Serotonergic modulation of glutamate neurotransmission

[Meso]

Some people are helped by psychedelic and/or alcohol hangover states. Since these states are highly glutamatergic in nature, it prompted me to type out this thread because we have symptoms of low glutamate tranmission (cognitive dysfunction, poor memory, blunted affect, hypersomnia, etc)

It's interesting to note that before PSSD, I used to have OCD and treatment-resistant anxiety that only responded to high dose alprazolam. OCD is closely linked to excessive glutamate firing (esp. cortical area), since glutamate modulators offer a rapid anti-obsessional effect, unlike SSRIs. I also used to be overly-emotional and hypersexual.

After PSSD, I have severe treatment-resistant blunted affect, anhedonia, complete absence of anxiety and OCD. My blunted affect somewhat responds to glutamate modulation (NAC, aspartic acid, Baclofen rebound, GABA-A negative allosteric modulation, etc).

5HT2A forms a heterocomplex with mGluR2, as such that 5HT2A agonism (via psychedelic 5HT2A agonism) would inhibit mGluR2 firing. Non-psychedelic 5HT2A agonists (Lisuride, serotonin, etc) don't cause alteration of mGluR2 firing.

mGlu2 receptors are autoreceptors for glutamate. Inhibition of those receptors causes glutamate neurotransmission enhancement, leading to disinhibition of various brain regulatory circuits, enhancing monoamine transmission, and ultimately inducing hallucinations.

N-acetylcysteine (NAC) stimulates the glial cystine/glutamate exchanger and leads to elevated extracellular glutamate levels. This activates mGluR2 (inhibitory), resulting in lessened glutamate release. At high doses, there's a spillover effect that could result in NMDA receptor activation. NAC would probably blunt all psychedelic effects, therefore.

But less about that. Let's get back to how serotonin affects this system:
Serotonin modulates glutamate neurotransmission through the 5-HT1A, 5-HT1B, 5-HT3, 5-HT2, and 5-HT7 receptors.

5-HT1A: It's of extreme importance to differentiate between the 2 types of 5HT1A receptors when reading scientific papers. There are presynaptic autoreceptors that are present on midbrain raphe nuclei, and there are postsynaptic heteroceptors present on the hippocampus, amygdala, cortical and limbic areas. The presynaptic receptors inhibit seronergic neurotransmission whilst postsynaptic ones have a drastically different function.

Regarding glutamate modulation, their activation either increases or decreases glutamate neurotransmission depending on brain area. For example, cortical and hippocampal 5HT1A are localized on GABAergic neurons, so their stimulation would inhibit those neurons, resulting in glutamate disinhibition and increased neuronal firing.

EDIT: Seems I was wrong in this regard:

In the cortex most of them are located postsynapically, on the glutaminergic pyramidal neurons (up to 80% in some layers in humans ) , much lower on GABAergic interneurons ( around 20% - 30% ) and fast spiking parvalbumin interneurons ( average 5 - 10 %, max 30% ) . The overall effect of their activation is a general hyperpolarization state, reduction of neuronal firing and excitability / inhibition coefficient in this area, clearly visible by direct electrophysiological recording or even in the intensity of fMRI's BOLD effect. Along it goes reduced overall glutaminergic transmission. Hence the antidepressant, antianxiety effects of the full 5-ht1a agonists. They should be avoided for those suffering emotional blunting

Whole brain 5-ht1a mRNA in humans
https://bit.ly/2Vn8J0z

5-HT1a expression human Prefrontal Cortex
https://bit.ly/2WHZl87

5HT1B/1D: These receptors are closely linked to OCD (and glutamate). Stimulation of these receptors facilitate glutamatergic transmission. Chronic SRI intake downregulates these receptors and improve OCD symptoms by dampening of glutamate.

5HT2: I already mentioned 2A. Regarding 5HT2C, activation of that receptor blunts glutamate transmission. Since 5HT2C plays a role in penile erection, outright antagonism or downregulation would be counterproductive for erectile dysfunction, so a partial agonist with a low intrinsic activity would be idea, I reckon.

5HT3: Activation of this receptor is inhibitory to glutamate transmission. 5HT3 antagonism reduces prolactin and enhances glutamate transmission.

5HT7: Activation of this receptor inhibits cortical and hippocampal glutamate transmission. That's why 5HT7 antagonists have antidepressant effect coupled with memory-enhancing effect as well.

My opinion: Direct agonism or antagonism of 5HT1 receptors cause downregulation and upregulation of those receptors, respectively. 5HT2 receptors downregulate in response to both agonism and antagonism (inverse agonism), whilst 5HT3 receptors upregulates in response to both agonism and antagonism at least in-vitro.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543613/

Even 5HT7 receptors might upregulate in response to agonism. https://www.sciencedirect.com/science/a ... 6117301584

Since 5HT receptor subtypes behave this way, a partial agonist with low intrinsic activity (similar to a silent antagonist) would be a more viable long-term solution, since partial agonism doesn't trigger transcriptional adaptation.

Bottomline: If PSSD is related to reduced SERT mRNA expression and 5HT1A-GIRK decoupling, then the abnormally elevated serotonin is dampening our glutamate transmission excessively, causing some of the symptoms. And since some receptors behave differently regarding ligands when it comes to regulation, then we may have abnormally elevated 5HT7/3 receptor density, and abnormally reduced 5HT2 and 5HT1 receptors densities, across different brain areas.

I haven't provided many references as I've typed this thread from memory, since my spare time is very limited. So feel free to double-check.

[Blueturtle]

Absolutely fascinating. Great post, it looks like you’ve done some excellent research here.

I can relate to you for some degree, I was hyper emotional, hyper hedonic, hypersexual, and had a bit of a problem with obsessive behaviour before I got PSSD. Now I’m much much calmer but my sexual sides are still fairly bad. I’ve been feeling great the last week this is the biggest relief of anhedonia I’ve felt for the last year and a half or so, I’ve been on Wellbutrin 300mg and that has helped quite a bit with anhedonia and libido and I’ve been taking ginkgo biloba and omega 3 fatty acids recently as well.

Not much success with the genital pain/numbness recently however sadly.

Researchers looking at the paper results in 3 studies discussing persistently impaired sexual behaviour from neonatal citalopram, 5-ht1b agonist, and clomipramine suggested that the data looks like these persistent negative effects on sexuality in these early treated animals is likely the result of abnormal stimulation of the 5-HT1b and 5-ht2a receptors.

Famously on this forum, the clomipramine exposed rats with serious persistent sexual effects were successfully treated with DHT + Estradiol

The citalopram rats maybe had 40-50% reduction in symptoms with imipramine.

http://www.pssdforum.com/viewtopic.php?f=5&t=2537

I really remember being so hyper hedonic and hypersexual back in the days, as well as with no self confidence or social skills and that’s all completely reversed now with PSSD. Women absoulutely love me now it seems and I’m just not feeling it.

I wonder if there is also a relationship between serious social anxiety and hyper pleasureability and sexuality? Likely there is, shyness can be hypersensitivity to stimuli and that could translate to hypersensitivity of emotional states.

[sylv]

I agree with the most and have similliar experiences. You are really good observer

But let me address some discrepancies

, cortical and hippocampal 5HT1A are localized on GABAergic neurons,

In the cortex most of them are located postsynapically, on the glutaminergic pyramidal neurons (up to 80% in some layers in humans ) , much lower on GABAergic interneurons ( around 20% - 30% ) and fast spiking parvalbumin interneurons ( average 5 - 10 %, max 30% ) . The overall effect of their activation is a general hyperpolarization state, reduction of neuronal firing and excitability / inhibition coefficient in this area, clearly visible by direct electrophysiological recording or even in the intensity of fMRI's BOLD effect. Along it goes reduced overall glutaminergic transmission. Hence the antidepressant, antianxiety effects of the full 5-ht1a agonists. They should be avoided for those suffering emotional blunting

Whole brain 5-ht1a mRNA in humans
https://bit.ly/2Vn8J0z

5-HT1a expression human Prefrontal Cortex
https://bit.ly/2WHZl87

N-acetylcysteine

NAC has also very important effect by increasing the expression of GLT1 / EAAT2, the core transporter regulating the gial uptake of glutamate. Excessively increased uptake could reduce synaptic glutamate transmission below the threshold needed to induce action potential. Increased EAAT2 expression / activity is found in schizoprenics suffering excessive negative symptoms ( blunted affect ) and may be a part of the problem in some PSSD cases.

If somebody found highly brain penetrable penicillin antibiotics like Ampicillin to be "psychoactive", emotion blunting in high dosages few hours / day after, the increased EAAT2 expression is the key answer.

[Meso]

Researchers looking at the paper results in 3 studies discussing persistently impaired sexual behaviour from neonatal citalopram, 5-ht1b agonist, and clomipramine suggested that the data looks like these persistent negative effects on sexuality in these early treated animals is likely the result of abnormal stimulation of the 5-HT1b and 5-ht2a receptors.

I think 5HT1B/D receptors downregulation plays a significant role in causing some of our symptoms. It's going to be difficult to upregulate these receptors again with the abnormally elevated serotonin level. I think a partial agonist is the only option.

Sumatriptan (5HT1B/1D full agonist) gave me one of the first "windows" with amelioration of many of the symptoms, but the effect was short-lived as rapid tolerance set in. This shouldn't happen with a partial agonist.

WAY-100135, a research compound, is a 5HT1B/1D partial agonist and 5HT1A antagonist. It looks very interesting, at least on paper.

Given that SERT is downregulated semi-permanently, a partial agonist of 5HT1 receptor (all subtypes) with moderate to high intrinsic activity would be beneficial, I reckon, for limiting serotonin transmission somewhat and offering some symptomatic relief without causing tolerance.

[taarn]

WAY-100135, a research compound, is a 5HT1B/1D partial agonist and 5HT1A antagonist. It looks very interesting, at least on paper.

I'm waiting for WAY-100635 to arrive. I was thinking the same so it'll turn out if we were right. Btw I want to take it with another less selective serotonin antagonist concurrently, because blocakge of 5-ht1a presynaptic autoreceptors will result in even more serotonin directed towards other problemmatic receptors, like 5-ht2.

EDIT: I misread that it was WAY-100135 that was mentioned. But I think WAY-100635 would be also beneficial.

[Meso]

WAY-100135, a research compound, is a 5HT1B/1D partial agonist and 5HT1A antagonist. It looks very interesting, at least on paper.

I'm waiting for WAY-100635 to arrive. I was thinking the same so it'll turn out if we were right. Btw I want to take it with another less selective serotonin antagonist concurrently, because blocakge of 5-ht1a presynaptic autoreceptors will result in even more serotonin directed towards other problemmatic receptors, like 5-ht2.

EDIT: I misread that it was WAY-100135 that was mentioned. But I think WAY-100635 would be also beneficial.

Are you going to try it to restore 5HT1A sensitivity / induce upregulation? What do you have on mind for SERT?

Gepirone is a partial agonist of 5HT1A receptor. Binospirone is a partial agonist at presynaptic 5HT1A and an antagonist at postsynaptic 5HT1A (causing upregulation).

[lookingforacure]

I don’t post on here often, but I just want to let you know that before PSSD I too was extremely emotional and ruminative and now I’m neither of these things at all. I’ve also experienced my only improvements when hungover. I’d tried many antidepressants for almost a decade and always had fine sexual function after going off them, but in early 2018 I was on a combination of 200 mg lamictal and 20 mg viibryd (I was also taking Wellbutrin and for sleep mirtazapine) and when I tried reducing these drugs I realized I had severe PSSD that still impacts me today. I don’t know anything about biochemistry but you really seem like you know what you’re talking about, and I’m confident our problem will one day be solved and glad it’s in the good hands of people like you. I really appreciate what you’re doing Mesolimbo, please don’t give up- for all of our sakes.

[taarn]

Are you going to try it to restore 5HT1A sensitivity / induce upregulation? What do you have on mind for SERT?

Yes, and I will very likely combine it with Metergoline or Ketanserin.

Unfortunately I don't have enough time for research recently, so as far as my current knowledge goes I'll have to stick to Forskolin and Evodiamine to enhance/upregulate SERT.
Otherwise I feel a bit embarrassed to admit it but I still haven't found enough courage to try Fenclonine. I've read a paper where it was shown that Fenclonine was toxic to rats' pancreas, and I'm also afraid of a rebound TPH upregulation.
So I don't know maybe I'll try to also add a combination of Beta-alanine and Siberian ginseng to keep serotonin levels in check. If nothing works then I'll have to grow a d* and try Fenclonine.
EDIT: I've left it out but I have very low DHT which has pro-sexual and anti-serotonergic properties, and my estradiol is out of range if I don't keep it in check with an AI. I'm planning to try complementing my low DHT with adding either Proviron or Masteron.

Another thing is that to be honest since getting full PSSD all of my windows happened the next day after drinking alcohol and combining it with some kind of dopaminergic. A combination of Bromocriptine and 4 glasses of wine (which is enough for me to feel hangover) has resulted in the most prominent window so far. After thinking about the glutamate relation it starts to make sense. I was also overly emotional and hypersexual, and I had severe anxiety which resulted from compulsive behavior and thoughts. I'm afraid it wasn't too healthy to take MDMA in an overaroused state, probably I'm suffering from the consequences of glutamate excitotoxicity. But I was always able to recover until I took mirtazapine.

[Meso]

But let me address some discrepancies

Thanks for the correction.

I'd somehow forgotten about NAC's upregulation of glutamate transporter, despite mentioning it in another post. That being said, excess tonic glutamate release can also induce blunted affect, as in the case of benzodiazepine withdrawal or GABA-A antagonism.

In contrary to tonic glutamate release, phasic glutamate firing is involved with the hedonistic response relative to dopamine, and may improve anhedonia.

IIRC, amphetamine is a mild glutamate releaser which could explain, in part, why it has more abuse potential than methylphenidate.

when I tried reducing these drugs I realized I had severe PSSD that still impacts me today.

Have you tried taking Wellbutrin again? Why were you on Lamictal?

I really appreciate what you’re doing Mesolimbo, please don’t give up- for all of our sakes.

Thanks. It's all educated speculation and trial-and-error. I find that the cognitive and sexual dysfunction are easier to address (at least for me) than the emotional and hedonistic aspect of PSSD, which I couldn't find symptomatic relief from so far. It can get really frustrating.

[magnilo]

doesent vortioxetine have a really similar profile? not sure about the ht1a if its pre or postsynaptic tho and couldnt find informations