Posted by SLS on July 24, 2006, at 23:20:03
In reply to Re: what is my problem, posted by linkadge on July 24, 2006, at 21:28:30
Hi Linkadge.
> Its difficult to say. It is necesarry to to consider too whether the study is talking about 5-ht1a post synaptic receptors or presynaptic autoreceptors.
I agree. I don't think the assay used allowed for that distinction to be made. The thing is, both receptor populations would tend to be downregulated in the presence of excess neurotransmitter. Such has been observed in SERT knockout mice.
Don't forget about those tricky somato-dendritic autoreceptors.
> Sometimes serotonergic receptor alterations are used as justification for SSRI or MAOI treatment, without considering that the problem may lie elsewhere.Again, I agree. It is a bit childish to treat the brain with such a simplistic approach. My lack of knowledge renders me childish most of the time.
> For instance, I was under the impression that post synaptic 5-ht1a recptors were upregulated in the frontal cortex suicide brain, as well as in schizophrenic patients. This may or may not have anything to do with the regulation of serotonin uptake. Serotonin 5-ht1a agonists like buspar, and clozapine have the ability to downregulate postsynaptic 5-ht1a receptors.I wasn't aware that clozapine had that property. I think one could make the argument that the increased number of 5-HT1a receptors in this region is indeed the result of reduced 5-HT activity. This might be secondary to another pathology, however.
> I think that upregulated 5-ht1a could be a result of some deficinacy of an endogenius serotonergic modulators like anandamide.
You might be right. I haven't looked much into the cannabinoid system. My guess, though, is that it depends upon how vulnerable this system is to becoming dysregulated after being exposed to stress. Whatever it is that goes wrong in depression, I feel that it must be triggerable by psychosocial stress and reside in systems that remain plastic and do not maintain homeostasis under such conditions.
> Anandamide potentiats 5-ht1a receptors and antagonizes 5-ht2a receptor responses (kind of like clozapine). Deficinacies in such agents could reusult in the abberent receptor binding found in some of these illnesses.
>
> The below study says that presynaptic 5-ht1a autoreceptors are enriched in suicide victomes. I think this is referring to an enrichment of presynaptic autorecptors, which would resut in more inhibition of serotonin firing.> In this case, SSRI's work to downregulate autoreceptors. (At lest thats how I see it), resulting in more serotonin release.
I think there is a re-calibration of the entire homeostatic feedback system. In the presence of increased synaptic neurotransmitter, presynaptic autoreceptors are downregulated as are the postsynaptic excitatory receptors. There is a change in the signal-to-noise ratio that must occur if neural signals are to be transduced efficiently. Reuptake inhibitors create a lot of noise when they are first applied. The first neuron gets muted and the second neuron doesn't know when to send a true signal. Only after a period of a few weeks do the two neurons shake hands and settle on a standard volume setting to communicate at. Well, that's kind of a weak analogy, but I'm too lazy to come up with a better one. For years, my focus had been on the presynaptic neuron and its autoreceptors. It would explain deficiencies in both the synthesis and release of neurotransmitters. It was an attractive idea to a child. :-)
> But, I have also seen that agents like buspar are able to achieve the same thing. So who knows how the autoreceptor became so overactive.
Buspar is a full agonist at presynaptic autoreceptors, but only a partial agonist at postsynaptic receptors. I guess they mean excitatory receptors when they say that. They never mention somato-dendritic autoreceptors.
> The below study suggests that 5-ht1a autoreceptors are upregulated in depression, which result in less serotonin release. Using buspar as a probe.> http://bjp.rcpsych.org/cgi/content/abstract/164/3/372
If something doesn't act as a braking system, it becomes a positive feedback loop. So, what exactly is this braking system? Is this the primary site of pathology?
less 5-HT -> upregulated 5-HT1a -> less 5-HT -> upregulated 5-HT1a -> less 5-HT -> upregulated 5-HT1a...
The presynaptic machinery is still attractive to me. It certainly looks easier to deal with than the second messenger cascades and gene regulation and transcription of the postsynaptic neuron. Maybe things aren't that easy. (Just being childish again).
> I think that potent and selective 5-ht1a and 5-ht1b autoreceptor antagonists would result in immediate reduction in depression, since then you would not have to wait for any autorecptor downregulation to occur.
That's why I had thought to use pindolol. The thing with pindolol, though, is that it acts only at somato-dendritic autoreceptors. Although debated, pindolol has been reported to accelerate the response to SSRI antidepressants. This would make sense in that it would perhaps prevent accomodation of the postsynaptic neuron due to its constant stimulation by serotonin. It would allow for repolarization to occur and provide for the induction of appropriate action potentials. This probably would not happen in the absence of pindolol for two or more weeks until the postsynaptic receptors downregulate and no longer chronically depolarize the cell.
> Lithium can have immediate antidepressant effects (through 5-ht1b autoreceptor antagonism). I'd like to see the effects of a lithium + pindolol combination. Lithium affects other things too. So, I think that immediate antidepressant effect can wane due to all the other stuff it does.
> Pindolol kindof sucks because its not too strong an autoreceptor agtagonist, and it has post syntaptic antagonist properties too.
What would be of interest are presynaptic 5-HT1a and 5-HT1b antagonists. I haven't looked into them.
> I personally think that SERT has little to do with the origins of depression at all.
I personally think that I have no idea what the hell is going on!
> I think its serotonin release that is the problem not serotonin uptake.
I doubt it is the reuptake that is the primary site of pathology, but is perhaps an added vulnerability factor. There are probably several things that have to go wrong for one to develop MDD.
> SS may have more episodes of depression for different reasons altogether. Perhaps the extra serotonin in the amygdala makes them more sensitive to stress and depression.
I think you would have to look at the distribution of receptor subtypes located there to be sure. SERT knockout mice did not show even downregulation of 5-HT receptors among subtypes or in all brain regions. However, I would say that if intense anxiety were one of the side effects of SS people who are placed on SSRIs, then you probably hit the nail on the head.
I'm sorry, Linkadge. This is a pretty crappy post. It rambles. I'm not going to bother to proofread this thing. It's getting late, but I wanted to respond to the wealth of information and brilliant thought that you always bring to this forum.
- Scott
poster:SLS
thread:669157
URL: http://www.dr-bob.org/babble/20060724/msgs/670220.html