Posted by Shawn. T. on July 11, 2002, at 3:08:54
In reply to Re: Some antidepressant theory, posted by katekite on July 10, 2002, at 21:32:23
You asked a good question, and I'm going to have to delve into this more; I've only been reading about all of this since my Remeron kicked in two weeks ago. I started slowly, but I am definitely picking up the pace. I'll have to get back to you on the issue of up/down regulation; I'm tired and I need to go to bed :) I also would like to find out more on 5-HT4; I believe SSRI's exert their antidepressanton action by acting on it as well. I'm also doing research on drugs and peptides that act to increase or decrease cortisol levels. I hope to be able to combine all this knowledge to suggest a better antidepressant than the one I described. I apologize for my lack of clarity; I wish to be able to explain all of this in a more accessible manner. Comments like yours contribute to my ability to do this.
My newfound understanding of sensitization, based on Eric Kandel's studies on the sea snail Aplysia californica, is as follows. (He used a sea snail because they have few and very large neurons, allowing for easy study.) Repeatedly stimulating sensory neurons axons from the head or tail causes an increase in serotonin. Increases in serotonin in the snail's brain activate receptors in neuron terminal membranes that are linked by a G-Protein to adenylate cyclase, which activates the second messenger cAMP, which activates protein kinase A, which phosphorylates (adds a phosphate group to) potassium ion channels in the terminal membrane. As a result of the last step mentioned, the terminal stays positive (potassium ions have a positive charge) for a longer period of time after an action potential comes down a sensory neuron axon (basically a terminal in the serotonin neuron is caused to stay opened longer). This allows more calcium ions (with a +2 positive charge) to enter the terminal and promote neurotransmitter release. Thus, you have just learned about short term learning (a little bit).
Taking the above into consideration, I will try to explain the best I can. 5-HT1a is very complicated. Activation of presynaptic 5-HT1a receptors induces both hyperphagia (increased appetite) and anxiolytic-like (anxiety relieving) effects in rats. This potentially explains Remeron's quick onset.
Ok, onto another type of 5-HT1a receptor. 5-HT1a receptors in the raphe nuclei act as somatodendritic autoreceptors which inhibit neuronal cell firing and 5-HT release onto postsynaptic sites. These are the receptors that may help explain the antidepressant actions of SSRI's and their sensitisation leads to increased levels of 5-HT in the synapses. I would propose that changes in mRNA are the meaning of sensitisation when referring to it in the long term sense. Tonic activation of these 5-HT1a receptors may affect gene expression in other words.
Moving along, stimulation of postsynaptic 5-HT1a receptors may cause anxiogenic-like (anxiety producing) responses. I would propose that these receptors are the ones that combine with 5-HT2a and 5-HT2c to increase the release of cortisol. This may help explain why drugs like Paxil can initially cause anxiety.
> I like it -- nice someone is thinking about it. I followed as far as 5HT1a activation.
>
> Now I'm confused or need clarification: so are you saying chronic 5HT1a activation/agonist therapy causes or could cause eventual down-regulation of 5HT1a receptors or decreased sensitivity or decreased induced cortisol release?
>
> Thanks,
>
> Kate
poster:Shawn. T.
thread:111957
URL: http://www.dr-bob.org/babble/20020709/msgs/112016.html