Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

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sylv
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by sylv »

What seems to "cure" me is a drug called Cyproheptadine (Periactin), which is a known serotonin antagonist. But the weird component is this. When I take 1mg of this drug, I will be sleepy (normal response) and wake up feeling tired. The following day I feel the same. BUT it's day 3 and 4 AFTER that first dose, I feel "Cured". I will literally wake up feeling fucking NORMAL again. Its like that vibrational rush is back. My symptoms of Genital numbness, No orgasm, No sexual arousal, no feeling, muscle weakness, all disappear on day 3-4. This stays like this for a week. But slowly slowly, I return back to my numb state.

So the question arises... HOW/WHY? I suspect looking into the 5-HT1a receptor, 5-HT2a receptor and the 5-HT2c receptors.
The answer lies in the 5-HT2a inverse agonism. Not simple antagonism.

I have had the same effect from mirtazapine, a combined 5-ht1a agonist and 5-ht2a inverse agonist.

The "hangover" effect may be due two possible things
- 5HT2a inverse agonism increases TNF-a expression which epigenetically ( after some time ) decreases expression of EAAT2 / GLT-1 glutmate transporter leading to decreased glutamate uptake in a synaptic clefts and increased NMDAr / AMPAr activation. TNF-a on it's own increases nociception, may also explain "flu improvement" phenomenon seen in the Post SSRI Syndrome
- 5HT2a is a constitutionally active receptor, that means it has some basal activity even in the absence of natural agonist - a serotonin. Thats why it's possible to "inverse agonise it" - lower basal receptor activity below normal. This is visible by temporary lowered intracellular signal transducer - Phosphoinositide 3-kinase . It's a known homeostatic mechanism that the temporary reduction of activity led to increased response in future.So, the action, may in turn re sensitize receptors to neurotransmitters by increased subsequent PI3K pathway activity response to natural agonists. As 5-HT2a and NMDArs share similar pathway, are co-expressed and recognized as an important excitatory receptors in the pyramidal neurons of the limbic and somatosensory cortex - their increased responsivity at hangover may explain improvement in an anaesthesia and emotional blunting. If true, this theory would mean that PI3K pathway in PSSD is overly constitutionally active- so desensitized in some key brain areas, screwed probably by either epigenetic or homeostatic mechanism . In this case the cure may lay in the selective restoring of pathway sensitivity. The glimpse is mirtazapine / mianserin / cyproheptadine hangover effect

5-HT2a is important component of the limbic system. By continuous taking of antagonists you will get a classic antidepressant / emotion blunting agent.
HereToHeal
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by HereToHeal »

sylv wrote: Sun Nov 24, 2019 7:34 am
What seems to "cure" me is a drug called Cyproheptadine (Periactin), which is a known serotonin antagonist. But the weird component is this. When I take 1mg of this drug, I will be sleepy (normal response) and wake up feeling tired. The following day I feel the same. BUT it's day 3 and 4 AFTER that first dose, I feel "Cured". I will literally wake up feeling fucking NORMAL again. Its like that vibrational rush is back. My symptoms of Genital numbness, No orgasm, No sexual arousal, no feeling, muscle weakness, all disappear on day 3-4. This stays like this for a week. But slowly slowly, I return back to my numb state.

So the question arises... HOW/WHY? I suspect looking into the 5-HT1a receptor, 5-HT2a receptor and the 5-HT2c receptors.
The answer lies in the 5-HT2a inverse agonism. Not simple antagonism.

I have had the same effect from mirtazapine, a combined 5-ht1a agonist and 5-ht2a inverse agonist.

The "hangover" effect may be due two possible things
- 5HT2a inverse agonism increases TNF-a expression which epigenetically ( after some time ) decreases expression of EAAT2 / GLT-1 glutmate transporter leading to decreased glutamate uptake in a synaptic clefts and increased NMDAr / AMPAr activation. TNF-a on it's own increases nociception, may also explain "flu improvement" phenomenon seen in the Post SSRI Syndrome
- 5HT2a is a constitutionally active receptor, that means it has some basal activity even in the absence of natural agonist - a serotonin. Thats why it's possible to "inverse agonise it" - lower basal receptor activity below normal. This is visible by temporary lowered intracellular signal transducer - Phosphoinositide 3-kinase . It's a known homeostatic mechanism that the temporary reduction of activity led to increased response in future.So, the action, may in turn re sensitize receptors to neurotransmitters by increased subsequent PI3K pathway activity response to natural agonists. As 5-HT2a and NMDArs share similar pathway, are co-expressed and recognized as an important excitatory receptors in the pyramidal neurons of the limbic and somatosensory cortex - their increased responsivity at hangover may explain improvement in an anaesthesia and emotional blunting. If true, this theory would mean that PI3K pathway in PSSD is overly constitutionally active- so desensitized in some key brain areas, screwed probably by either epigenetic or homeostatic mechanism . In this case the cure may lay in the selective restoring of pathway sensitivity. The glimpse is mirtazapine / mianserin / cyproheptadine hangover effect

5-HT2a is important component of the limbic system. By continuous taking of antagonists you will get a classic antidepressant / emotion blunting agent.
What are some examples of some 5HT2A inverse agonists?
Tree
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by Tree »

It seems that regulator of g proteins is partially responsible for desensitized pi3k. "RGS4 induced non-activation of PI3K/AKT pathway". RGS4 has shown to be elevated during ssri use. It makes sense since pi3k increases pip3, which inhibits RGS4. We need to focus on regulator proteins and their significance in pssd.
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