my information once I dive deeper.

cool, so what do we need to use to make for recovery trhough on this ?

[Ghost]

Wait, I understand Doxycyclines action as a switcher for allready manipulated genes i.e. that are made prone to Doxy.
So by using Doxy, it shouldnt change anything.
Correct me if I´m wrong.
But You never know..

Yea that's right. They used it in a study for turning on and off manipulated genes.

[iull1k]

Someone asked there why we don't all get pssd. There is evidence how much is important genetics in response to SSRI.

"5-HT1A And 5-HTTLPR Combined Effect

5-HTL/L–1AC/C genotype
While there would be no marked difference in initial extracellular 5-HT levels between 5-HTTLPR genotypes, after SSRI treatment high amounts of extracellular 5-HT in the synapse would be present, specifically in contrast with individuals with the 5-HTTS/S genotype. The high amounts of extracellular 5-HT would then bind to the low amounts of 5-HT1A autoreceptors (when compared with the 1AG/G genotype) on the presynaptic cell and would lead to a mild-to-moderate amount of inhibition. After downregulation 5-HT1A autoreceptors after somatodendritic 5-HT1A receptor binding, larger amounts of serotonin would be released into the synapse when compared to the 1AG/G genotype (as demonstrated by Richardson-Jones et al., 2010). Due to the high amounts of extracellular 5-HT from 5-HTT binding and increased 5-HT release from reduced presynaptic terminal inhibition, the largest increase in 5-HT levels would occur in these individuals. This genotype is hypothesized to result in the highest amount of postsynaptic 5-HT signaling and would show the most favorable response to SSRI treatment.

5-HTTL/L–1AG/G genotype
After SSRI treatment, individuals with this genotype would initially have the same increase in extracellular 5-HT levels as the 5-HTTL/L–1AC/C genotype, but due to the higher number of 5-HT1A autoreceptors there would be an increased amount of inhibition in the presynaptic terminal, leading to low amounts of 5-HT released. After somatodendritic downregulation, only a moderate increase in 5-HT levels would be observed, owing to the high serotonin concentration from the blocked 5-HTT and the low amount of 5-HT released due to the high 5-HT1A autoreceptor density. This genotype is hypothesized to result in a moderate amount of postsynaptic 5-HT signaling and would show an intermediate response to SSRI treatment.

5-HTTS/S–1AC/C genotype
After SSRI treatment, individuals with the 5-HTS/S genotype would have a small increase in extracellular 5-HT concentrations when compared with the 5-HTTL/L genotype. This small amount of 5-HT binding to the low number of 5-HT1A autoreceptors would lead to a smaller magnitude in the downregulation of the somatodendritic cell, when compared with downregulation from the 5-HTL/L genotypes. This reduced amount of downregulation, and consequently the low amounts of disinhibition, would be offset, however, by the reduced expression of presynaptic 5-HT1A autoreceptors already present due to the 1AC/C genotype, resulting in a moderate increase in 5-HT levels. This genotype is hypothesized to result in a moderate level of postsynaptic 5-HT signaling and show an intermediate response to SSRI treatment (possibly similar to that of the 5-HTTL/L–1AG/G genotype).

5-HTTS/S–1AG/G genotype

Following SSRI treatment, individuals with the 5-HTTS/S–1AG/G genotype would have the same increase in extracellular 5-HT concentrations as the genotype 5-HTTS/S–5-HTTC/C, but, due to the increased number of 5-HT1A autoreceptors present, a higher amount of presynaptic inhibition would occur. In addition, once downregulation of the somatodendritic 5-HT1A receptors occurred (similar to that of the 5-HTTS/S–1AC/C genotype), less 5-HT would be released into the synapse due to the higher density of the 5-HT1A autoreceptors inhibiting the presynaptic terminal. The small amount of extracellular serotonin from 5-HTT binding, combined with the small amounts of 5-HT being released due to high 5-HT1A autoreceptor density, would lead to the smallest increase in 5-HT levels. This genotype is hypothesized to result in the least amount of postsynaptic 5-HT signaling and would show the least favorable response to SSRI treatment.

Discussion

The proposed model predicts that the 5-HTTL/L–1AC/C genotype will produce the highest amount of postsynaptic 5-HT signaling, that the 5-HTTL/L–1AG/G and 5-HTTS/S–1AC/C genotypes will produce a moderate amount of postsynaptic 5-HT signaling, and that the 5-HTTS/S–1AG/G genotype will produce the least amount of postsynaptic 5-HT signaling. In addition to predicting which individuals will respond more favorably to antidepressant treatments, this model can also be used to predict the temporal dynamics associated with response to treatment. More specifically, while the functional outcomes of the 5-HTTL/L–1AG/G and 5-HTTS/S–1AC/C genotypes are predicted to be similar, these genotypes may behave differently before they reach equilibrium. Because the 5-HTTL/L–1AG/G genotype contains a high density of inhibitory 5-HT1A autoreceptors, the benefits of the SSRI treatment will be observed only after the autoreceptors have been downregulated. Only after the autoreceptors have been downregulated will the increase in extracellular 5-HT levels be detectable. In contrast, the 5-HTTS/S–1AC/C genotype has a significantly lower density of inhibitory 5-HT1A autoreceptors. It is possible that the main benefits of SSRI treatment could be observed earlier than the 5-HTTL/L–1AG/G genotype, as the model predicts that the 5-HTTS/S–1AC/C genotype relies less on somatodendritic downregulation of 5-HT1A autoreceptors and more on the initial inhibition of 5-HT reuptake. Future research can examine whether genotype moderates the temporal response to antidepressant treatment, as well as the end response.

Ultimately, though, the model predicts the response to SSRI treatment based on genotypic modulation of postsynaptic 5-HT signaling. This genotype-dependent modulation of postsynaptic serotonin signaling is important, as higher postsynaptic serotonin signaling is associated with reduced depressive symptoms. This is, in part, thought to be due to the triggering of chemical cascades that ultimately results in both increased dendritic arborization and brain-derived neurotrophic factor (BDNF) expression within hippocampal cells (Nestler et al., 2002). Increased 5-HT signaling via SSRI treatment has been reported to enhance BDNF expression (Duan et al., 2004), which is associated with a reduction in depressive symptoms (Martinowich and Lu, 2008). It is because of these downstream pathways that 5-HT levels are implicated in both susceptibility to and treatment of depression, and why SSRIs, which increase postsynaptic 5-HT signaling, are effective in treating depression. This also explains why participants with the 5-HTL/L–1AC/C genotype respond more favorably to SSRI treatment than other genotypes and why individuals with the 5-HTTS/S–1AC/C genotype have poorer treatment response than those with other genotypes (Arias et al., 2005; Hong et al., 2006), as the modulated 5-HT increases associated with each genotype would alter induced BDNF expression.

Further research should be conducted to determine whether differences in BDNF expression, and other downstream responses associated with 5-HT signaling, are observed between individuals with differing genotypes, as this would add further support for the proposed model. Additionally, researchers have recently developed a 5-HT1A agonist (F15599) specifically targeted for 5-HT1A heteroreceptors (Lladó-Pelfort et al., 2010). Individuals with a blunted response to SSRI treatment due to genotype could benefit from 5-HT1A heteroreceptor agonist augmentation as it could compensate for the marginal increase in extracellular 5-HT available for postsynaptic signaling."

http://eneuro.org/content/2/3/ENEURO.0032-14.2015

[Ghost]

YES! THANK YOU SO MUCH! Looking for one like that! I'm thinking of getting a full genetic test done. This would help me decode it a bit.

[Ghost]

Seriously one of the best articles that I've read in a while. Took a lot of notes. I'll post something about them eventually. Every time I read something like this I think that I'm finally getting closer to understanding PSSD. This time around, I think I learned more about why auto receptors are auto receptors (which I never understood)

" Pet-1 is a transcription
factor, expressed only in raphe-specific cells, that binds
to several Pet-1 binding sites upstream of the 5HTR1A
gene (Jacobsen et al., 2011). Because Pet-1 is only expressed
in serotonergic neurons found in the raphe nuclei,
all 5-HT1A receptors produced by Pet-1 are considered
autoreceptors. "

and I also found a genetic sequence that inhibits 5HT1a AR creation.

"Another transcription factor regulating the expression
of 5HTR1A is NUDR/Deaf1... (Deaf1) acts as a repressor in
RN serotonergic cells. A study supporting this reported a
50% increase in 5-HT1A autoreceptor expression in the
dorsal and medial RN following removal of the Deaf1
repressor (Czesak et al., 2012). This relatively recent discovery
has elucidated some of the mechanisms surrounding
5-HT1A receptor regulation and 5-HT1A receptor
binding in depression, as multiple conflicting studies report
both increased and decreased 5-HT1A binding in
depressed individuals"