Time, the serotonin transporter and SSRIs

[Kdem]

How long till an SSRI has downregulated the serotonin transporter ? What timeframe ?

 

[palmanita]

Antagonists usually cause upregulation of their target had to look this up several times myself before I got it..

Think up-/downregulation happens quickly to a certain degree when one's exposed to an agent 24/7 as with SSRIs. At least at the point where you get any sort of discontinuation symptoms if you skip a dose, regulation has happened. I'd say it begins in the first week, also after a week off most should be reversed probably.

I might be wrong here but what I do worry more about are gene transcription factors like the infamous DeltaFosB, but they exist for everything and continued exposure to a strong drug might cause genes being switched on or off.

Also a reasonable part of the whole picture is the neuronal plasticity - this is just my current thinking, but maybe receptor regulation isn't the end. We or our brain, soul and consciousness get to know the effects a drug has, regardless how strong it's percipable at a given moment, and over time used to it. This will cause countless tiny changes in the neuronal network like everything else we experience, read and learn etc. So, you'll never be exactly the same after any drug you take (or decide not to take), as with anything we do all day long ... so a psychoactive drug never acts totally the same as last time. Granted it's borderline-philosophy but afaik neuroscience needs to take consciousness and all the tiny little changes that happen everyday and cumulate more into account.

 

[seep]

It's a competitive inhibitor of SERT, so it doesn't downregulate SERT.

The elevated levels of serotonin in the synapse will downregulate presynaptic 5HT-1 (the autoreceptors) and postsynaptic 5HT-2 receptors. This happens within hours according to my notes.

 

[WSH]

Antagonists usually cause upregulation of their target had to look this up several times myself before I got it...

The emphasis is on usually! 5-ht2a antagonists for example cause downregulation of the 5-ht2a receptor and SSRIs (which could be called "SERT antagonists") also cause downregulation of the serotonin transporter.

It's a competitive inhibitor of SERT, so it doesn't downregulate SERT.

Except for the fact that SSRIs definitely do downregulate the SERT!

How long till an SSRI has downregulated the serotonin transporter ? What timeframe ?

After 10 days they are down by ~30% and after 15 days they are down ~80%:

Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter

 

[seep]

Except for the fact that SSRIs definitely do downregulate the SERT!

I wasn't aware of that. That's very interesting.

 

[palmanita]

Yes, indeed. Thanks for the info - now the delayed action of SSRIs finally makes sense, and why many people don't notice much of immediate changes when they skip a dose or cease SSRI use.
Just how does the SSRI withdrawal syndrome fit into the picture? If SERT is down by 80% after just about two weeks then we'll have this or even less remaining after long-term use. Are these 15-20% remaining enough to disturb neuronal activity that much? And/or how fast does it recover / upregulate again after the SSRI is removed?

Okay, I've found that:

Previously, we have shown that 21 d of treatment with the SSRI paroxetine had no effect on SERT gene expression (Benmansour et al., 1999). To determine if changes occurred at earlier stages during treatment, mRNA for the SERT was measured in the dorsal raphe nucleus (DRN) by in situ hybridization in the same rats used for the [³H]-CN-IMI binding experiments. Message levels for the SERT increased slowly, reaching a statistically significant increase, by a maximum of 29% after 10 d of treatment, then decreased back to baseline after 21 d of treatment (Fig. 4). Message levels again rose significantly 6 d after 21 d of treatment was terminated, and then returned back to control levels rapidly (Fig. 4). Shown also for comparative purposes in Figure 4 are SERT binding sites in the DRN. Transient increases in mRNA early in the course of treatment may have opposed the SSRI-induced downregulation of SERT binding sites. Only when message levels had declined after the initial increase did SERT binding sites show a marked reduction. However, the short-lived increase in message after the cessation of treatment is accompanied by a more sustained increase in binding sites.

This would indeed fit with my experience of SSRI W/D symptoms increasing during the first days of abstinence, reaching a peak after 4-7 days and then subsiding (albeit not completely sometimes, here again I suspect the brain to have 'learned' / sensitized to these damn brain zaps to a certain extent. Isn't exactly a nice time, but compared to other withdrawals more bizarre than awful for me.)

Concerning the blockade-induced downregulation: We need something similar for DAT!!!!!11 (what, of course, would probably end up as a manic compulsive mess. But when used in strict moderation it'd be a godsend for ADD people)

 

[Cotcha Yankinov]

I'll add that with presynaptic autoreceptor downregulation there is reduced clearance of serotonin because autoreceptors like 5-HT1B can facilitate clearance of serotonin, but probably not because of increased expression of SERT from the cell body transported out to the nerve terminal but because of increased Vmax (I don't know about SERTs sequestered in the nerve terminal)

 

[WSH]

Yes, indeed. Thanks for the info - now the delayed action of SSRIs finally makes sense

There are actually at least 2 reasons for the delay:

1) increased reuptake inhibition, because of the SERT downregulation that I mentioned

2) desensitization (no downregulation this time!, just a decoupling from the G-proteins) of somatodendritic (5-HT1a) and terminal (5-HT1d) autoreceptors

I think it's a combination of these two that explains the fact that SSRIs acutely only increase serotonin by ~2x and after a couple of weeks they increase it by ~5x.

 

[plumbus-nine]

Am I understanding correctly that SERT antagonists cause lower SERT density over time, so negative tolerance? Where do then the abstinence symptoms like brain zaps, dysphoria, akathisia come from? I know SSRIs will desensitize (downregulate? I always confuse them, down and upregulation but understand that up equals to more density and down to less) serotonin receptors like the famous 5ht2a but also 1a etc.. so when removing the SSRI it's not SERT but downregulated receptors causing problems?

Any idea of how to reverse this? I have been and am struggling literally for years to come off venlafaxine. Now I am "down" from 300 to 150mg's/d but added 10mg paroxetine in evening for better sleep, so still far from baseline. Anything less than 150mg venla will cause horrible abstinencia, I never made it through more than 2 days and this is from someone who was on and off opioids also for years now - they can be shut off with dissociatives but will the 5-HT system ever recover?
Slowly titrate a 5-HT antagonist? But which one, for sure I don't wanna touch antipsychotics anymore, they are next to naloxone to me, horror.

Since I've started venla, I wasn't able to trip on shrooms anymore. 1cP-LSD worked though. Other thingies even dissos don't cause any real visuals, only some times black-white schemes..

 

[plumbus-nine]

Ugh: How a single dose of antidepressants can trigger post-SSRI sexual dysfunction (PSSD): a hypothesis (theresearchzone.com)