why are serotonin–norepinephrine reuptake inhibitors used for anxiety when norepinephrine causes anxiety?
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Like almost anything in the body: too much of a thing can be a problem just as too little of that same thing is also a problem. Also, when it comes to hormones and neurotransmitters, they often do more than one thing in the body and can either cause something or it’s opposite to occur. Norepinephrine is a stress modulator, among other things. Too much of it can cause feelings of anxiety in response to stress, but too little of it can cause lethargy, attention disorders, and anxiety as well. It also has an effect on emotions. SNRIs work by blocking the re-uptake of Serotonin and Norepinephrine. Re-uptake is absorption. Blocking re-uptake (absorption) leads to higher levels available for use by the body. The science behind SNRIs show that increasing levels of serotonin and norepinephrine can help alleviate symptoms of depression and anxiety.
Yes you are correct! Patients will often feel an increase in anxiety when they first start taking these meds. Your brain responds to this increase in anxiety by then turning off the receptors that are responsible for causing the anxiety in the first place.
https://www.anxiety.org/serotonin-norepinephrine-reuptake-inhibitor-snri
Outside of serotonin, since that is a bit more complicated, the norepinephrine aspect lies solely with the presynaptic a2 receptor. That is the key. Faulty signaling can lead to that receptor becoming desensitized, or downregulated. The extra NE helps make sure that receptor is saturated, begins to upregulate, and eventually return to normalcy. The presynaptic a2 receptor is the negative feedback loop mechanism of NE, so basically your entire fight or flight response. When NE hits it, it causes further NE release to be stopped, it basically ends the fight or flight response.
The activity of SNRI’s influence the ability of serotonin and norepinephrine, when acting as neurotransmitters in the nervous system, to deliver the neuroelectochemical signal across the synaptic cleft between neurons. They do not influence the activity of norepinephrine acting as a hormone in the body, where it is alternatively called adrenaline. Serotonin, norepinephrine, and dopamine are in family of neurotransmitters with a common parent molecule and all three are vital neurotransmitters in the areas of the brain responsible for emotional experience. Different qualities of emotional experience seem to relate to the functioning of the neuron clusters using those various neurotransmitters. Dopamine activity is associated with pleasure and joy, serotonin with serenity and wellbeing, and norepinephrine more subtly with the somatic qualities of emotion. The SSRI and SNRI medicines and the one DNRI medicine slow down how quickly neurons “clean” the synapse after neurotransmitters are released, as the next signal needs a clean synapse to work properly. Giving the neurotransmitters an extra moment to deliver their signal increases the chance that the signal is propagated from one neuron to the next across the synapse, which is the crux activity of the brain itself. Successful synaptic signaling influences the support cells in the brain to reinforce, or up-regulate, that activity and strengthen the neurons involved, allowing them to work more effectively. Depression and anxiety are due to pathologically under-active neurons, so medicines that promote or increase activity will stimulate growth and regeneration of those neurons given time. All three types of medicines can cause a side-effect of anxiety but most people can take them without that happening.
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There is a [fantastic](https://youtube.com/playlist?list=PL848F2368C90DDC3D) series of lectures by Robert Sapolski on YouTube. He doesn’t get into this specifically (I think it came out before SNRIs but I’m not sure.)
One point he makes is that the brain and neurotransmitters are fantastically complicated and we should be cautious with simplifications.
Seratonin is not the “happy” chemical. It’s a messenger involved in a wide variety of functions in a massively complicated system.
This isn’t a direct answer to your question, other than to challenge the basic premise of it. There’s a lot more under the hood.
Hopefully this comment is helpful perspective, even though I’m not able to answer the specifics.
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