Posted by Shawn. T. on January 2, 2003, at 22:08:16
In reply to I do believe in norepinephrine, posted by linkadge on January 1, 2003, at 9:48:04
I made a web page for this post rather than list all of the references in the message: http://www.neurotransmitter.net/nedepression.html ... I'm not sure how difficult my arguments might be to understand, but they're a general overview of what I know about the connections between unipolar depression and norepinephrine. Note that Cymbalta/duloxetine is much more selective than TCA's for the norepinephrine and serotonin transporters. The question that I pose is whether or not that is selective enough.
I find the fact that norepinephrine reuptake inhibitors are effective antidepressants to be intriguing given the fact that people with unipolar depression typically exhibit unusually high measures of norepinephrine activity. In responders, antidepressants in general tend to decrease the levels of a norepinephrine metabolite called MHPG, which is a general indicator of overall norepinephrine turnover. I looked into this, and the common denominator when it comes to antidepressant drugs seems to be their ability to reduce the responsivity of CRF neurons to stress (see Stout et al., 2002). They do not decrease the expression of CRF under normal conditions, so the effects are specific to conditions where the CRF neurons would be activated in response to stress. The fact that drugs that inhibit the reuptake of norepinephrine exhibit this activity seems to be a result of their ability to down-regulate beta-adrenoceptors. I say this because beta-adrenoceptors are located on CRF neurons and cause CRF secretion when activated. Apparently, the unusually high levels of norepinephrine seen in depression are not significant enough to cause the down-regulation of beta-adrenoceptors, but the artificially high levels caused by norepinephrine reuptake inhibiting drugs are significant enough. The cause of the high noradrenergic tone in unipolar depression seems to be, at least in part, due to the excitation of norepinephrine neurons by CRF. The decrease in MHPG, the primary metabolite of norepinephrine, that is often apparent in responders to antidepressants is therefore likely due to a normalization of the activity of CRF neurons. For anyone familiar with CRF, it also indirectly causes the release of the "stress hormone" cortisol among other functions.How do serotonin reuptake inhibitors fit into this scheme of CRF primacy in unipolar depression? SSRI's like Prozac do inhibit the stress sensitivity of CRF neurons, so they are similar to selective norepinephrine reuptake inhibitors in this sense. 5-HT2A receptors are the most likely candidates for serotonin receptors involved in the stimulation of CRF neurons. Increased activation of 5-HT2A receptors as one would expected from increased extracellular serotonin levels will either desensitize of down-regulate them. So SSRI's desensitize 5-HT2A receptors, blocking their ability to cause the secretion of CRF when activated under stressful conditions by serotonin. SSRI's often decrease MHPG with successful treatment, which is, in my opinion, likely secondary to their effects on CRF neurons.
So when you consider the increased efficacy of drugs that inhibit the reuptake of both norepinephrine and serotonin, you are correct in assuming that the combination of mechanisms could enhance the positive neurobiological effects. This is assuming, however, that the cause of depression being treated with this type of drug is due to CRF hyperactivity. Bipolar depression and some types of unipolar depression seem to involve other factors much moreso than CRF and norepinephrine. The real implication of all of this is that CRF antagonists are an ideal choice of antidepressant for people with unipolar depression that involves CRF dysfunction. The CRF theory of unipolar depression seems to hold much more weight than theories involving serotonin or norepinephrine. Note that speaking of HPA axis dysfunction doesn't necessarily imply CRF dysregulation, so those who make their case for CRF- centered theories (Nemeroff seems to be the researcher most convinced) are providing a more specific argument.
As a side note, the subsensitivity of norepinephrine alpha-2 receptors in depression may be a result of CRF's stimulatory effects on norepinephrine release. In other words, persistent activity due to CRF at alpha-2 receptors could decrease their responsiveness to norepinephrine. The significance of this subsensitivity is more evident if you consider the fact that the activation of alpha-2 receptors has a generally inhibitory effect on the HPA axis (but not CRF). So the desensitization of alpha-2 receptors decreases the brain's ability to counteract some of the effects of stress. Cortisol seems to cause both the down- and up- regulation of alpha-2 receptors depending on how long levels remain abnormally high, which would probably explain why people with unipolar depression can exhibit either extreme.
Shawn
poster:Shawn. T.
thread:133959
URL: http://www.dr-bob.org/babble/20021230/msgs/134221.html