A few questions

[aced126]

I've always wondered why serotonin reuptake inhibitors produce a distinctly different behavioural response to serotonin releasing agents. Even at high doses, no sort of empathic or rewarding response is elicited by SSRIs, unlike SRAs. Furthermore, why is it that DA reuptake inhibitors like methylphenidate produce similar responses to DA releasers like amphetamine (actually a lot of compounds thought to be reuptake inhibitors like cocaine are now believed to act on DAT in a different way, causing a sort of inverse agonism and not exactly just reuptake inhibition per se. But I'll just leave the point about DA in anyway). Is it something to do with the kinetics of 5HT release? Releasers essentially force the presynaptic neuron to propogate the action potential at all times, but the post-synaptic neuron can only fire as fast as its maximum frequency. Reuptake inhibitors can't initiate an action potential and the presynaptic neuron needs to actually fire on its own to get the NTs in the synaptic cleft anyway. Could it be that some 5HT neurons fire quite infrequently and a SERT blocker won't do much because there isn't much 5HT in the cleft anyway.

Secondly, if one were to administer serotonin directly into the brain (too much ADME issues with oral), would it elicit a response similar to a serotonin releaser? I have a feeling it wouldn't. Although releasers release serotonin, is it correct to assume that the density of SERT is uniform across all serotonergic terminals (I'm guessing not). If this is the case, then at terminals where SERT is densely expressed, direct serotonin will just be taken up faster, whereas releasers will actually increase serotonin transmission into the synaptic cleft, because they make SERT transport in reverse.
Of a different topic, some peptide hormones synthesised in the brain like ACTH and vasopressin, and are secreted into the blood. How are they able to cross the BBB? Are there specific transporters for each protein?

 

[WSH]

I've always wondered why serotonin reuptake inhibitors produce a distinctly different behavioural response to serotonin releasing agents. Even at high doses, no sort of empathic or rewarding response is elicited by SSRIs, unlike SRAs.

SSRIs only increase serotonin to ~2-4x, whereas releasers can increase it to at least ~15x.

IFurthermore, why is it that DA reuptake inhibitors like methylphenidate produce similar responses to DA releasers like amphetamine (actually a lot of compounds thought to be reuptake inhibitors like cocaine are now believed to act on DAT in a different way, causing a sort of inverse agonism and not exactly just reuptake inhibition per se. But I'll just leave the point about DA in anyway)

Actual DRIs like mazindol only increase dopamine to ~2-4x (similar to SSRIs) and they do not cause euphoria and addiction.
DAT inverse agonists like cocaine increase dopamine to ~10x and they do cause euphoria and addiction.

Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine

summary:
- both serotonin and dopamine reuptake inhibitors (~2-4x) cause only subtle effects (e.g. fluoxetine, mazindol)
- both serotonin and dopamine releasers (>15x) cause major effects (e.g. MDMA, methamphetamine)
- DAT inverse agonists (~10x) cause major effects (e.g. cocaine)
PS: they didn't check if cocaine is also a SERT inverse agonist

 

[Limpet_Chicken]

ACTH is created INSIDE the brain, via cleavage of a prepropeptide thats then cleaved into ACTH, beta-endorphin , alpha-MSH (involved in skin pigmentation) and the enkephalins)

God damn that above subject was the subject of WAY too much research. Did years of research then to find out the end recipient of same, did not want it. Somewhat of a kick up the chocolate starfish, but not about to tell them that, Still, OW.

 

[Cotcha Yankinov]

I like the point about some neurons not firing much anyways, therefore reuptake inhibiton is not magnifying the activity of those post-synaptic neurons. Maybe the axons that can increase activity of euphoria related/linked areas normally don't get activated too much because over activation could be very harmful to the organisms survival.

It could also be an activation - response type deal. Maybe at a lower serotonin level one brain circuit reigns dominant, and then like gears in a car, as the serotonin level increases another brain circuit reigns dominant like another gear would at a certain throttle level. Of course two circuits, one supreme at a lower serotonin level and another supreme at a higher serotonin level, is probably a gross oversimplification.

Differential homeostasis among receptors, with the probable ability of SRA to extremely rapidly downregulate receptors, is another scenario. For example, 5HT2C antagonists cause DA/NE increases, so rapid desensitization of 2C might result in DA/NE release? Rapid desensitization of autoreceptors is another thing to consider.

Also, the varied responses of humans to SSRIs should be considered. I think they do make some people good (upon initiation, not just months down the road when depression pathology should be reversing). That could just be the hypomania kicking in and something their brain is naturally capable of, and SSRIs just tilt them onto that "track" that they can already race on without drugs.

 

[Cotcha Yankinov]

God damn that above subject was the subject of WAY too much research. Did years of research then to find out the end recipient of same, did not want it. Somewhat of a kick up the chocolate starfish, but not about to tell them that, Still, OW.

Dearest limpet chicken, I am so confuzzled, you did years of research for someone to find out that the person didn't want it? Sounds horrible man I sowwy

 

[serotonin2A]

Because the effects of 5-HT reuptake inhibitors are subject to modulation by 5-HT autoreceotors. When the 5-HT concentration increases then the autoreceptors are activated, and the level of 5-HT release declines.

When peptide transmitters are released into the blood stream then they usually do not get back into the brain. Peptides used in the brain are released in the brain.

 

[Limpet_Chicken]

No, it was worth it because they know they can find the option now. Spent a whole fuckton of time looking for type II melanocortin receptor agonists of nonpeptidic nature (the price of cosyntropin/synacthen absolutely shot up in the states and someone was in a shitter of a bind really. I'm only glad I didn't have to test it first. Because THAT would have sucked ass. Well the doing of it would have been pretty foul anyway, I HATE adrenergic crap like that.

The someone, is, well, worth my life, many fold. And I'd give it them gladly if it were of use. So yeah, no worry. It just took a long time. At least I learned a fair bit about the glucocorticoids, mineralocorticoids, CRF (was also searching for CRF-binding protein ligands, in a similar vein of thinking, not that I was aware of them at the time, synthetic receptors for cytokines and the like, such as 'tricking' TNF-alpha by presenting a false, synthetic binding domain which it then binds preferentially. Was for stalker/ex gf, a very special lady.

 

[aced126]

Because the effects of 5-HT reuptake inhibitors are subject to modulation by 5-HT autoreceotors. When the 5-HT concentration increases then the autoreceptors are activated, and the level of 5-HT release declines.

When peptide transmitters are released into the blood stream then they usually do not get back into the brain. Peptides used in the brain are released in the brain.

How are the peptides released specifically from the neuron into the blood stream?

Is there not an equivalent autoreceptor for dopamine (D2sh)?

Why are releasers not subject to modulation by the same 5HT autoreceptors? Wouldn't they activate more autoreceptors due to the greater concentration of 5HT they are able to release into the cleft?

Would administering a 5HT releaser be functionally different to simply administering intracranially a load of serotonin (that is to say, is presynaptic SERT density always the same at serotonergic innervations?).

 

[Cotcha Yankinov]

So you're saying that SERT occupancy with SRIs is never high enough to really disable the effects of autoreceptors that mediate their homeostasis effects through increased Cmax of SERTs or activating more SERTs etc., but SRAs increase serotonin to such a degree that it can overwhelm autoreceptors, or even if there is an adequate autoreceptor mediated increase in Cmax of SERTs, those SERTs can just spill everything back out again? (With increased Cmax? OR also if there are any newly activated SERTs coming out of the membrane then they are available to be reversed as well, however in the case of SRIs they would have an opposite function, clearing more 5HT).

 

[serotonin2A]

How are the peptides released specifically from the neuron into the blood stream?

Is there not an equivalent autoreceptor for dopamine (D2sh)?

Why are releasers not subject to modulation by the same 5HT autoreceptors? Wouldn't they activate more autoreceptors due to the greater concentration of 5HT they are able to release into the cleft?

Would administering a 5HT releaser be functionally different to simply administering intracranially a load of serotonin (that is to say, is presynaptic SERT density always the same at serotonergic innervations?).

To answer your different questions:

Cells can secrete hormones in vesicles. This is how adrenalin and insulin are released into the blood stream.

D2 autoreceptors inhibit dopamine release. But the action of a releasing agent is by definition not dependent on impulse flow or vesicular docking, so autoreceptor activation does not come into play. A parallel situation would be if your car is being driven towed. Putting on the breaks or stepping on the gas pedal isn't going to have any effect.

Releasers do indirectly activate autoreceptors, which inhibits endogenous transmission. But releasers work by bypassing normal vesicular release, so whether or not autoreceptors are active doesn't matter.

So you're saying that SERT occupancy with SRIs is never high enough to really disable the effects of autoreceptors that mediate their homeostasis effects through increased Cmax of SERTs or activating more SERTs etc., but SRAs increase serotonin to such a degree that it can overwhelm autoreceptors, or even if there is an adequate autoreceptor mediated increase in Cmax of SERTs, those SERTs can just spill everything back out again? (With increased Cmax? OR also if there are any newly activated SERTs coming out of the membrane then they are available to be reversed as well, however in the case of SRIs they would have an opposite function, clearing more 5HT).

There seems to be a fundamental misunderstanding of how 5-HT autoreceptors work...they generally function independently of SERT. 5-HT1A inhibits the firing of serotonergic neurons. 5-HT1B/1D activation reduces the ability of action potentials to drive transmitter release. Neither of those effects is dependent on SERT. Although there may also be some regulation of SERT function, that isn't a classically recognized mode of 5-HT autoreceptor action.

How could SERT occupancy ever be high enough to completely overcome autoreceptor activation? A high level of autoreceptor activation can potentially shut off all firing and transmitter release...if that happens then it won't matter if SERT is completely inactive, because there won't be any serotonin release, and hence synaptic levels of serotonin will be low.

 

[Cotcha Yankinov]

Sorry, I misunderstood the magnitude of the role of autoreceptor facilitated SERT function increases in decreasing serotonin concentrations compared to autoreceptor facilitated inhibition of neuron firing.

But I am curious if an increase in SERT Cmax or SERT expression can work to the opposite effect that nature intended when an SRA is introduced, and rather than clearing serotonin, much more serotonin can be dumped out into the synapse with that Cmax-increased-SERT compared to a normal SERT. Even if the autoreceptor facilitated increase in SERT Cmax doesn't result in a significant increase in clearing serotonin, maybe the reversed Cmax SERT can really dump a lot.

I've also heard talk of ions leaking out of transporters. Does that come into play with the physiological effects of reversed transporters?

 

[DotChem]

Of a different topic, some peptide hormones synthesised in the brain like ACTH and vasopressin, and are secreted into the blood. How are they able to cross the BBB? Are there specific transporters for each protein?

The peptides hormones are synthesized by the pituitary gland which is located OUTSIDE the BBB. Technically it is not a brain structure but it connects with the hypothalamus through the hypothalamus-pituitary axis... ACTH, oxytocin, vasopressin, endorphins, enkephalins, TRH TSH, MSH...etc etc) are synthesized from a single gene pro-opiomelanocortin in the pituitary and released in the blood stream.
The brain peptides secreted by the hypothalamus (like sex hormones eg GnRH gonadotropin releasing hormones) do not have to cross BBB but travel via hypothalamus-pituitary-gonads axis to stimulate the release of for example Gonadstropin in the blood stream. So technically the BBB is by-passed if I remember my old medchem classes correctly.. correct me if I am wrong

 

[serotonin2A]

Sorry, I misunderstood the magnitude of the role of autoreceptor facilitated SERT function increases in decreasing serotonin concentrations compared to autoreceptor facilitated inhibition of neuron firing.

But I am curious if an increase in SERT Cmax or SERT expression can work to the opposite effect that nature intended when an SRA is introduced, and rather than clearing serotonin, much more serotonin can be dumped out into the synapse with that Cmax-increased-SERT compared to a normal SERT. Even if the autoreceptor facilitated increase in SERT Cmax doesn't result in a significant increase in clearing serotonin, maybe the reversed Cmax SERT can really dump a lot.

I've also heard talk of ions leaking out of transporters. Does that come into play with the physiological effects of reversed transporters?

No need to say you are sorry!

The autoreceptors and transporters play very different roles in serotonergic trsnsmission, and it wouldn't be all that useful to link their function. SERT is there to reduce the signal to noise ratio by terminating transmission. Some serotonergic signaling occurs by volume transmission, where serotonin is released from varicosities and then stimulates extrasynaptic receptors. In that situation, SERT helps to terminate transmission by keeping the extrasynaptic 5-HT level below the level where all the 5-HT receptors in the brain are saturated. Obviously there is also classical 5-HT synaptic transmission, where SERT acts to terminate signaling and to recycle some of the transmitter.

By contrast, the autoreceptors allow 5-HT neurons to monitor transmitter release, thereby fine-tuning transmission.

In terms of your question about Cmax, if MDMA is doing what you are asking about then binding studies with a radioligand such as [3H]paroxetine should have found that MDMA increases the Bmax. That is a difficult study because of competition between the radioligand and MDMA, but theoretically it should be possible to demonstrate a Bmax increase. But as far as I am aware there isn't an acute increase in SERT function.

SERT is driven by ion gradients, and transport results in current flow across the membrane. However, such effects probably don't make a huge contribution to the overall effects of releasers or reuptake inhibitors.

 

[Cotcha Yankinov]

Thank you for the detailed insight

Regarding homeostatic mechanisms fine-tuning transmission, is there any particular circuit/phenomenon (such as storing memories etc.) that would be good to take a more in-depth look at in the context of autoreceptors? Or maybe SERT is better studied in regards to specific phenomenon, and if the circuitry/biology is delineated then the reasons why excess serotonin might result in less functionality/signal to noise ratio would be somewhat precise?

For example when you previously explained working memory a bit - that the correct cell ensembles need to fire, and that excess dopamine can silence all of the cells that represent the stimulus being held in working memory (as well as noise), it really clicked, but the underlying mechanisms were very interesting.