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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 15 of 15. This is the beginning of the thread.
Posted by SLS on June 17, 2008, at 12:49:45
A thought just occurred to me.
Perhaps tianeptine (Stablon) ultimately produces an increase in synaptic concentrations of serotonin via an increase in vesicular stores of this neurotransmitter, and an attendant increase in the amount released as the result of the arrival of an action potential. If the vesicular serotonin transporter is accelerated in the same fashion as the neuronal transporter, the vesicles may become "fatter" and store more serotonin available for each release.
In other words, tianeptine might cause the presynaptic neuron to spit out more neurotransmitter, but only as the result of an action potential.
I am only just now considering the consequences of such an acceleration in the activity of vesicular 5-HT transporter.
One consequence is that tianeptine may not be safe to take in combination with an MAOI.
- Scott
Posted by Phillipa on June 17, 2008, at 13:05:39
In reply to Possible Eureka., posted by SLS on June 17, 2008, at 12:49:45
So since you take an MAOI how can you test it? Phillipa
Posted by SLS on June 17, 2008, at 13:23:20
In reply to Re: Possible Eureka. » SLS, posted by Phillipa on June 17, 2008, at 13:05:39
> So since you take an MAOI how can you test it? Phillipa
I'll leave the testing for the rats.
- Scott
Posted by Phillipa on June 17, 2008, at 13:53:28
In reply to Re: Possible Eureka. » Phillipa, posted by SLS on June 17, 2008, at 13:23:20
Scott good idea. Love Phillipa
Posted by linkadge on June 17, 2008, at 17:43:31
In reply to Re: Possible Eureka. » Phillipa, posted by SLS on June 17, 2008, at 13:23:20
But wouldn't an increase in activity at the serotonin transporter lead to an increase in serotonin break down and metabolism?
SSRI's tend to cerebral spinal fluid levels of serotonin breakdown products, it would be interesting to see how tianeptine affects serotonin metabolites.
There may also be some final regulatory activity on the serotonin transporter. SSRI's initially decrease SERT activity, but some studies suggest long term administration upregulates the transporter.
Most studies on serotonin transporter levels in depression seem to suggest there is a decreased activity of the transporter (midbrain/frontal cortex) perhaps as a compensatory effect of reduced serotonin synthesis and release. It is the same with the NET transporter. When there is a monoamine deficiacny, the brain naturally decreases the level of the transporter to compensate.
Maybe the uptake system naturally oscilates and inhibitors/acellerators simply pull in one direction then let go.
Linkadge
Posted by SLS on June 17, 2008, at 18:42:59
In reply to Re: Possible Eureka., posted by linkadge on June 17, 2008, at 17:43:31
> But wouldn't an increase in activity at the serotonin transporter lead to an increase in serotonin break down and metabolism?
An increase in the rate of vesicular uptake of neurotransmitter from the cytoplasm by tianeptine (if this should occur) would sequester more neurotransmitter and protect it from the actions of cytoplasmic enzymes such as MAO.
> SSRI's tend to cerebral spinal fluid levels of serotonin breakdown products, it would be interesting to see how tianeptine affects serotonin metabolites.
Yes, it would be very helpful to ascertain this as it would render a clue as to what's happening with 5-HT turnover.
> There may also be some final regulatory activity on the serotonin transporter. SSRI's initially decrease SERT activity, but some studies suggest long term administration upregulates the transporter.
In what way is it upregulated? Is there an increase in the numbers of transporter molecules or is there a functional change in the transporter itself?
- Scott
Posted by SLS on June 17, 2008, at 19:08:19
In reply to Re: Possible Eureka. » linkadge, posted by SLS on June 17, 2008, at 18:42:59
My model depends on tianeptine having the capability of enhancing the activity of vesicular monoamine transporter (VMAT2). I haven't found anything to confirm this.
- Scott
Posted by linkadge on June 18, 2008, at 21:55:59
In reply to Re: Possible Eureka., posted by SLS on June 17, 2008, at 19:08:19
Tianeptine has a sensitizing effect on the d2/d3 receptors like the other TCA antidepressants. This is not generally shared by the SSRIs.
I think there is some other target of these drugs that is far beyond monoamine reuptake.
Linkadge
Posted by SLS on June 19, 2008, at 5:40:34
In reply to Re: Possible Eureka., posted by linkadge on June 18, 2008, at 21:55:59
> Tianeptine has a sensitizing effect on the d2/d3 receptors like the other TCA antidepressants. This is not generally shared by the SSRIs.
>
> I think there is some other target of these drugs that is far beyond monoamine reuptake.
Or not.My ideas are still not solidified, and I in no way want to express the following as fact:
Tianeptine is not an SSRI. However, it may end up being shown to be a 5-HT amplifier. While the nerve is at rest, the concentration of synaptic 5-HT is decreased. Because of this, the postsynaptic membrane becomes upregulated. When an action potential arrives at the terminal button, a greater amount of 5-HT is released. Tianeptine might act as a 5-HT amplifier that also increases 5-HT tone when the background noise is mitigated. As far as the sensitization of DA receptors is concerned, this is precisely what one would expect from an increase in 5-HT tone along with an increase in the release of 5-HT.
More 5-HT = Less DA?
Less DA = DA receptor upregulation?
Could work.
- Scott
Posted by linkadge on June 19, 2008, at 8:16:41
In reply to Re: Possible Eureka., posted by SLS on June 19, 2008, at 5:40:34
>More 5-HT = Less DA?
>Less DA = DA receptor upregulation?
>Could work.
The only problem with the dopamine receptor upregulation is that it is selective to certain deep limbic regions. This is not really consistent with supersensitivity due to a widespread dopamine transmission reduction. Also, if there was a general dopamine reduction, you would expect an upregulation of *all* dopamine receptor subtypes (d1,d2,d3,d4...)
Certain other compounds with AD effect also upregulate d2/d3. Surmontil does, but it has no general effect on monoamine levels. DHEA upregulates d2/d3 receptors but there is nothing I am aware of that says it decreases overall dopamine neurotransmission.
I think I agree with Dave Pierce who suggests that this adaptive process is literally what makes the drug work.
Linkadge
Posted by linkadge on June 19, 2008, at 8:17:33
In reply to Re: Possible Eureka., posted by SLS on June 19, 2008, at 5:40:34
"Free your mind".
Don't get institutionalized on the serotonin bandwagon :)
Linkadge
Posted by bleauberry on June 19, 2008, at 21:02:08
In reply to Possible Eureka., posted by SLS on June 17, 2008, at 12:49:45
I typed tianeptine into the search box at pubmed and clicked on a few pages of abstracts. Tianeptine appears pretty complicated and unique. It has something to do with neuroplasticity, modulating the inflammatory response, modulating the stress induced GABA/glutamate response, and as you already mentioned has indirect effects on neurotransmitters. Decreases plasma serotonin but increases platelet serotonin. Decreases plasma noradrenaline, no effect on plasma adrenaline. Must have some kind of dopamine function because there are cases of tianeptine abuse and dependence at high doses. It has worked in treatment resistant depression by itself or combined with other conventional antidepressants. Good for depression in parkinsons and heart disease patients. Interesting drug.
Your theory SLS makes sense to me. I have often wondered if with some people their depression is not a matter of how much neurotransmitter is sitting at the synapse, but rather how powerful the stream of neuros is. Kind of like a still pond versus a flowing stream. I think I am the kind that needs a flowing stream, because the still pond stuff makes me feel worse. Tianeptine might be the kind of drug that creates a flowing stream, where during the depression it was an erratic trickle.
Posted by SLS on June 20, 2008, at 4:25:03
In reply to Re: Possible Eureka., posted by bleauberry on June 19, 2008, at 21:02:08
Hi BB.
> I typed tianeptine into the search box at pubmed and clicked on a few pages of abstracts. Tianeptine appears pretty complicated and unique.
It must be to fly in the face of the putative mechanism of SRIs.
> It has something to do with neuroplasticity, modulating the inflammatory response, modulating the stress induced GABA/glutamate response,
I didn't know about the anti-inflammatory effects of tianeptine. Very interesting.
> Decreases plasma serotonin but increases platelet serotonin.
This makes perfect sense. According to my current model, tianeptine would decrease 5-HT turnover (and thus decrease plasma levels) by sequestering more of this neurotransmitter in the vesicles and making less available for cytosolic catabolism by MAO. Of course, 5-HT levels in platelets would be increased through an accelerated rate of reuptake produced by tianeptine.
> Decreases plasma noradrenaline,
This could be due to a reduction in NE turnover as would be the case with a drug that amplifies 5-HT signaling and consequently reduces NE through an indirect effect.
> Your theory SLS makes sense to me.
I thought I was the only one. I have very little emotional investment in the accuracy of my theory. I just seek understanding, regardless if my idea is wrong or right.
- Scott
Posted by dapper on June 20, 2008, at 16:20:33
In reply to Tianeptine: Possible Mechanism of Action » bleauberry, posted by SLS on June 20, 2008, at 4:25:03
I need to go to med school to understand this post better...
Posted by SLS on June 20, 2008, at 17:25:12
In reply to Re: Tianeptine: Possible Mechanism of Action, posted by dapper on June 20, 2008, at 16:20:33
> I need to go to med school to understand this post better...
No you don't. I never did. :-)
Synapse: The structure through which the neuronal signal is passed along from one neuron to the next.
1. Synaptic cleft: the gap between the sending and receiving neurons through which the neurotransmitter signal traverses.
2. Presynaptic: sending neuronal membrane
3. Postsysnaptic: receiving neuronal membrane
4. Receptors: binding sites located on neuronal membranes that the neurotransmitter molecules perform either an excitatory or an inhibitory function.Tianeptine causes the presynaptic neuron to reuptake (suck up) more neurotransmitter from the synaptic cleft than what is normal. The rate of neurotransmitter reuptake is accelerated or enhanced. In this case, the neurotransmitter is serotonin (5-HT). With less 5-HT in the cleft, the number of receptors along the postsynaptic membranes increases to compensate. More receptors on the postsynaptic membrane means higher sensitivity to the action of 5-HT release by the presynaptic neuron. Not only is there greater sensitivity, there is also more 5-HT stored and released by the presynaptic neuron, as tianeptine has caused it to accumulate at a greater rate.
The net effect of tianeptine might be that it amplifies a true neuronal signal and at the same time reduces background noise to produce greater fidelity.
There is a lot that I haven't gone into here. There is even more that I don't have a clue to. To incorporate all of the known properties of tianeptine and produce a theory as to the etiology of depression and why tianeptine is therapeutically efficacious would require a lot of research. I'll leave that to the true geniuses, though.
- Scott
This is the end of the thread.
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