New review: on to dopamine phasic & tonic release [116 studies]

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Meso
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Re: New review: on to dopamine phasic & tonic release [116 studies]

Unread post by Meso »

kamikaz3 wrote:I can confirm, I have experiences intense sexual emotions and feelings whilst asleep. Upon waking though, that's another story - back to emotional blunting nothingness.

Sleep deprivation also helps greatly with being able to 'feel' again. Sleeping 'resets' me back to crapness.
Sleep deprivation increases allopreganolone, which triggers more dopamine release to help keep you awake. Maybe this is why you can "feel' again, since your phasic dopamine response is potentiated.
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Re: New review: on to dopamine phasic & tonic release [116 studies]

Unread post by lukejimmy »

Mesolimbo wrote: Postsynaptic 5HT1A receptors are known to take a very long time to upregulate/sensitize again, as with the case of MDMA tolerance.
Can you provide some sources? I am struggling to find anything in relation 5ht1a downregulation let alone its effects in relation to MDMA tolerance but to the contrary found evidence opposing this claim after some research:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578032/
https://www.ncbi.nlm.nih.gov/pubmed/9652358
https://www.ncbi.nlm.nih.gov/pubmed/30439373

Could these downregulation versus upregulation by SSRI's and MDMA respectively on 5ht1a receptor explain the CRUCIAL difference between their effects on orgasm with MDMA reported to increase orgasmic intensity/pleasure and the enjoyment of sexual activities in general wheres as the opposite is experienced in my experience in the form of Sexual Anhedonia causing completely pleasuress orgasm. Why does MDMA cause Euphoria and intense emotions whereas SSRI's cause permanent anhedonia (personally) and an apathy syndrome.
Mesolimbo you say have studied neuropharmacology so prove me wrong please if I am but like Fluoxetine, the drug that caused PERMANENT side effects for me, MDMA auto-INHIBITS ITS OWN METABOLISM which is mediated by CYP2D6 AND CYP3a4 by acting as an enzyme inhibitor of CYP2D6. Therefore an increase in MDMA OR Fluoxetine will cause an increase in its potency to inhibit its own metabolism. This could explain the permanent effects that Fluoxetine has caused for me personally not to mention all the other people on this forum but also the permanent detrimental effects of MDMA observed in the literature, especially chronic users and large does binges/overdosed where these effects are noted:

" Furthermore, the preconditioning regimen of MDMA did not alter tissue concentrations of 5-HT, whereas the binge regimen of MDMA resulted in a long-term reduction of 40% of tissue 5-HT concentrations. " https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578032/
https://www.ncbi.nlm.nih.gov/pubmed/10664829


This theory of mine explains the permanent effects of SSRI's but does not DISPROVE or ARGUE with any other theories as 5-HT1A desensitisation is proven effect of SSRI's. 5-HT1A desensitisation would reduce oxytocin release (correct if I am wrong) and oxytocin increases during Orgasm, MDMA increases oxytocin to levels similar to that during orgasm which could explain the increase in Orgasmic Pleasure and Intensity.

MDMA is Dopamine Re-uptake Inhibitor and causes dopamine depletion. Fluoxetine has a low affinity (4180 ki) for DAT but due to inhibition of its own metabolism and a Poor Metaboliser CYP2D6 phenotype would lead to extremely high levels of Fluoxetine causing dopamine re-uptake inhibition and eventual dopamine depletion? This would explain Neuroleptic induced deficit symptoms, elevated prolactin and pleasuress orgasm due to dopamine depletion that are also caused by D2 antagonists like Risperidone.
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Meso
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Re: New review: on to dopamine phasic & tonic release [116 studies]

Unread post by Meso »

lukejimmy wrote: Can you provide some sources? I am struggling to find anything in relation 5ht1a downregulation let alone its effects in relation to MDMA tolerance but to the contrary found evidence opposing this claim after some research:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578032/
https://www.ncbi.nlm.nih.gov/pubmed/9652358
https://www.ncbi.nlm.nih.gov/pubmed/30439373
The 2nd study that you have referenced involves MDMA-induced presynpatic 5HT1A supersensitivity. 8-OH-DPAT, the 5HT1A agonist that was used in the study, binds preferentially to autoreceptors. The 1st and 3rd studies entail SERT downregulation.
https://www.ncbi.nlm.nih.gov/pubmed/2469021

Although 8-OH-DPAT can also bind (less preferentially) to postsynaptic 5HT1A receptors, MDMA is known to induces presynaptic 5HT1A supersensitivity through depleting 5HT level and decreasing trypotophan hydoxylase expression:
https://www.ncbi.nlm.nih.gov/pubmed/18611291
https://www.ncbi.nlm.nih.gov/pubmed/23354536
https://www.ncbi.nlm.nih.gov/pubmed/23958955

MDMA's empathogenic and pro-sociability effect is mediated in part through oxytocin release mediated by postsynaptic 5HT1A activation:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221206/
https://www.ncbi.nlm.nih.gov/pubmed/17383105

People who use MDMA recreationally have been using SJW to reverse their tolerance to its empathogenic effect. This makes sense to me as SJW upregulates postsynaptic 5HT1A receptors.
https://www.ncbi.nlm.nih.gov/pubmed/11277608
lukejimmy wrote:Could these downregulation versus upregulation by SSRI's and MDMA respectively on 5ht1a receptor explain the CRUCIAL difference between their effects on orgasm with MDMA reported to increase orgasmic intensity/pleasure and the enjoyment of sexual activities in general wheres as the opposite is experienced in my experience in the form of Sexual Anhedonia causing completely pleasuress orgasm. Why does MDMA cause Euphoria and intense emotions whereas SSRI's cause permanent anhedonia (personally) and an apathy syndrome
Orgasmic intensity is mainly mediated by mu opioid receptor signalling with contributions from oxytocin, DA, and NE. SSRIs can blunt orgasms and cause anhedonia and apathy in part by activation of prefrontal brain regions. When these regions are activated, limbic regions are suppressed since they are under their control.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130136/

MDMA's euphoric effects are mediated through TAAR1 activation.
lukejimmy wrote:Fluoxetine, the drug that caused PERMANENT side effects for me, MDMA auto-INHIBITS ITS OWN METABOLISM which is mediated by CYP2D6 AND CYP3a4 by acting as an enzyme inhibitor of CYP2D6. Therefore an increase in MDMA OR Fluoxetine will cause an increase in its potency to inhibit its own metabolism. This could explain the permanent effects that Fluoxetine has caused for me personally not to mention all the other people on this forum but also the permanent detrimental effects of MDMA observed in the literature, especially chronic users and large does binges/overdosed where these effects are noted:

" Furthermore, the preconditioning regimen of MDMA did not alter tissue concentrations of 5-HT, whereas the binge regimen of MDMA resulted in a long-term reduction of 40% of tissue 5-HT concentrations. " https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578032/
https://www.ncbi.nlm.nih.gov/pubmed/10664829
Wait, are you implying that the permanent effects of Fluoxetine are due to its ability to prevent its own breakdown? Inhibiting its own metabolism would only prolong its half-life but it will eventually be completely eliminated through other CYPs.

As for MDMA's long-term reduction of serotonin, that's a whole different story. MDMA depletes serotonin through various mechanisms (via TAAR1, VMAT), and Fluoxetine can prevent this btw:
https://www.ncbi.nlm.nih.gov/pubmed/10607865/
lukejimmy wrote:Fluoxetine has a low affinity (4180 ki) for DAT but due to inhibition of its own metabolism and a Poor Metaboliser CYP2D6 phenotype would lead to extremely high levels of Fluoxetine causing dopamine re-uptake inhibition and eventual dopamine depletion? This would explain Neuroleptic induced deficit symptoms, elevated prolactin and pleasuress orgasm due to dopamine depletion that are also caused by D2 antagonists like Risperidone.
Multiple CYPs are involved in drug metabolism. Inhibiting the main CYP would prolong its half-life, sure, but it won't prevent elimination so this scenario is impossible. Even if it did, dopamine reuptake inhibition doesn't deplete dopamine. And D2 antagonists don't deplete dopamine either, they just block the receptors or inhibit its release.
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finities infinities
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Re: New review: on to dopamine phasic & tonic release [116 studies]

Unread post by finities infinities »

Increasingly, I believe in your theories about: presynaptic 5ht1a supersensitivity or downregulation postsynaptic 5ht1a. Especially since:
presynaptic 5ht1a = increase rem sleep
postsynaptic 5ht1a = block rem sleep.
I read your article and associated it with:
tonic dopamine activation: creepy empathy ( amisulpride!)
phasic dopamine activation: good feeling and natural emotion! ( postsynaptic 5ht1a activation?)
Do i understand you well I'm new here and I wrote a thread in the New Members section but it has not been published. I will do it again.
lukejimmy
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Re: New review: on to dopamine phasic & tonic release [116 studies]

Unread post by lukejimmy »

Meso wrote: Sat Aug 24, 2019 1:27 pm.
Multiple CYPs are involved in drug metabolism. Inhibiting the main CYP would prolong its half-life, sure, but it won't prevent elimination so this scenario is impossible. Even if it did, dopamine reuptake inhibition doesn't deplete dopamine. And D2 antagonists don't deplete dopamine either, they just block the receptors or inhibit its release.
[/quote]

On the Wikipedia it says Fluoxetine inhibits it’s own metabolism WITH TIME as reflected in its increasing half life the longer it’s taken right? Fluoxetine’s most potent in inhibition is CYP2D6 yes, but it also inhibits CYP2C19 CYP3a4 and CYP3a5 too! Although to varying degrees wouldn’t they all be potently inhibited eventually if the statement “Fluoxetine inhibits it’s own metabolism WITH TIME” is true? Could this be what keeps the brain from recovering from a withdrawal syndrome?

Keeping this in mind when I reinstated Prozac my PSSD symptoms improved in a WINDOW as others have described it.
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